WO2023039125A1 - Agonistes du récepteur de l'adénosine destinés à être utilisés dans le traitement du cancer - Google Patents

Agonistes du récepteur de l'adénosine destinés à être utilisés dans le traitement du cancer Download PDF

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WO2023039125A1
WO2023039125A1 PCT/US2022/042993 US2022042993W WO2023039125A1 WO 2023039125 A1 WO2023039125 A1 WO 2023039125A1 US 2022042993 W US2022042993 W US 2022042993W WO 2023039125 A1 WO2023039125 A1 WO 2023039125A1
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substituted
unsubstituted
alkyl
cancer
heterocycloalkyl
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PCT/US2022/042993
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Peidong Fan
Lina Yao
Robert Sikorski
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Teon Therapeutics, Inc.
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Publication of WO2023039125A1 publication Critical patent/WO2023039125A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TNBC triple-negative breast cancer
  • MSI/MMR DNA mismatch repair system
  • described herein is a method of treating hormone-resistant or hormone-sensitive cancer in a patient in need thereof.
  • the method comprises administering to the patient an A2B antagonist, wherein the A2B antagonist is not a dual antagonist of A2A.
  • the A2B antagonist is a selective antagonist.
  • described herein is a method for treating cancer in a patient in need thereof.
  • the method comprises administering to the patient an A 2B antagonist, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug of the A 2B antagonist, or a pharmaceutically acceptable salt or solvate thereof, and at least one antiandrogen, provided that when the A 2B antagonist is a compound of Formula (I): then the antiandrogen is not flutamide.
  • the cancer is selected from the group consisting of bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, rectal cancer, head and neck cancer, stomach cancer, cervical cancer, testicular cancer, urothelial cancer, sarcoma and skin cancer.
  • the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.
  • the cancer is a prostate cancer.
  • the hormone-resistant cancer is a sarcoma, carcinoma, or lymphoma.
  • the antiandrogen is selected from the group consisting of flutamide, hydroxyflutamide, bicalutamide, enzalutamide, nilutamide, apalutamide, darolutamide, seviteronel, zanoterone, proxalutamide, cimetidine, ketoconazole, and topilutamide.
  • the antiandrogen is selected from the group consisting of abiraterone, canrenone, chlormadinone, cyproterone, delmadinone, dienogest, drospirenone, medrogestone, megestrol, nomegestrol, osaterone, oxendolone, potassium canrenoate, and spironolactone.
  • the antiandrogen is selected from the group consisting of aminoglutethimide, ketoconazole, or abiraterone acetate, finasteride, and dutasteride.
  • the antiandrogen is selected from the group consisting of leuprorelin, goserelin, triptorelin, histrelin, degarelix, relugolix and cetrorelix. In some embodiments, the antiandrogen is enzalutamide, darolutamide, apalutamide, or abiraterone. In some embodiments, the antiandrogen is enzalutamide. [0010] In some embodiments, the A 2B antagonist is of Formula (i) above, or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • an effective amount of therapeutic agent in the monotherapy described herein, or effective amounts of each therapeutic agent in the combination therapies described herein is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal.
  • an effective amount of therapeutic agent in the monotherapy described herein, or effective amounts of each therapeutic agent in the combination therapies described herein is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal.
  • further embodiments comprising single administrations of effective amount of therapeutic agent, or effect amounts of each therapeutic agent, including further embodiments in which each therapeutic agent is administered once a day to the mammal or each therapeutic agent is administered to the mammal multiple times over the span of one day.
  • each therapeutic agent is administered on a continuous dosing schedule. In some embodiments, each therapeutic agent is administered on a continuous daily dosing schedule.
  • FIG.2 Illustrates the effects of Compound 1 in hormone-resistant human prostate PC-3 cancer cells, in comparison with other A2B adenosine receptor antagonists.
  • FIG.3 Illustrates the effects of the combination of Compound 1 and the androgen receptor antagonist enzalutamide in hormone-sensitive human prostate LNCaP cancer cells, in comparison with effect of enzalutamide alone.
  • FIG.4 Illustrates the effects of the combination of Compound 1 and the androgen receptor antagonist enzalutamide in hormone-resistant human prostate PC-3 cancer cells, in comparison with effect of enzalutamide alone.
  • a 2B adenosine receptor antagonists which is hereinafter interchangeably referred to as A 2B antagonists.
  • the compounds, compositions, formulations, and methods disclosed herein also relate to hormone deprivation agents (such as antiandrogens).
  • the compounds, compositions, formulations, and methods disclosed herein relate to the combination of the A 2B adenosine receptor antagonists and the hormone deprivation agents.
  • the compounds, compositions, and/or formulations disclosed herein can be used in a method of treating a condition in a subject (e.g. a patient) in need thereof.
  • the condition can be cardiovascular diseases, chronic and acute liver disease, lung disease, renal disease, diabetes, sickle cell disease, inflammatory bowel diseases, and/or obesity.
  • the condition can also be fibrosis, neurological disorders, and/or type I hypersensitivity disorders.
  • the condition can further be cancer at any development stages and with or without metastases.
  • 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-ethyl-1-propyl-1H-purine-2,6(3H,7H)-dione (Compound 1) is an A2B adenosine receptor antagonist, which is a xanthine unsubstituted at 7-position.
  • prodrugs of the A2B adenosine receptor antagonist can be developed to improve the formulation, pharmacokinetic profile, and/or bioavailability the A 2B adenosine receptor antagonist.
  • Compound 1 [0020]
  • prodrugs can be hydrolyzed by esterase (e.g., in gastrointestinal tract and/or in blood) and converted into Compound 1 in an aqueous solution.
  • acid labile prodrugs can be converted into Compound 1 in an acidic environment (e.g., in the stomach).
  • prodrugs which are stable in the acidic environment and/or stable against hydrolysis by esterase, may not be a good prodrug candidate for Compound 1.
  • the amount “about 10” includes amounts from 9 to 11, including the reference numbers of 9, 10, and 11.
  • the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • hormone-sensitive refers to a disease (e.g. a cancer or tumor) that is responsive to hormone therapy, such as hormone-deprivation therapy. This term includes castration-sensitive (or “non- castrate”) diseases.
  • hormone-resistant refers to a disease (e.g.
  • a cancer or tumor that progresses in an environment of collateral androgen depletion where androgen levels are ablated beyond castrate levels.
  • the term for example in the context of prostate cancers, includes patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens.
  • selective refers to the preference of a ligand (e.g. a drug molecule) to bind to a first substrate (e.g. a receptor) to form a complex over a second substrate (e.g. another receptor).
  • selectivity or “selectivity coefficient” is used to quantify the preference and is defined as the ratio of the equilibrium constant of the binding reaction between the ligand with the first substrate and the equilibrium constant of the binding reaction between the ligand with the second substrate.
  • selectivity is greater than a threshold value
  • the ligand may be referred to as a selective ligand to the first substrate.
  • the threshold value is determined based on specific applications.
  • prodrug refers to any compound that becomes an active form of a drug (e.g., Compound I) when administered to a subject, e.g., upon metabolic processing of the prodrug.
  • Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug.
  • the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • the design of a prodrug increases the effective water solubility.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of Compound 1 described herein include, but are not limited to, compounds where the nitrogen atom is incorporated into an alkyl carbamate, (acyloxy)alkyl carbamate, acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, N- acyloxyalkoxycarbonyl, N-acyloxyalkyl. dihydropyridinepyridinium salt system (redox systems), (phosphoryloxy)methyl carbamate, (acyloxy)alkyl carbamate, and the like.
  • prodrugs of Compound 1 are formed by N-acyloxyalkylation, N- hydroxyalkylation, N-(phosphoryloxy)alkylation, N-acyloxyalkylation, N-hydroxyalkylation , N- (phosphoryloxy)alkylation, N-acylation (amides and carbamates), N-(oxodioxolenyl)methylation, and the like.
  • pharmaceutically acceptable component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation and/or amelioration of the signs, symptoms, or causes of a disease, slowing of disease progression, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective amount” in any individual case is optionally determined using techniques such as a dose escalation study.
  • treating encompasses administration of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and/or (iii) prophylactic treatment for preventing the onset of additional symptoms of the disease, such as cancer.
  • subject or “patient” refers to a mammal that has been or will be the object of treatment, observation or experiment.
  • mammal is intended to have its standard meaning, and encompasses for example humans, dogs, cats, sheep, and cows. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the mammal is a human.
  • derivative can be used interchangeably with the term “analog.”
  • Compound 1 can be a derivative or analog if 1, 2, 3, 4, or 5 atoms of compound 1 is replaced by another atom or a functional group (e.g., amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl) to form the compounds of the disclosure.
  • solvate can include, but is not limited to, a solvate that retains one or more of the activities and/or properties of the compound and that is not undesirable.
  • solvates include, but are not limited to, a compound in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J.
  • salt can include, but are not limited to, salts that retain one or more of the activities and properties of the free acids and bases and that are not undesirable.
  • Illustrative examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenz
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. [0046] Unless otherwise indicated, whenever there is a stereocenter in a structure disclosed or illustrated herein, the stereocenter can be R or S in each case.
  • stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • stereoisomers are obtained by stereoselective synthesis.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • amino refers to functional groups that contain a basic nitrogen atom with a lone pair.
  • amino can include the radical NH2 , H , or R' , wherein each R’ is independently H, halo, alkyl, aryl, arylalkyl, cycloalkyl, or acyl.
  • C1-Cx includes C1-C2, C1-C3... C1-Cx.
  • a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms,6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, or t-butyl.
  • an alkyl includes, but is not limited to, methyl, ethyl, propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, and the like.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • the term “lower alkyl” can refer to a monoradical branched or unbranched saturated hydrocarbon chains having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
  • alkyl when an alkyl is unsaturated, then the alkyl is an alkenyl or alkynyl.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • an alkenyl includes, but is not limited to, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH3 -C ⁇ CCH 2 CH3, -CH 2 C ⁇ CH.
  • an alkynyl includes, but is not limited to, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • the term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • An “fluoroalkoxy” group refers to a (fluoroalkyl)O- group, where fluoroalkyl is as defined herein.
  • the term “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, -N(alkyl)-), sulfur (-S-, - S(O)-, -S(O) 2 -), phosphorus (-PH-, -P(O) 2 -), or combinations thereof (e.g. -O-P(O) 2 -).
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 - C 6 heteroalkyl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Typical aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, indanyl, indenyl, and the like.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C6-C10 aryl.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C 1 -C 9 heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • arylalkyl refers to an alkyl that is substituted with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, and the like.
  • heteroarylalkyl refers to an alkyl that is substituted with a heteroaryl group.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are monocyclic, bicyclic (spirocyclic, fused or bridged), or polycyclic.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3 –C 10 ) cycloalkyl).
  • a cycloalkyl is a ( C 3 -C 6 ) cycloalkyl.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • a cycloalkyl is partially unsaturated (“cycloalkenyl”, including but not limited to, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like).
  • a “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 -C 10 heterocycloalkyl.
  • a heterocycloalkyl is a C4-C10 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • acyl can refer to -C(O)R′, in which R′ is hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.
  • substituted can refer to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • optional substituents are independently selected from halo, alkyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or acyl.
  • optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3) 2 , -CH3, -CH 2 CH3, -CF3, - OCH3, and -OCF3.
  • substituted groups are substituted with one or two of the preceding groups.
  • R 1 and R 2 are each independently selected from hydrogen, and substituted or unsubstituted alkyl; R 3 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl, wherein if R 3 is substituted then R 3 is substituted with one or more groups selected from halogen, -CN, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and substituted or unsubstituted C1-C4 heteroalkyl; R 4 is substituted or unsubstituted alkyl; R 6 is hydrogen or substituted or unsubstituted alkyl; or R
  • m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, 5, or 6. [0074] In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 3. In some embodiments, n is 2, 3, 4, 5, or 6. [0075] In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6. [0076] In some embodiments, R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 1 and R 2 are each independently selected from unsubstituted C1-C3 alkyl.
  • R 1 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 1 is ethyl and R 2 is n-propyl.
  • R 3 is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 is substituted phenyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from halogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from C 1 -C 4 fluoroalkyl.
  • R 3 is selected from phenyl substituted with one, two, or three -CF 3 substituents. In some embodiments, R 3 is selected from phenyl substituted with one -CF 3 substituent. In some embodiments, R 3 . [0078] In some embodiments, R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n- hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl; R 2 is n-propyl; and R 3 is 3-(trifluoromethyl) p henyl.
  • R 4 is methyl, ethyl, or n-propyl and R 6 is selected from hydrogen, methyl, ethyl, and n-propyl. In some embodiments, R 4 is methyl or ethyl.
  • R 5 is R 7 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH 2 -(substituted or unsubstituted phenyl), -CH 2 -(substituted or unsubstituted heteroaryl), -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloal
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, -CH 2 - (substituted or unsubstituted phenyl), -CH 2 -(substituted or unsubstituted heteroaryl), -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), -CH(R 10 )O-R 11 , or -(CH 2 CH 2 O)n-R 11 ;
  • R 10 is hydrogen and methyl;
  • R 12 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 9 is hydrogen.
  • R 7 is -(CH 2 CH 2 O) n -R 11 , wherein R 11 is unsubstituted alkyl.
  • R 11 is methyl, ethyl, n-propyl, n-butyl, or n-pentyl.
  • R 7 is -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl). In some embodiments, R 7 is -CH 2 -(substituted C 5 -C 6 heterocycloalkyl). In some embodiments, . [0091] In some embodiments, R 7 is substituted or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is monocyclic C 3 -C 10 cycloalkyl.
  • R 7 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 7 is cyclohexyl. In some embodiments, R 7 is spirocyclic C 3 -C 10 cycloalkyl. In some embodiments, R 7 is adamantyl.
  • R 4 is methyl or ethyl
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]oct
  • R 7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, s bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.
  • R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl. In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.
  • the compound has the following structure of Formula (III): Formula (III) or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n- hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl) p henyl.
  • the compound has the following structure of Formula (IIIa): Formula (IIIa): or a pharmaceutically acceptable salt or solvate thereof.
  • R 5 is R 7 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH 2 -(substituted or unsubstituted phenyl), -CH 2 -(substituted or unsubstituted heteroaryl), -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloal
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, -CH 2 - (substituted or unsubstituted phenyl), -CH 2 -(substituted or unsubstituted heteroaryl), -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), -CH(R 10 )O-R 11 , or -(CH 2 CH 2 O)n-R 11 ;
  • R 10 is hydrogen and methyl;
  • R 5 is ethyl, and the compound is referred to as Compound 2.
  • Compound 2 Compound 2
  • the compound has one of the following structures Formulae (IIIb) and (IIIc):: Formula (IIIb) Formula (IIIc) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has one of the following structures: or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has the following structure of Formula (I): Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl; R 2 is n-propyl; and R 3 is 3-(trifluoromethyl) p henyl.
  • the compound has the following structure of Formula (Ia): Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof.
  • R 4 is methyl or ethyl
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]oct
  • the compound has the following structure of Formula (II): wherein: Y is selected from -CH 2 -, O, S, -NR 15 -, and -S(O) 2 -; Z is O or S; or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl; R 2 is n-propyl; and R 3 is 3-(trifluoromethyl) p henyl.
  • the compound has the following structure of Formula (IIa): Formula (IIa) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has the following structure: or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has the following structure of Formula (IIb): Formula (IIb) wherein: Y is selected from -CH 2 -, O, S, -NR 15 -, and -S(O) 2 -; or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl) p henyl.
  • the compound has the following structure: or a pharmaceutically acceptable salt or solvate thereof.
  • compounds of Formula (A) include those described in Table 1. TABLE 1
  • R 1 and R 2 are each independently selected from hydrogen, and substituted or unsubstituted alkyl;
  • R 3 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl, wherein if R 3 is substituted then R 3 is substituted with one or more groups selected from halogen, -CN, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, and substituted or unsubstituted C 1 -C 4 heteroalkyl;
  • R 4 is hydrogen or substituted or unsubstituted alkyl;
  • R 6 is hydrogen or substituted or unsubstituted
  • m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, 5, or 6. [00127] In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 3. In some embodiments, n is 2, 3, 4, 5, or 6. [00128] In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6.
  • R 4 is hydrogen;
  • R 6 is hydrogen;
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 1 and R 2 are each independently selected from unsubstituted C1-C3 alkyl. In some embodiments, R 1 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 1 is ethyl and R 2 is n-propyl. [00131] In some embodiments, R 3 is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 is substituted phenyl.
  • R 3 is phenyl substituted by one or more groups independently selected from halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from C1-C4 fluoroalkyl. In some embodiments, R 3 is selected from phenyl substituted with one, two, or three -CF3 substituents. In some embodiments, R 3 is selected from phenyl substituted with one -CF 3 substituent. In some embodiments, R 3 .
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n- hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl; R 2 is n-propyl; and R 3 is 3-(trifluoromethyl) p henyl.
  • the compound has the following structure of Formula (IV): Formula (IV) or a pharmaceutically acceptable salt or solvate thereof.
  • R 12 is substituted or unsubstituted alkyl or substituted or unsubstituted C 3 - C10 cycloalkyl. In some embodiments, R 12 is unsubstituted C 1 -C 6 alkyl or unsubstituted C3-C10 cycloalkyl. In some embodiments, R 12 is unsubstituted C1-C3 alkyl. In some embodiments, R 12 is unsubstituted C3-C6 cycloalkyl. [00139] In some embodiments, the compound has one of the following structures: or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has the following structure of Formula (V): or a pharmaceutically acceptable salt or solvate thereof.
  • R a is substituted or unsubstituted bicyclic cycloalkyl that is a fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro bicyclic cycloalkyl; or R a is substituted or unsubstituted bicyclic heterocycloalkyl that is a fused bicyclic heterocycloalkyl, bridged bicyclic heterocycloalkyl, or spiro bicyclic heterocycloalkyl; or R a is substituted or unsubstituted bicyclic heteroaryl.
  • R a is substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted decalinyl.
  • the compound has one of the following structures of Formulae (Va) and (Vb): or a pharmaceutically acceptable salt or solvate thereof.
  • R a is substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl.
  • R a is substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrodioxanyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl
  • R a is substituted or unsubstituted tetrahydrodioxanyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, or substituted or unsubstituted pyrimidinyl.
  • R a is a substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring that is substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted oxepanyl, substituted or unsubstituted oxazepinyl, or substituted or unsubstituted dioxanyl.
  • R a is a substituted or unsubstituted 5-membered heteroaryl that is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl.
  • the compound has one of the following structures: , or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 is ethyl;
  • R 2 is n-propyl;
  • R 3 is 3-(trifluoromethyl) p henyl;
  • the compound has one of the following structures: , or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 is ethyl;
  • R 2 is n-propyl;
  • R 3 is 3-(trifluoromethyl) p henyl;
  • R 5 is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), - alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl),-alkyl- (substituted or unsubstituted heterocycloalkyl).
  • R 5 is -CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl). In some embodiments, R 5 is -CH 2 -(substituted C5-C6 heterocycloalkyl). In some embodiments, .
  • the compound has the following structure: or a pharmaceutically acceptable salt or solvate thereof.
  • compounds of Formula (B) include those presented in Table 2. TABLE 2 [00155]
  • the prodrug of Compound 1 has any one of the following structures: ,
  • Prodrugs of these A2B adenosine receptor antagonists can be designed and synthesized in a similar way to the prodrugs of the Compound 1 by substituting the xanthine at 7-position.
  • Additional compounds for use in the combination therapies described herein include any one of the compounds described in WO 2019/135259.
  • Such compounds include: 5-propyl-2-[1-[[3- (trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-3H-imidazo[2,1-b]purin-4-one (Al), 2-(l-benzylpyrazol-4-yl)- 5-propyl-3H-imidazo[2,l-b]purin-4-one (A2), 5-methyl-2-[1-[[3-(trifluoromethyl) p henyl]methyl]pyrazol-4- yl]-3H-imidazo[2,1-b]purin-4-one (A3), 5-propyl-2-[1-[2-[3-(trifluoromethyl) p henyl]ethyl]pyrazol-4-yl]- 3H-imidazo[2,1-b]purin-4-one (A4), 2-[1-[2-(3-fluorophenyl)ethyl]pyrazol-4-yl]-5-propyl
  • the A2B adenosine receptor antagonist e.g. the Compound 1
  • a pharmaceutically acceptable salt or solvate thereof a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a hormone deprivation agent is administered to the subject in need thereof along with a hormone deprivation agent.
  • the hormone deprivation agent is an antiandrogen.
  • the hormone deprivation agent is a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • the hormone deprivation agent is an antiandrogen.
  • the antiandrogen may be an androgen receptor antagonist, an androgen synthesis inhibitor, or an antigonadotropin.
  • the hormone deprivation agent is an androgen receptor antagonist.
  • the androgen receptor antagonists include steroidal antagonists and nonsteroidal antagonists.
  • the androgen receptor antagonist is a steroidal antagonist.
  • the androgen receptor antagonist may be 7 ⁇ -thioprogesterone, 7 ⁇ -thiospironolactone, 7 ⁇ - thiomethylspironolactone, 11 ⁇ -hydroxyprogesterone, 15 ⁇ -hydroxycyproterone acetate, abiraterone, abiraterone acetate, allyltestosterone, benorterone, BOMT, canrenoic acid, canrenone, chlormadinone acetate, clascoterone, clometerone, cyproheptadine, cyproterone, cyproterone acetate, delanterone, delmadinone acetate, dicirenone, dienogest, drospirenone, DU-41165 (6-fluoro-16-methylene-17 ⁇ -acetoxy- ⁇ 6-retroprogesterone), edogestrone, EM-4350 (from Endoceutics), EM-5854 (4-Fluoro-17
  • the androgen receptor antagonist is a nonsteroidal antagonist.
  • the androgen receptor antagonist may be 5N-bicalutamide, AA560 (N-2-chloromethyl-2-hydroxypropionyl)- 3, 4, 5-trichloroaniline), antarlides, arabilin, apalutamide, atraric acid, AZD-3514 (CAS No.: 1240299-33-5), bakuchiol, BAY-1024767 (1273068-71-5), bicalutamide, bisphenols (e.g., BADGE (5,5-dimethyl-3,7-dioxa- 1,9(2)-bis(oxirana)-4,6(2,4)-dibenzenanonaphane), BFDGE (bis[4-(glycidyloxy)phenyl]methane), bisphenol A (4,4′-(propane-2,2-diyl)diphenol), bisphenol F (4,4′-methylenedi
  • BADGE bisphenols
  • RU-57073 (4-[3-(2-hydroxyethyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile), RU-58642 (CAS No.143782-63-2), RU-58841 (4-[3-(4-hydroxybutyl)-4,4- dimethyl-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)benzonitrile), seviteronel, thalidomide, topilutamide (fluridil), valproic acid, vinclozolin, YM-580 ((+)-(2R,5S)-4-[4-cyano-3- (trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide), YM- 92088
  • the androgen receptor antagonist is one of enzalutamide, darolutamide, apalutamide, and abiraterone. In an exemplary embodiment, the androgen receptor antagonist is enzalutamide.
  • hormone deprivation agent is an androgen synthesis inhibitor.
  • the hormone deprivation agent may be aminoglutethimide, ketoconazole, or abiraterone acetate, alone or in combination with a glucocorticoid like prednisone.
  • the hormone deprivation agent is a 5 ⁇ -Reductase inhibitor, such as finasteride and dutasteride.
  • hormone deprivation agent is an antigonadotropin.
  • the hormone deprivation agent may be LHRH modulators.
  • the LHRH modulator may be an LHRH agonist, such as leuprorelin (leuprolide), triptorelin, histrelin, and goserelin.
  • the LHRH modulator may be an LHRH antagonist, such as degarelix, relugolix, and cetrorelix.
  • the hormone deprivation agent may be estrogens, such as estradiol, estradiol esters like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol, and bifluranol.
  • the hormone deprivation agent may be progestogen, such as chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.
  • the hormone-deprivation agent is administered to a cancer patient in need thereof as part of a hormone therapy.
  • a pharmaceutically acceptable salt or solvate of the hormone-deprivation agent is administered in place of the hormone-deprivation agent.
  • a prodrug of the hormone-deprivation agent or a pharmaceutically acceptable salt or solvate thereof is administered in place of the hormone-deprivation agent.
  • the term “cancer” as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • the cancer is a solid tumor.
  • the cancer is bladder cancer, bowel cancer, colon cancer, brain cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, thyroid cancer, gastric cancer, rectal cancer, urothelial cancer, testicular cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck cancer, urothelial cancer, sarcoma and skin cancer.
  • the cancer may be at any stage of the disease with or without metastases.
  • a mammal treated with an A 2B antagonist compound described herein, or with a combination of the A 2B antagonist compound and the hormone deprivation compound described herein has a disease or disorder that is or is associated with a cancer or tumor.
  • the mammal is a human that is an oncology patient.
  • diseases and disorders and cancers include carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, blood tumors, leukemias and lymphomas, and primary and metastatic tumors.
  • the A2B antagonist compounds described herein, or the combination of the A2B antagonist compound and the hormone deprivation compounds described herein are used in the treatment of solid tumors.
  • a solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.
  • Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.
  • Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.
  • Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts).
  • Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like.
  • Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
  • hemangiomas e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,
  • Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs.
  • lung cancer e.g., breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain;
  • the A 2B antagonist compound described herein, or a combination of the A 2B antagonist compound and the hormone deprivation compound described herein reduces, ameliorates or inhibits immunosuppression and cell proliferation associated with cancers.
  • the cancer being treated with the compositions and methods described herein may be a hormone-sensitive cancer.
  • the hormone-sensitive cancer is dependent upon a hormone for its growth or survival.
  • cancer cells of a hormone-sensitive cancer include hormone receptors on the cell surfaces. When hormone binds to the hormone receptors on the surfaces, the cancer cells grow and proliferate, resulting in the spread of cancer cells.
  • the hormone-sensitive cancer may a prostate cancer.
  • the hormone-sensitive cancer may be a castrate-sensitive prostate cancer (CSPC).
  • CSPC castrate-sensitive prostate cancer
  • Hormone-sensitive cancers are generally receptive or responsive to hormone therapy. Hormone therapy blocks the synthesis or action of the hormone, or removes the organs producing the hormone altogether.
  • androgen deprivation therapy may be used to treat hormone-sensitive prostate cancer (such as CSPC), and estrogen deprivation therapy may be used to treat hormone-sensitive breast cancer.
  • the cancer being treated with the compositions and methods described herein may be hormone-resistant cancer.
  • Hormone-resistant cancers are often developed following persistent treatment with hormone therapy.
  • persistent treatment of CSPC with androgen receptor antagonists may lead to progression into so-called castrate-resistant prostate cancers (CRPC), where cancer cells progress in an environment of collateral hormone depletion (e.g. when testosterone levels are ablated beyond the castrate level).
  • CRPC castrate-resistant prostate cancers
  • HRPC hormone-refractory prostate cancer
  • Patients with hormone-resistant cancer generally have low survival rates.
  • A2B antagonist compounds and combinations of an A2B antagonist compound and a hormone deprivation compound that are useful for treating one or more diseases or disorders associated with or would benefit from modulation of A2B adenosine receptor activity and/or from modulation of hormone receptor activity.
  • described herein are methods for treating a disease or disorder, wherein the disease or disorder is cancer, or a hyperproliferative disorder.
  • the A 2B antagonist compound described herein, or a combination of the A 2B antagonist compound and the hormone deprivation compound described herein are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of A 2B adenosine receptor activity and/or inhibition or reduction of hormone levels.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one A 2B antagonist compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • the cancer being treated with the methods described herein is either a hormone-sensitive cancer or a hormone-resistant cancer.
  • the treatment includes administering to the subject in need thereof a combination of the A2B antagonist compound and the hormone deprivation compound described herein.
  • the A2B antagonist compound selected for the treatment is one of the A2B antagonist compound described above but not Compound 1 or a pharmaceutically acceptable salt or solvate thereof, and not a prodrug of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.
  • the hormone deprivation compound may be any suitable hormone deprivation compounds described herein.
  • the A2B antagonist compound selected for the treatment is Compound 1, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof.
  • the hormone deprivation compound may be any suitable hormone deprivation compound described herein other than flutamide.
  • the cancer is a prostate cancer, either hormone-sensitive or hormone- resistant.
  • a combination of the A 2B antagonist compound and an androgen receptor antagonist is selected for the treatment.
  • the A2B antagonist compound selected for the treatment is Compound 1, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and the androgen receptor antagonist selected for the treatment is one of enzalutamide, darolutamide, apalutamide, and abiraterone.
  • the A2B antagonist compound may be Compound 1, and the androgen receptor antagonist may be enzalutamide.
  • the A2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be enzalutamide.
  • the A2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be apalutamide.
  • the A2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be darolutamide.
  • Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 1, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and an androgen receptor antagonist selected from enzalutamide, darolutamide, apalutamide, and abiraterone; and wherein the prostate cancer is hormone-sensitive or hormone-resistant.
  • Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof; and an androgen receptor antagonist selected from enzalutamide, darolutamide, apalutamide, and abiraterone; and wherein the prostate cancer is hormone-sensitive or hormone-resistant.
  • Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof; and enzalutamide; and wherein the prostate cancer is hormone-sensitive or hormone-resistant.
  • Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof; and darolutamide; and wherein the prostate cancer is hormone-sensitive or hormone-resistant. Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof; and apalutamide; and wherein the prostate cancer is hormone-sensitive or hormone-resistant. Some embodiments provide for a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof; and abiraterone; and wherein the prostate cancer is hormone-sensitive or hormone-resistant.
  • the cancer is treated with an A2B receptor antagonist other than the A2B antagonist described above, along with an hormone deprivation compound (such as an androgen receptor antagonist) described herein.
  • the androgen receptor antagonist described herein is combined with an A 2B receptor antagonists of one of TT-3 (Tarus Therapeutics), TT-4 (Tarus Therapeutics), ISAM 140 (CAS No.: 932191-62-3), MRS 1706 (CAS No.: 693288-97-0), MRS 1754 (CAS No.: 264622-58-4), PSB 0788 (CAS No.: 1027513-54-7), PSB 603 (CAS No.: 1092351-10-4), PSB 1115 (CAS No.: 409344-71-4), PSB 1901 (CAS No.: 1092351-10-4), PBF-1129 (Palobiofarma S.L), CVT- 6694 (from CV Therapeutics), CVT-7124 (from CV Therapeutics), ATL-852,
  • the androgen receptor antagonist described herein is combined with allosteric modulators of the A2B receptor, such as 1-benzyl-3-ketoindole derivatives, benzofurane derivatives (e.g. N-(4-chlorobenzyl)-2-(benzofuran-2-yl)glyoxylamide).
  • allosteric modulators of the A2B receptor such as 1-benzyl-3-ketoindole derivatives, benzofurane derivatives (e.g. N-(4-chlorobenzyl)-2-(benzofuran-2-yl)glyoxylamide).
  • the androgen receptor antagonist described herein is combined with an inverse A2B receptor agonist, such as ZM241385 (4- ⁇ 2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl ⁇ phenol) and DPCPX (8-cyclopentyl-1,3-dipropylxanthine).
  • an inverse A2B receptor agonist such as ZM241385 (4- ⁇ 2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl ⁇ phenol) and DPCPX (8-cyclopentyl-1,3-dipropylxanthine).
  • the androgen receptor antagonist described herein is combined with an anti-A2B antibody, such as ab222901 (available from Abcam), STJ70777 (available from St John’s Lab), AAR-003, AB1589P (available from Sigma Aldrich), ADORA2b (available from Invitrogen), in combination with the androgen receptor antagonist described herein.
  • an anti-A2B antibody such as ab222901 (available from Abcam), STJ70777 (available from St John’s Lab), AAR-003, AB1589P (available from Sigma Aldrich), ADORA2b (available from Invitrogen), in combination with the androgen receptor antagonist described herein.
  • the adenosine receptor antagonist is not a dual antagonist for A 2A receptor.
  • the adenosine receptor antagonist is not AB928 or theophylline.
  • the adenosine receptor antagonist may be a selective A 2B antagonist, such as the Compound 1, TT-3, TT-4, MRS 1706, MRS 1754, ISAM-140, BAY-545, CVT-6694, CVT-7124, LAS101057, PSB-12105, PSB 1115, PSB 0788, PSB 1901, or PSB 603.
  • the A 2B antagonist has a selectivity towards the A 2B adenosine receptor subtype over other subtypes that is greater than about 10. In some embodiments, this selectivity is greater than about 20. In some embodiments, this selectivity is greater than about 50. In some embodiments, this selectivity is greater than about 100.
  • the androgen receptor antagonist used in the combination is one of enzalutamide, darolutamide, apalutamide, and abiraterone. In an embodiment, the androgen receptor antagonist used in the combination is enzalutamide.
  • the cancer being treated is a hormone-resistant cancer.
  • the cancer may be prostate cancer and not responsive towards hormone therapy (such as not responsive to the administration of androgen receptor antagonists).
  • the hormone-resistant cancer is treated with a combination of the A2B antagonist compound and the hormone deprivation compound described herein.
  • the combination may include any suitable A2B antagonist compound and any suitable hormone deprivation compounds described herein.
  • the cancer is a hormone resistant prostate cancer (such as CRPC or HRPC), and a combination of the A2B antagonist compound and an androgen receptor antagonist is selected for the treatment.
  • the A2B antagonist compound selected for the treatment is Compound 1, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and the androgen receptor antagonist selected for the treatment is one of enzalutamide, darolutamide, apalutamide, and abiraterone.
  • the A 2B antagonist compound may be Compound 1, and the androgen receptor antagonist may be enzalutamide.
  • the A 2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be enzalutamide.
  • the A2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be apalutamide.
  • the A2B antagonist compound may be prodrug Compound 2, and the androgen receptor antagonist may be flutamide.
  • the cancer being treated is a triple-negative breast cancer (TNBC).
  • the cancer being treated is a microsatellite instability/mismatch repair (MSI/MMR) defective tumor.
  • a method for treating CRPC, TNBC or MSI/MMR defective tumor in a patient in need thereof comprising administering to said patient an effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof and enzalutamide.
  • a method for treating CRPC, TNBC or MSI/MMR defective tumor in a patient in need thereof comprising administering to said patient an effective amount of Compound 2 or a pharmaceutically acceptable salt or solvate thereof and enzalutamide.
  • Some embodiments provide for a method of treating a hormone-resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 1, a pharmaceutically acceptable salt or solvate thereof, or a prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and an androgen receptor antagonist selected from enzalutamide, darolutamide, apalutamide, and abiraterone.
  • Some embodiments provide for a method of treating a hormone-resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 1, a pharmaceutically acceptable salt or solvate thereof, and enzalutamide.
  • Some embodiments provide for a method of treating a hormone- resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof, and enzalutamide. Some embodiments provide for a method of treating a hormone-resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof, and apalutamide. Some embodiments provide for a method of treating a hormone-resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof, and darolutamide.
  • Some embodiments provide for a method of treating a hormone-resistant prostate cancer in a patient in need thereof, comprising administering to the patient Compound 2, a pharmaceutically acceptable salt or solvate thereof, and abiraterone.
  • the cancer is treated with an A2B receptor antagonist other than the A2B antagonist described above, and along with an hormone deprivation compound (such as an androgen receptor antagonist).
  • the cancer is treated with A2B receptor antagonists of one of ISAM 140, MRS 1706, MRS 1754, PSB 0788, PSB 603, PSB 1115, PSB 1901, CVT-6694, CVT-7124, CVT-6883, ATL-852, ATL-801, QAF805, LAS101057, BAY-545, theophylline, caffeine, other suitable A 2B receptor antagonists, in combination with the androgen receptor antagonist described herein.
  • the treatment with the combination of the A 2B antagonist compound and the hormone deprivation compound results in a synergistic effect.
  • the hormone-resistant cancer is treated with an A2B antagonist compound described herein alone, e.g. in absence of other therapeutically active agents.
  • the A2B antagonist compound is not a dual antagonist for the A2A receptor.
  • the A2B antagonist compound is not AB928.
  • the hormone-resistant cancer is treated with the Compound 1 alone in absence of any hormone-deprivation agent.
  • the hormone-resistant cancer is treated with the Compound 2 alone in absence of any hormone-deprivation agent.
  • compositions described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a mammal already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions described herein are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
  • a mammal susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose.”
  • the precise amounts also depend on the mammal’s state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition in order to prevent a return of the symptoms of the disease or condition.
  • a pharmaceutical composition in order to prevent a return of the symptoms of the disease or condition.
  • the dose of drug(s) being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the A 2B antagonist compound described herein are from about 0.01 to about 50 mg/kg per body weight.
  • the daily dosages appropriate for the hormone-deprivation compound described herein are from about 0.01 to about 50 mg/kg per body weight.
  • the daily dosage or the amount of active agent in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage amount of the hormone-deprivation compound described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • composition including the effective amount of the A2B antagonist compound described herein, alone or in combination with the hormone-deprivation compound, or a pharmaceutically acceptable salt of each thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the A2B antagonist compound alone or in combination with the effective amount of the hormone-deprivation compound, including further embodiments in which (i) the composition is administered once a day; or (ii) the composition is administered to the mammal multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the A2B antagonist compound alone or in combination with the effective amount of the hormone deprivation compound, including further embodiments in which (i) the composition is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the composition is administered to the mammal every 8 hours; (iv) the composition is administered to the mammal every 12 hours; (v) the composition is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the composition is temporarily suspended or the dose of the composition being administered is temporarily reduced; at the end of the drug holiday, dosing of the composition is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the composition administered is appropriate to further comprise one or more other therapeutic agents.
  • the pharmaceutical composition further comprises one or more anti-cancer agents.
  • the pharmaceutical composition may further comprise an immune checkpoint inhibitor targeting the PD-1 checkpoint.
  • the therapeutic effectiveness of one of the A2B antagonist compounds described herein, or the combination with the hormone-deprivation compound described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the A2B antagonist compounds described herein, or the hormone-deprivation compound described here, with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • an A 2B antagonist compound described herein, or the combination with the hormone-deprivation compound described herein is co-administered with another therapeutic agent, wherein the A 2B antagonist compound described herein, the hormone-deprivation compound described herein (if present), and the another therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.
  • different therapeutically-effective dosages of the A2B antagonist compounds alone or in combination with the hormone deprivation compound disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • additional agent such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of an A 2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which an A 2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the A2B antagonist compound described herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents one of which is one of the A 2B antagonist compounds described herein, alone or in combination with a hormone deprivation compound described herein
  • the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the A2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the A2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • an A2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • an A2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein is administered after the onset of the disease or condition, and subsequent to progression of the disease or condition to a substantially different stage.
  • the A 2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein is administered after the hormone-sensitive cancer progresses to a stage no longer responsive to hormone therapy (e.g.
  • an A 2B antagonist compound described herein, alone or in combination with a hormone deprivation compound described herein, or a formulation containing such is administered for at least 2 weeks, about 1 month to about 5 years.
  • an A 2B antagonist compound described herein, alone or in combination with a hormone deprivation compound is administered in combination with chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Chemotherapy includes the use of anti-cancer agents.
  • the A2B adenosine receptor antagonist e.g. Compound 1
  • A2B antagonist compound(s) is formulated into pharmaceutical compositions.
  • the A2B antagonist compound is formulated into pharmaceutical compositions alone and in absence of other therapeutically active reagents.
  • the A 2B antagonist compound is formulated into pharmaceutical compositions along with a hormone deprivation agent (e.g.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the A2B antagonist compound described herein, or the combination of the A2B antagonist compound and the hormone deprivation compound described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • compositions incorporating the A 2B antagonist compound or the combination of the A 2B antagonist compound and the hormone deprivation compound described herein may take any physical form that is pharmaceutically acceptable.
  • Pharmaceutical compositions for oral administration are particularly preferred.
  • such pharmaceutical compositions include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Known methods of formulating used in pharmaceutical science may be followed to prepare pharmaceutical compositions. All of the usual types of compositions are contemplated, including, but not limited to, tablets, chewable tablets, capsules, and solutions.
  • Capsules may be prepared by mixing the A 2B antagonist compound described herein, or the combination of the A 2B antagonist compound and the hormone deprivation compound described herein, with a suitable diluent and filling the proper amount of the mixture in capsules.
  • Tablets may be prepared by direct compression, by wet granulation, or by dry granulation.
  • Their formulations usually incorporate diluents, binders, lubricants, and disintegrators, as well as the A2B antagonist compound described herein, or the combination of the A2B antagonist compound and the hormone deprivation compound described herein, as an active therapeutic agent or active therapeutic agents.
  • a lubricant in a tablet formulation may help prevent the tablet and punches from sticking in the die.
  • Tablet disintegrators are substances that swell when wetted to break up the tablet and release the active therapeutic agent(s).
  • Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach and to delay disintegration and absorption in the gastrointestinal tract.
  • Such formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in acid environments, and soluble in basic environments. Tablets are often coated with sugar as a flavor and sealant. Examples [00225] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
  • Example 1 Inhibiting effect of Compound 1 to the proliferation of hormone-sensitive human prostate cancer cells LNCaP
  • Hormone-sensitive human prostate cancer cells LNCaP purchased from American Type Culture Collection (ATCC) were seeded at 5,000 cells per well of 96-well plate in RPMI-1640 medium supplemented with 10 % FBS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and were cultured for 24 hours. Cells were then treated with Compound 1, AB928 (etrumadenant) or AZD4635 (imaradenant), each at varying concentrations, in the absence of exogenous adenosine for 3 days.
  • Compound 1 purchased from American Type Culture Collection (ATCC)
  • ATCC American Type Culture Collection
  • Example 2 Inhibiting effect of Compound 1 to the proliferation of hormone-resistant human prostate cancer cells PC-3
  • Hormone-resistant human prostate cancer cells PC-3 purchased from American Type Culture Collection (ATCC) were seeded at 5,000 cells per well of 96-well plate in RPMI-1640 medium supplemented with 10 % FBS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and were cultured for 24 hours.
  • Example 3 Inhibiting effect of the combination of Compound 1 and androgen receptor antagonist enzalutamide to the proliferation of hormone-sensitive human prostate cancer cells LNCaP
  • Hormone-sensitive human prostate cancer cells LNCaP purchased from American Type Culture Collection (ATCC) were seeded at 5,000 cells per well of 96-well plate in RPMI-1640 medium supplemented with 10 % FBS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and cultured for 24 hours.
  • Example 4 Inhibiting effect of the combination of Compound 1 and an androgen receptor antagonist to the proliferation of hormone-resistant human prostate cancer cells PC-3
  • Hormone-resistant human prostate cancer cells PC-3 purchased from American Type Culture Collection (ATCC) were seeded at 5,000 cells per well of 96-well plate in RPMI-1640 medium supplemented with 10 % FBS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and cultured for 24 hours.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés, des compositions, des formulations et des méthodes de modulation du récepteur de l'adénosine A2B seuls ou en combinaison avec des composés de privation d'hormone chez des mammifères atteints d'un cancer.
PCT/US2022/042993 2021-09-10 2022-09-09 Agonistes du récepteur de l'adénosine destinés à être utilisés dans le traitement du cancer WO2023039125A1 (fr)

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WO2023205629A3 (fr) * 2022-04-20 2023-11-30 The Penn State Research Foundation Utilisation de mécanismes médiés par le récepteur des androgènes dans le traitement de la leucémie myéloïde aiguë

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