Pyridylxanthin containing cyclic amides as an A2B antagonist

Abstract

Described herein are cyclic amide-containing pyridylxanthines and pharmaceutical compositions thereof that are useful as antagonists of the A2B adenosine receptor.

Description

[Technical Field]

[0001] This specification includes A 2B This document describes pyridylxanthine containing a cyclic amide, which is useful as an adenosine receptor antagonist, and its pharmaceutical composition. [Background technology]

[0002] A 2B Adenosine receptor antagonists are used in a variety of applications, including asthma and chronic obstructive pulmonary disease (COPD). As a result of these efforts, selective and potent A 2B An antagonist was obtained. However, A 2B Antagonists (e.g., xanthine-based CVT-6883) typically have poor solubility, resulting in low bioavailability and insufficient tissue distribution (see, for example, Bedford, ST et al., Bioorg. Med. Chem. Lett. 2009, 19, 5945-9 and Wang, G. et al., US7, 601, 732).

[0003] Therefore, in order to develop new and improved therapeutic drugs, further A 2B It is important to synthesize and test receptor antagonists. [Overview of the project]

[0004] Therefore, in one embodiment, A 2B This paper describes novel cyclic amide-containing pyridylxanthines or their pharmaceutically acceptable salts that act as antagonists.

[0005] In another embodiment, a novel pharmaceutical composition is described comprising a pharmaceutically acceptable carrier and at least one of the compounds described herein, or a stereoisomer thereof or a pharmaceutically acceptable salt form, in a therapeutically effective amount.

[0006] In another embodiment, A 2BDescribed is a novel method for treating a mammalian condition or symptom in which a receptor is involved and antagonism of the receptor provides a therapeutic effect by administering to a subject an effective amount of a compound described herein.

[0007] In another aspect, a novel method for treating an adenosine A 2B receptor-related condition in a subject is described by administering to the subject an effective amount of a compound described herein.

[0008] In another aspect, compounds for use in medical therapy are described.

[0009] In another aspect, the use of a compound described herein for the manufacture of a medicament for treating a mammalian condition or symptom in which an A 2B receptor is involved and antagonism of the receptor provides a therapeutic effect is described.

[0010] The above and other objects will become apparent in the following detailed description of the invention, but the described compounds or their stereoisomers or pharmaceutically acceptable salt forms are achieved by the inventors' discovery that they are A 2B antagonists.

Detailed Description of the Invention

[0011] All references cited herein are hereby incorporated by reference in their entirety.

[0012] In one aspect, a novel compound of formula I or its stereoisomers or pharmaceutically acceptable salts:

Chemical Formula

[0013] In another aspect, n is selected from 2 to 10, and (CH2) n Group is substituted with 0 to 1 group selected from C 1-2 Alkyl, C 3-6 Cycloalkyl, and -C 1-2 Alkylene-C 3-6 Cycloalkyl, Ring A is selected from phenyl, naphthyl, and 5 to 10-membered heteroaryl, R 1 Is C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2)2-OCH3, -(CH2)3-OCH3, -(CH2)4-OCH3, -(CH2)2-NH(C(O)CH3,

Chemical formula

Chemical formula

Chemical formula

[0014] In another embodiment, n is selected from 2 to 4. Ring A is selected from phenyl, pyridyl, and pyrimidyl. R 1 However, n-propyl, cyclopropyl, -(CH2)2-OCH3, -(CH2)3-OCH3, -(CH2)4-OCH3, -(CH2)2-NH(C(O)CH3, [ka] Selected from, R 2However, n-propyl, cyclopropyl, -(CH2)2-OCH3, -(CH2)3-OCH3, -(CH2)4-OCH3, -(CH2)2-NH(C(O)CH3, [ka] Selected from, R 3 but, [ka] Selected from, R 4 However, H, F, Cl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, OR 6 , NR 6 R 7 Selected from CF3 and OCF3, R 5 However, H, F, Cl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, OR 6 , NR 6 R 7 Selected from CF3 and OCF3, R 6 However, independently, H, C 1-4 Alkyl, C 3-6 Cycloalkyl and -CH2-C 3-6 Selected from cycloalkyl groups, R 7 However, independently, H, C 1-4 Alkyl, C 3-6 Cycloalkyl and -CH2-C 3-6 Selected from cycloalkyl groups, Alternatively, -(CH2) n -R 3 However, C 1-4 Alkyl, -CH2-C 3-6 Selected from cycloalkyl, -(CH2)2-OCH3, -(CH2)3-OCH3, and -(CH2)4-OCH3, however R 1 and R 2At least one of them independently -(CH2)2-NH(C(O)CH3, [ka] Selected from, This document describes novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts.

[0015] In another embodiment, n is selected from 2 to 4. Ring A is selected from phenyl and pyridyl. R 1 However, n-propyl, cyclopropyl, -(CH2)2-OCH3, -(CH2)3-OCH3, [ka] Selected from, R 2 However, n-propyl, cyclopropyl, -(CH2)2-OCH3, -(CH2)3-OCH3, [ka] Selected from, R 3 but, [ka] And, R 4 However, H, F, Cl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C1 alkylene-C 3-6 Cycloalkyl and OR 6 Selected from, R 5 However, selected from H and F, R 6 However, independently, H and C 1-4 Selected from alkyl groups, Alternatively, -(CH2) n -R 3However, it is selected from -(CH2)2-OCH3 and -(CH2)3-OCH3, where R 1 and R 2 At least one of them [ka] Selected from, This document describes novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts.

[0016] In another embodiment, n is selected from 2 to 3. Ring A is selected from phenyl and pyridyl. R 1 However, n-propyl, cyclopropyl, -(CH2)2-OCH3, -(CH2)3-OCH3, [ka] Selected from, R 2 However, n-propyl, cyclopropyl, -(CH2)2-OCH3, and -(CH2)3-OCH3 is selected, R 3 but, [ka] And, R 4 However, H, F, Cl, CH3, cyclopropyl, and OR 6 Selected from, R 5 However, selected from H and F, R 6 However, independently selected from H and CH3, Alternatively, -(CH2) n -R 3 However, it is selected from -(CH2)2-OCH3 and -(CH2)3-OCH3, where R 1 but [ka] Selected from, This document describes novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts.

[0017] In another embodiment, R 3 but, [ka] Selected from, This document describes novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts.

[0018] In another embodiment, R 3 but [ka] This document describes novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0019] In another embodiment, novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts are described herein, as listed in Table 1.

[0020] In another embodiment, novel compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts are described herein, as listed in Table 2.

[0021] In another aspect, novel compounds of formula I listed in Table 3, or their stereoisomers or pharmaceutically acceptable salts are described. [Table 1] TIFF0007862445000020.tif230162TIFF0007862445000021.tif235162TIFF0007862445000022.tif237162TIFF0007862445000023.tif141162

[0022] In another embodiment, novel compounds of formula I listed in Table 4, or their stereoisomers or pharmaceutically acceptable salts are described. [Table 2] TIFF0007862445000025.tif224162TIFF0007862445000026.tif224162TIFF0007862445000027.tif98162

[0023] In another embodiment, novel compounds of formula I or their stereoisomers or pharmaceutically acceptable salts are described that are deuterium-rich (for example, one or more H atoms are replaced by D atoms, or the percentage of D atoms present is higher than that found in nature (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% to 100%), either at a particular position, part, or in the compound as a whole. For example, R 1 This can be a deuterated propyl group (e.g., -CD2CD2CD3). Furthermore, hydrogen-containing rings A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 The groups described in (e.g., alkyl, cycloalkyl, alkylene, aryl, and heteroaryl) may be partially or completely replaced by D (e.g., CD3, CD2CD3, CD2CD(CD3)2, d5-cyclopropyl, d7-cyclobutyl, d9-cyclopentyl, d5-cyclopropyl-CD2, d5-phenyl, d4-phenyl (with one substituent), d3-phenyl (with two substituents), d4-pyridyl, d3-pyridyl (with one substituent), and d2-pyridyl (with two substituents)).

[0024] In another embodiment, Equation I A ~I C A novel compound of formula I, which is a deuterium-rich compound or its stereoisomer or a pharmaceutically acceptable salt thereof, [ka] In formula TIFF0007862445000029.tif87162, the -D or CD group in ring A is R 4 / R 5 (If applicable. Formula I) A~C This section describes novel compounds of formula I in which H is considered absent (in the case of H, it is assumed not to exist) or N (when ring A is a pyridyl ring).

[0025] The deuterium-rich compounds described herein can be prepared by several known methods, including deuterium exchange of acid-unstable hydrogen (e.g., contact of the compound with NaOD in D2O) and the use of deuterated starting materials (e.g., deuterated iodoadenosineuronamide).

[0026] In another embodiment, a novel pharmaceutical composition is described comprising a therapeutically effective amount of a compound described herein or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] In another embodiment, the target adenosine A 2B A novel method for treating receptor-associated conditions is described, comprising administering a therapeutically effective amount of a compound described herein or its stereoisomer or pharmaceutically acceptable salt to a target.

[0028] In another aspect, adenosine A 2BReceptor-related conditions are selected from asthma, bronchoconstriction, chronic obstructive pulmonary disease (COPD), angiogenesis, pulmonary fibrosis, emphysema, allergy, allergic diseases (e.g., allergic rhinitis (e.g., perennial, seasonal, and occupational) and sinusitis), autoimmune diseases, inflammation, atherosclerosis, hypertension, congestive heart failure, retinopathy, diarrheal diseases, insulin resistance, type 1 diabetes, type 2 diabetes, obesity, fatty liver, pain (e.g., nociceptive pain), wound healing, inflammatory gastrointestinal disorders (e.g., inflammatory bowel disease), sickle cell disease, cancer (e.g., bladder cancer (e.g., MB49 cell line) and breast cancer (e.g., 4T1-12B cell line)), heart attack, diabetic retinopathy, hyperbaric oxygen-induced retinopathy, inhibition of angiogenesis in neoplastic tissue, gastrointestinal disorders, immune disorders, hypersensitivity disorders, neuropathy, and cardiovascular diseases resulting from both cell overgrowth and apoptosis.

[0029] In another embodiment, the above condition is an autoimmune disease selected from Addison's disease, autoimmune hemolytic anemia, Crohn's disease, Goodpasture syndrome, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, post-streptococcal glomerulonephritis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, spontaneous infertility, and systemic lupus erythematosus.

[0030] In another aspect, adenosine A 2B Receptor-related conditions are selected from asthma, insulin resistance, atherosclerosis, fatty liver disease, bladder cancer, and breast cancer.

[0031] In another aspect, adenosine A 2B The receptor-associated state is human cell line MDA-MB-231 breast cancer.

[0032] In another embodiment, A is used as an analgesic adjuvant in subjects requiring pain relief. 2B A novel method using an antagonist, wherein the target a. A therapeutically effective amount of the compound described herein or its stereoisomer or a pharmaceutically acceptable salt thereof, b. A therapeutically effective dose of analgesic, The method, including the administration of [the substance], is described. The advantage of this technology is that it allows the use of a smaller dose of a second analgesic (e.g., an opioid such as morphine). Examples of analgesics include opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Examples of opioids include morphine, oxycodone, hydrocodone, dihydrocodone, codeine, fentanyl, hydromorphone, and methadone. Examples of NSAIDs include aspirin, ibuprofen, naproxen, nabumetone, and celecoxib.

[0033] In another aspect, novel compounds for therapeutic use are described.

[0034] In another aspect, the use of novel compounds for the manufacture of pharmaceuticals for the treatment of indications described herein is described.

[0035] In another embodiment, examples of molecular weights of the compounds described herein include (a) less than about 500 grams, less than 550 grams, less than 600 grams, less than 650 grams, less than 700 grams, less than 750 grams, less than 800 grams, less than 850 grams, less than 900 grams, less than 950 grams, or less than 1000 grams per mole; (b) less than about 950 grams per mole; (c) less than about 850 grams per mole; and (d) less than about 750 grams per mole.

[0036] In another embodiment, examples of solubility of the compounds described herein include 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 400, 500, 600, 700, 800, 900, and greater than 1000 μg / mL.

[0037] The present invention may be embodied in other specific forms without departing from its spirit or essential features. The present invention encompasses all combinations of the embodiments of the present invention described herein. It is understood that all embodiments of the present invention may be taken together with any other embodiments to illustrate further embodiments. It should also be understood that each individual element of each embodiment is intended to be interpreted individually as an independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any other element of any embodiment to illustrate further embodiments.

[0038] definition

[0039] The examples provided in the definitions in this application are non-exclusive unless otherwise specified. They include, but are not limited to, the listed examples.

[0040] The compound(s) may include, as necessary, its stereoisomers and / or pharmaceutically acceptable salts.

[0041] "Adenosine A 2B "Receptor antagonists" include those with a K₂M of less than 1 μM determined by known binding assays. i Adenosine A 2B It contains compounds that inactivate receptors. Adenosine A 2B Receptor antagonists also work with other adenosine receptor subtypes (e.g., A1, A1). 2A , and A3) may cross-react. In another embodiment, adenosine A 2B Receptor antagonists are A 2B It may be selective for (e.g., at least 2, 10, 50, or 100 / 1 compared to another adenosine receptor subtype).

[0042] "Adenosine A 2B "Receptor-associated state" includes adenosine A 2B This includes diseases or disorders that directly or indirectly involve receptor pathways. While not bound by theory, adenosine A2B The administration of an antagonist is A 2B It is thought to inhibit the biological activity of native adenosine at the receptor. Therefore, adenosine A 2B Receptor-associated states include adenosine A 2B Receptor activity or adenosine A 2B This includes diseases and disorders directly related to the activity of receptor-related biological pathways.

[0043] The compounds described herein may have chiral centers, geometric centers (e.g., double bonds), or both. Unless a specific stereochemical or isomeric form is specifically indicated, all chiral, diastereomer, racemic, and geometric isomeric forms of the structure are intended. Compounds described herein containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms are well known in the art and include, for example, by splitting racemic forms, by synthesis from optically active starting materials, or through the use of chiral auxiliaries. Geometric isomers of olefins, C=N double bonds, or other types of double bonds may exist in the compounds described herein, and all such stable isomers are included herein. Specifically, cis and trans geometric isomers of the compounds described herein may also exist and may be isolated as mixtures of isomers or as separated isomeric forms. All processes used to prepare the compounds described herein and the intermediates produced in the process are considered part of the present invention. All tautomers of the compounds shown or described are also considered to be part of the present invention.

[0044] This invention includes all isotopes of the atoms present in the compound. An isotope is an atom that has the same atomic number but a different mass number. Common examples, though not limited to them, include tritium and deuterium as isotopes of hydrogen, and C-13 and C-14 as isotopes of carbon.

[0045] The term "substituted" means that one or more hydrogen atoms on a given atom are replaced by a group of choice from the indicated group, provided that the substitution does not exceed the normal valence of the given atom and the result is a stable compound. If the substituent is keto (i.e., =O), two hydrogen atoms on that atom are replaced. Keto substituents are not present in aromatic moieties.

[0046] "Stable" means that the compound is suitable for pharmaceutical use.

[0047] The embodiments described herein are for stable compounds, and therefore, unless otherwise specified, the following bond types: heteroatom-halogen, NS, OS, OO, and SS are avoided.

[0048] "Alkyl" includes both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. 1-6 Alkyl groups include, for example, C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

[0049] When "ene" is at the end of a group, it indicates that the group is bonded to two other groups. For example, methylene refers to the -CH2- portion.

[0050] "Cycloalkyl" refers to a saturated ring containing a specified number of hydrocarbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-8 Cycloalkyls include C3, C4, C5, C6, C7, and C8 cycloalkyl groups.

[0051] A "cyclic amide" refers to any stable 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heterocycle containing a ring amide (NC(O)) and bonded via the nitrogen of the ring amide. A cyclic amide consists of an amide (NC(O)) moiety and 0, 1, or 2 further heteroatoms independently selected from the group consisting of N, O, and S. One or two double bonds may be present in the amide-containing ring. If the cyclic amide is bicyclic, the non-amide-containing ring may be aromatic (e.g., benzo, pyrimide, or other heteroaryl). The further nitrogen group, if present, may be N, NH, or an N substituent, depending on the selected ring and substituent description. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)2, and NO). The cyclic amides described herein may be substituted on the carbon or nitrogen atom if the resulting compound is stable.

[0052] Alternatively, the cyclic amide is bonded via a carbon atom instead of the amide nitrogen. For these cyclic amides, the amide nitrogen is C 1-6 It is substituted with an alkyl group, which is optional C 3-6 Cycloalkyl groups or C 1-3 Alkylene-C 3-6 It is substituted with a cycloalkyl group.

[0053] A "heteroaryl" refers to any stable 5-, 6-, 7-, 8-, 9-, or 10-membered monocyclic, bicyclic, or tricyclic heterocycle that is aromatic and consists of a carbon atom and one, two, three, or four heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl group is bicyclic or tricyclic, at least one of the two or three rings must contain heteroatoms, but both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, only one ring must be aromatic. The N group may be N, NH, or an N substituent, depending on the selected ring and substituent description. Nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)2, and NO). The heteroaryl ring may be bonded to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable.

[0054] Examples of heteroaryls include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzoxazolinil, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinil, carbazolyl, 4aH-carbazolyl, carborinil, chromanil, clomenil, sinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinyl, di Hydroflo[2,3-b]tetrahydrofuran, furanil, furazanil, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolidinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxioindolyl, Pyrimidinyl, Phenanthrolinyl, Phenanthrolinyl, Phenadhiazinyl, Phenoxathinyl, Phenoxadinyl, Phthalazinyl, Pteridinyl, Pyrazolyl, Pyrazolyl, Pyridazinyl, Pyridoxazole, Pyridoimidazole, Pyridhiazole, Pyridinyl, Pyridyl, Pyrimidinyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Quinolidinyl, Ki Examples include noxalinyl, quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0055] "Mammals" and "patients" typically include warm-blooded mammals under treatment (e.g., humans and livestock). Examples include cats, dogs, horses, cattle, non-human primates, and humans, as well as humans only.

[0056] "To treat" or "to cure" encompasses the treatment of a disease state in a mammal, including (a) preventing the development of a disease state in a mammal, in particular when such mammal is at risk of contracting the disease state but has not yet been diagnosed with it; (b) inhibiting the disease state, e.g., blocking its manifestation; and / or (c) mitigating the disease state, e.g., regressing the disease state to reach a desired endpoint. Treatment also includes improving the symptoms of the disease (e.g., reducing pain or discomfort), such improvement may or may not directly affect the disease (e.g., its cause, transmission, manifestation, etc.).

[0057] A "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound obtained by modifying the parent compound to produce an acid salt or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include ordinary non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such common non-toxic salts include 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, EDTA, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, iodine. Examples include, but are not limited to, those derived from inorganic and organic acids selected from hydrochloric acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0058] The pharmaceutically acceptable salts described herein can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are useful. A list of preferred salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0059] "Therapeutic dose" includes the amount of the compounds described herein that, when administered alone or in combination, is effective for the indications listed herein. "Therapeutic dose" also includes the amount of a claimed combination of compounds that is effective in treating the desired indication. A combination of compounds may be a synergistic combination. Synergy occurs when the effect of the compounds when administered in combination exceeds the additive effect of the compounds when administered individually, as described, for example, Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55. Generally, synergy is most clearly demonstrated when the concentration of the compounds is below the optimal level. Synergy may be in the form of reduced cytotoxicity, increased efficacy, or any other beneficial effect of the combination compared to the individual components.

[0060] Formulation and Dosage

[0061] The compounds described herein can be formulated as pharmaceutical compositions and administered to mammalian hosts, such as human patients, in various forms suitable for a selected route of administration, e.g., oral or parenteral, intravenous (e.g., sequential or bolus), intrathecal, intramuscular, topical, intradermal, intraperitoneal, intraocular, inhalation, or subcutaneous. Exemplary pharmaceutical compositions are disclosed in “Remington: The Science and Practice of Pharmacy,” A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0062] Therefore, the compound can be administered systemically, for example, orally, in combination with pharmaceutically acceptable carriers / excipients, such as inert diluents or absorbable food carriers. They can be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the active compound may be used in combination with one or more excipients in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. The amount of the active compound in such therapeutically useful compositions is such that an effective dose level is obtained.

[0063] The amount of any compound or active salt or derivative described herein required for therapeutic use varies depending not only on the specific compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately determined at the discretion of the attending physician or clinician. However, appropriate doses are generally in the range of (a) approximately 1.0 to 1000 mg per kg of body weight per day, (b) approximately 10 to 500 mg per kg of body weight per day, and (c) approximately 5 to 20 mg per kg of body weight per day.

[0064] In the case of eye drops, the composition usually contains the active ingredient at concentrations of generally 0.000001-10% (w / v), 0.00001-3% (w / v), 0.0001-1% (w / v), and 0.001-0.1% (w / v), and can be instilled into the eyes of adults once to several times a day.

[0065] When administered orally, the compounds described herein can be administered to adults in one or more divided doses, generally in amounts of 0.001 to 5000 mg per day, 0.1 to 2500 mg per day, or 1 to 1000 mg per day.

[0066] In the case of liquid compositions (e.g., in lotions), the concentrations of the compounds described herein may be (a) about 0.1 to 25% by weight and (b) about 0.5 to 10% by weight. In semi-solid or solid compositions such as gels or powders, the concentrations may be (a) about 0.1 to 5% by weight and (b) about 0.5 to 2.5% by weight.

[0067] The compounds described herein can be conveniently administered in unit dosage forms, such as tablets and caplets, containing (a) about 4 to 400 mg, (b) about 10 to 200 mg, and (c) about 20 to 100 mg of the active ingredient per unit dosage form.

[0068] The compounds described herein may be administered to achieve peak plasma concentrations of the active compound of (a) about 0.02–20 μM, (b) about 0.1–10 μM, and (c) about 0.5–5 μM. These concentrations can be achieved, for example, by intravenous injection (e.g., sequential or bolus) of a 0.005–0.5% solution of the active ingredient, or by oral administration as a bolus containing about 4–400 mg of the active ingredient.

[0069] When the compounds described herein are administered in combination with other drugs (e.g., co-administration), the compounds described herein and the other drugs may be administered simultaneously or in any order. They may be administered as a single pharmaceutical composition or as separate compositions. The compounds described herein may be administered within minutes prior to the administration of other drugs, or within hours (e.g., 24 or 48) or even days after the administration of other drugs. For example, the compounds described herein may be administered within approximately 24 hours or within approximately 12 hours.

[0070] Tablets, lozenges, pills, capsules, etc. may contain the following: binders, e.g., tragacanth gum, acacia, corn starch, or gelatin; excipients, e.g., dicalcium phosphate; disintegrants, e.g., corn starch, potato starch, alginic acid, etc.; lubricants, e.g., magnesium stearate; and sweeteners, e.g., sucrose, fructose, lactose, or aspartame; or flavorings, e.g., peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, in addition to the above types of substances, it may contain a liquid carrier such as vegetable oil or polyethylene glycol. Various other substances may be present as a coating or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. The syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propylparaben as preservatives, dyes, and flavorings such as cherry or orange. Naturally, any substances used in preparing any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts used. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0071] The compounds described herein may also be administered intravenously (e.g., sequentially or as a bolus) or intraperitoneally by drip infusion or injection. Solutions of the compounds described herein or their salts may be prepared in water and optionally mixed with a non-toxic surfactant. Dispersants may also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, as well as in oil. These preparations contain preservatives to inhibit microbial growth under normal storage and use conditions.

[0072] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersants or sterile powders containing the active ingredient, optionally encapsulated in liposomes, suitable for immediate preparation of sterile injection or infusion solutions or dispersants. In all cases, the final dosage form should be sterile, fluid, and stable under manufacturing and storage conditions. The liquid carrier or vehicle may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by liposome formation, by maintaining the required particle size in the case of dispersants, or by the use of surfactants. Inhibition of microbial activity may be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Sustained absorption of injectable compositions can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0073] Sterile injectable solutions can be prepared by incorporating the required amount of active compound, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield, in addition to the active ingredient powder, any additional desired components present in the previously sterile filtered solution.

[0074] For topical administration, the compounds described herein may be applied in their pure form, for example, if they are liquids. However, it is generally preferable to administer them to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which may be solid or liquid.

[0075] Useful solid carriers include pulverized solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol or glycol, or water-alcohol / glycol formulations, in which the compound can be dissolved or dispersed at an effective level, optionally with a non-toxic surfactant. Auxiliaries such as fragrances and additional antibacterial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied from an absorbent pad, impregnated into bandages and other dressings, or sprayed onto the affected area using a pump or aerosol spray.

[0076] Examples of useful dermatological compositions that can be used to deliver the compounds described herein to the skin are known in the art. See, for example, Jacquet et al. (US Patent No. 4,608,392), Geria (US Patent No. 4,992,478), Smith et al. (US Patent No. 4,559,157), and Wortzman (US Patent No. 4,820,508). Useful doses of the compounds described herein can be determined in animal models by comparing their in vitro and in vivo activities. Methods for extrapolating effective doses in mice and other animals to humans are known in the art. See, for example, US Patent No. 4,938,949.

[0077] The compounds described herein may also be administered by inhalation from inhalers, blowers, nebulizers, or other means of supplying aerosol sprays, such as pressurized packs or aerosol sprays. Pressurized packs may contain a suitable propellant, such as carbon dioxide or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a value for delivering a measured amount. Inhalers, blowers, and nebulizers are described in detail in pharmaceutical reference books such as Remington's Pharmaceutical Sciences Volumes 16 (1980) or 18 (1990), Mack Publishing Co.

[0078] The desired dose of the compounds described herein may be conveniently provided as a single dose or as multiple doses administered at appropriate intervals, for example, two, three, four, or more times per day. These divided doses themselves may be further divided into several doses administered at discontinuous intervals, for example, multiple inhalations from a blower or multiple eye drops.

[0079] synthesis The compounds described herein can be prepared by several methods known to those skilled in the art of organic synthesis. The compounds described herein can be synthesized using the following methods, along with synthetic methods known in the field of organic synthesis chemistry, or by variations thereof as understood by those skilled in the art. Useful methods include, but are not limited to, those described below. The reactions are carried out in solvents suitable for the reagents and substances used and suitable for the resulting transformations. Those skilled in the art of organic synthesis will understand that the functional groups present in the molecules should be consistent with the proposed transformations. This may, in some cases, require the decision to change the order of the synthetic steps or to choose a particular process scheme in preference to another scheme in order to obtain the desired compounds of the present invention. It will also be recognized that another major consideration in planning any synthetic route in this art is the wise selection of protecting groups used to protect the reactive functional groups present in the compounds described herein. An authoritative description of many alternatives to a trained physician is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are incorporated herein by reference in their entirety.

[0080] One stereoisomer of a compound described herein is more potent than its corresponding(s) A 2BIt may be an antagonist. Therefore, stereoisomers are included herein. If necessary, separation of racemic materials can be achieved by HPLC using a chiral column, by resolution using resolving agents such as those described in Wilen, SH Tables of Resolving Agents and Optical Resolutions 1972, 308, or by resolution using enantiomerically pure acids and bases. The chiral compounds described herein may also be synthesized directly using chiral catalysts or chiral ligands, e.g. Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431, or using other enantio- and diastereoselective reactions and reagents known to those skilled in the art of asymmetric synthesis.

[0081] Other features of the present invention will become apparent in the course of describing the following exemplary embodiments, which are provided for illustrative purposes and are not intended to limit the invention. [Examples]

[0082] The following examples are representative of the procedures used to prepare the compounds described herein.

[0083] General procedure

[0084] The compounds described herein can be prepared by methods such as those described in PJScammells, et al., J.Med.Chem. 37, 2704-2712 (1994). For example, a desired intermediate can be obtained by reacting 1,3-disubstituted-8-(6-chloropyridine-3-yl)xanthine with a cyclic amide such as N-(3-aminopropyl)-2-pyrrolidinone. The desired final product can then be obtained by reacting the intermediate with a suitable acid chloride.

[0085] [ka]

[0086] Synthesis of 3-(2-methoxyethyl)-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-1-propylxanthine:

[0087] 8-(6-chloropyridine-3-yl)-3-(2-methoxyethyl)-1-propylxanthine (0.7000 g, 1.92 mmol) was combined with N-(3-aminopropyl)-2-pyrrolidinone (1.094 g, 7.70 mmol) in a pressure flask, with or without a small amount of isopropanol. If isopropanol was present, it was removed by boiling, and the solution was heated and stirred at 145-165°C until the HPLC showed a complete reaction (approximately 47 hours). This solution was transferred to a flask containing DCM (dichloromethane) and silica. The solvent was removed using a rotary evaporator, and the solid was dried under vacuum (less than 1 mmHg). The dried compound on silica was dry-packed into a small column for column chromatography. This compound was purified by chromatography using a gradient of 0-4% MeOH in DCM. Yield: 0.7000 g, 1.49 mmol, yield 77.48%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 7.821, LRMS ESI m / z 470.20 (M+1). [ka]

[0088] Preparation example B:

[0089] Synthesis of 1-(2-methoxyethyl)-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-3-propylxanthine:

[0090] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(2-methoxyethyl)-3-propylxanthine was used as the starting material. Yield: 0.7500 g, 1.60 mmol, yield 52.83%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 7.659, LRMS ESI m / z 470.20 (M+1). [ka]

[0091] Preparation Example C: Synthesis of 1-cyclopropyl-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-3-propylxanthine:

[0092] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-cyclopropyl-3-propylxanthine was used as the starting material. Yield: 0.6470 g, 1.4329 mmol, 33.03%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 8.292, LRMS ESI m / z 452.15 (M+1). [ka]

[0093] Preparation Example D: Synthesis of 1-(3-methoxypropyl)-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-3-propylxanthine:

[0094] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(3-methoxypropyl)-3-propylxanthine was used as the starting material. Yield: 5.5 g, 11.37 mmol, 85.95%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 9.514, LRMS ESI m / z 484.35 (M+1). [ka]

[0095] Preparation Example E: Synthesis of 8-(6-(N-(2-methoxyethyl)amino)-3-pyridyl)-1-((2-oxo-1-pyrrolidinyl)propyl)-3-propylxanthine:

[0096] This was prepared in the same manner as Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(2-oxo-1-pyrrolidinyl)propyl)-3-propylxanthine and 2-methoxyethylamine were used as starting materials. Yield: 0.8 g, 1.49 mmol, 64.24%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 8.826, LRMS ESI m / z 470.25 (M+1). [ka]

[0097] Preparation Example F: Synthesis of 8-(6-((1-methyl-5-oxo-3-pyrrolidinyl)methylamino)-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine:

[0098] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(2-methoxyethyl)-3-propylxanthine and 4-(aminomethyl)-1-methyl-2-pyrrolidinene were used as starting materials. Yield: 0.18 g, 0.40 mmol, 28.93%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt=8.701, LRMS ESI m / z 456.25 (M+1). [ka]

[0099] Preparation Example G: Synthesis of 1,3-dicyclopropyl-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)xanthine:

[0100] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(3-methoxypropyl)-3-propylxanthine was used as the starting material. Yield: 1.16 g, 2.58 mmol, 88.81%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 6.804, LRMS ESI m / z 450.2 (M+1). [ka]

[0101] Preparation Example H: Synthesis of 3-(3-methoxypropyl)-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-1-propylxanthine:

[0102] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-3-(3-methoxypropyl)-1-propylxanthine was used as the starting material. Yield: 0.3 g, 0.62 mmol, 10.56%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 9.378, LRMS ESI m / z 484.3 (M+1). [ka]

[0103] Preparation Example I. Synthesis of 1-(2-acetylaminoethyl)-8-(6-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-3-pyridyl)-3-propylxanthine:

[0104] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(2-acetylaminoethyl)-3-propylxanthine was used as the starting material. Yield: 0.2 g, 0.4 mmol, 39.35%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 6.546, LRMS ESI m / z 497.35 (M+1). [ka]

[0105] Preparation Example J: Synthesis of 8-(6-(N-ethylamino)-3-pyridyl)-1-((2-oxo-1-pyrrolidinyl)propyl)-3-propylxanthine:

[0106] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(2-oxo-1-pyrrolidinyl)propyl)-3-propylxanthine and ethylamine were used as starting materials. Yield: 0.500 g, 1.14 mmol, 29.71%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=8.875, LRMS ESI m / z 440.25 (M+1). [ka]

[0107] Preparation Example K: Synthesis of 1-(3-methoxypropyl)-8-(6-((1-methyl-5-oxo-3-pyrrolidinyl)methylamino)-3-pyridyl)-3-propylxanthine:

[0108] This was prepared in the same manner as Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(3-methoxypropyl)-3-propylxanthine and 4-(aminomethyl)-1-methyl-2-pyrrolidinene were used as starting materials. Yield: 0.265 g, 0.56 mmol, 42.65% HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt=10.696, LRMS ESI m / z 470.20 (M+1). [ka]

[0109] Preparation Example L: Synthesis of 1-cyclopropyl-8-(6-(((1-methyl-5-oxo-3-pyrrolidinyl)methylamino))-3-pyridyl)-3-propylxanthine:

[0110] This was prepared in the same manner as in Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-cyclopropyl-3-propylxanthine and 4-(aminomethyl)-1-methyl-2-pyrrolidinenon were used as starting materials. Yield: 0.600 g, 1.37 mmol, 94.84%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt=10.059, LRMS ESI m / z 438.15 (M+1). [ka]

[0111] Preparation Example M: ​​Synthesis of 1,3-dicyclopropyl-8-(6-(((1-methyl-5-oxo-3-pyrrolidinyl)methylamino))-3-pyridyl)xanthine:

[0112] This was prepared in the same manner as Preparation Example A, except that 8-(6-chloropyridine-3-yl)-1-(3-methoxypropyl)-3-propylxanthine and 4-(aminomethyl)-1-methyl-2-pyrrolidinenon were used as starting materials. Yield: 1.035 g, 2.38 mmol, 90.78%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=7.831, LRMS ESI m / z 436.20 (M+1). [ka]

[0113] Example 1: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-1-cyclopropyl-3-propylxanthine

[0114] In a 50 mL flask, Preparation C (0.1000 g, 0.22 mmol) was heated at 40°C for approximately 5 minutes until dissolved in dry pyridine (15 mL). 3,4-difluorobenzoyl chloride (0.056 mL, 0.44 mmol) was added to this solution, and the reaction mixture was stirred at 40°C for 48 hours. HPLC indicated completion of the reaction. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography (26 g). The column was eluted with 0-7% MeOH in DCM, and the same fraction was collected and dried under vacuum. Yield: 0.0901 g, 0.15 mmol, yield 68.76%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.570, LRMS ESI m / z 592.25 (M+1).

[0115] Example 2: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-1-cyclopropyl-3-propylxanthine

[0116] In a 50 mL flask, Preparation C (0.1000 g, 0.22 mmol) was stirred at 40°C for approximately 5 minutes until dissolved in 15 mL of dry pyridine. 4-Fluorobenzoyl chloride (0.05 mL, 0.44 mmol) was added, and the reaction mixture was stirred at 40°C for 4 days. Further acid chloride was added, and the reaction mixture was stirred overnight. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bound to silica for column chromatography. Yield: 0.0855 g, 0.14 mmol, yield 67.86%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 12.113, LRMS ESI m / z 574.25 (M+1).

[0117] Example 3: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-1-cyclopropyl-3-propylxanthine:

[0118] In a 50 mL flask, Preparation C (0.1000 g, 0.22 mmol) was heated at 40°C for approximately 5 minutes until dissolved in dry pyridine (15 mL). 6-fluoronicotinoyl chloride (0.050 mL, 0.44 mmol) was added to this solution, and the reaction mixture was stirred at 40°C for 24 hours. HPLC indicated completion of the reaction. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography (26 g). Yield: 0.0794 g, 0.14 mmol, yield 62.39%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 10.790, LRMS ESI m / z 575.25 (M+1).

[0119] Example 4: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine

[0120] In a 50 mL flask, Preparation Example B (0.100 g, 0.21 mmol) was combined with 3,4-difluorobenzoyl chloride (0.054 mL, 0.43 mmol) in dry pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 h. HPLC indicated that the reaction was complete. Water (ca. 2 mL) was added to quench the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography (26 g). The column was eluted with 0 - 5% MeOH in DCM. Similar fractions were collected and dried under vacuum. Yield: 0.128 g, 0.21 mmol, 98.58% yield. HPLC-MS conditions: 40% - 80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) over 10 min. Hold for 5 min, Rt = 12.277, LRMS ESI m / z 610.20 (M+1).

[0121] Example 5: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine:

[0122] In a 50 mL flask, Preparation Example B (0.100 g, 0.21 mmol) was combined with 4-fluorobenzoyl chloride (0.049 mL, 0.43 mmol) in dry pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 h. HPLC indicated that the reaction was complete. Water was added to quench the reaction and the solvent was removed under vacuum. The resulting solid was dissolved in DCM for column chromatography (26 g). The column was eluted with 0 - 5% MeOH in DCM. Similar fractions were collected and dried. Yield: 0.0855 g, 0.14 mmol, 67.86% yield. HPLC-MS conditions: 40% - 80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) over 10 min. Hold for 5 min, Rt = 11.815, LRMS ESI m / z 592.20 (M+1).

[0123] Example 6: 8-(6-{[3-(2-Oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine

[0124] In a 50 mL flask, Preparation Example B (0.1000 g, 0.21 mmol) was dissolved in dry pyridine (15 mL). To this solution, 6-fluoronicotinoyl chloride (0.049 mL, 0.43 mmol) was added and the reaction was stirred at 40 °C for 24 hours. HPLC indicated that the reaction was complete. Water was added to stop the reaction and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bound to silica for purification. The chromatography column (26 g) was eluted with 0 - 5% MeOH in DCM, similar fractions were collected and dried under vacuum. Yield: 0.0829 g, 0.14 mmol, 65.68% yield. HPLC-MS conditions: 40% - 80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 10.547, LRMS ESI m / z 593.25 (M+1).

[0125] Example 7: 8-(6-{[3-(2-Oxo-1-pyrrolidinyl)propyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-3-(2-methoxyethyl)-1-propylxanthine

[0126] In a 50 mL flask, Preparation A (0.100 g, 0.21 mmol) was combined with 3,4-difluorobenzoyl chloride (0.054 mL, 0.43 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM. This compound was purified using a 26 g silica chromatography column and eluted with 0-3% MeOH in DCM. A similar fraction was collected. Yield: 0.129 g, 0.21 mmol, yield 99.36%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 12.010, LRMS ESI m / z 610.25 (M+1).

[0127] Example 8: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-3-(2-methoxyethyl)-1-propylxanthine

[0128] In a 50 mL flask, Preparation A (0.100 g, 0.21 mmol) was combined with 4-fluorobenzoyl chloride (0.049 mL, 0.43 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. HPLC indicated that the reaction was incomplete, so an acid chloride was added, and the reaction mixture was stirred at 40 °C for another 24 hours. Water (2 mL) was added to stop the reaction, and the solution was dried under vacuum to obtain a solid. Further water was added and removed under vacuum. The obtained solid was dissolved in DCM and purified by 26 g silica chromatography column with a gradient of 0-4% MeOH in DCM. A similar fraction was collected and dried. Yield: 0.077 g, 0.13 mmol, yield 61.11%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=11.483, LRMS ESI m / z 592.20 (M+1).

[0129] Example 9: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-3-(2-methoxyethyl)-1-propylxanthine

[0130] In a 50 mL flask, Preparation A (0.100 g, 0.21 mmol) was combined with 6-fluoronicotinoyl chloride (0.049 mL, 0.43 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. HPLC indicated that the reaction was not complete. Further acid chloride was added, and the reaction mixture was continued to stir for 24 hours. Further acid chloride was added, and the reaction mixture was stirred for 24 hours. The reaction was stopped with water (2 mL), and the solvent was removed under vacuum. DCM was added, and the mixture was purified by column chromatography. A 26 g column was eluted with 0-3% MeOH in DCM. A similar fraction was collected and dried. Yield: 0.055 g, 0.09 mmol, yield 43.58%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=9.802, LRMS ESI m / z 593.25 (M+1).

[0131] Example 10: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0132] In a 50 mL flask, Preparation D (0.150 g, 0.32 mmol) was combined with 3,4-difluorobenzoyl chloride (0.080 mL, 0.64 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.1728 g, 0.28 mmol, yield 86.73%. HPLC-MS conditions: 40-85% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.994, LRMS ESI m / z 624.35 (M+1).

[0133] Example 11: 8-{6-[(2-methoxyethyl)(3,4-difluorophenyl)carbonylamino]-3-pyridyl}-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-propylxanthine

[0134] In a 50 mL flask, Preparation E (0.150 g, 0.32 mmol) was combined with 3,4-difluorobenzoyl chloride (0.080 mL, 0.64 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.105 g, 0.17 mmol, yield 53.92%. HPLC-MS conditions: 40-85% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.632, LRMS ESI m / z 610.25 (M+1).

[0135] Example 12: 8-(6-{N-[3-(2-oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0136] In a 50 mL flask, Preparation D (0.1500 g, 0.31 mmol) was dissolved in dried pyridine (10 mL) and dried DCM (1.585 mL). 6-fluoronicotinoyl chloride (0.049 mL, 0.43 mmol) was added to this solution, and the reaction mixture was stirred at 40°C for 24 hours. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. Similar fractions were collected and dried under vacuum. Yield: 0.159 g, 0.26 mmol, yield 67.41%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.327, LRMS ESI m / z 607.3 (M+1).

[0137] Example 13: 8-{6-[N-(2-methoxyethyl)[6-(trifluoromethyl)-3-pyridyl]carbonylamino]-3-pyridyl}-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-propylxanthine

[0138] In a 50 mL flask, Preparation Example E (0.150 g, 0.32 mmol) was combined with 3,4-difluorobenzoyl chloride (0.080 mL, 0.64 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.114 g, 0.18 mmol, yield 55.53%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=13.061, LRMS ESI m / z 643.25 (M+1).

[0139] Example 14: 8-{6-[N-(2-methoxyethyl)[6-fluoro-3-pyridyl]carbonylamino]-3-pyridyl}-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-propylxanthine

[0140] In a 50 mL flask, Preparation Example E (0.200 g, 0.43 mmol) was combined with 6-fluoronicotinoyl chloride (0.194 mL, 1.7 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.130 g, 0.22 mmol, yield 51.50%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=11.996, LRMS ESI m / z 593.25 (M+1).

[0141] Example 15: 8-(6-{[(1-methyl-5-oxo-3-pyrrolidinyl)methyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine

[0142] In a 50 mL flask, preparation example F (0.100 g, 0.21 mmol) was combined with 3,4-difluorobenzoyl chloride (0.054 mL, 0.43 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: 0.124 g, 0.21 mmol, yield 52.34%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 13.310, LRMS ESI m / z 596.25 (M+1).

[0143] Example 16: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3,4-difluorophenyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0144] In a 50 mL flask, preparation example G (0.150 g, 0.33 mmol) was combined with 3,4-difluorobenzoyl chloride (0.084 mL, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: 0.0777 g, 0.13 mmol, yield 39.49%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 12.581, LRMS ESI m / z 590.20 (M+1).

[0145] Example 17: 8-(6-{[3-(2-Oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0146] In a 50 mL flask, Preparation Example G (0.150 g, 0.33 mmol) was combined with 6-fluoronicotinoyl chloride (0.076 mL, 0.67 mmol) in dry pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (about 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0 - 7% MeOH in DCM. Similar fractions were collected and dried under vacuum. Yield: 0.105 g, 0.18 mmol, 54.95% yield. HPLC-MS conditions: 40% - 80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 10.436, LRMS ESI m / z 573.30 (M+1).

[0147] Example 18: 8-(6-{[3-(2-Oxo-1-pyrrolidinyl)propyl](cyclopropyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0148] In a 50 mL flask, Preparation D (0.150 g, 0.31 mmol) was combined with cyclopropane carbonyl chloride (0.056 mL, 0.62 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.147 g, 0.27 mmol, yield 86.02%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=13.270, LRMS ESI m / z 552.4 (M+1).

[0149] Example 19: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](tert-butyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0150] In a 50 mL flask, Preparation D (0.150 g, 0.31 mmol) was combined with trimethylacetyl chloride (0.076 mL, 0.62 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.1611 g, 0.28 mmol, yield 91.49%. HPLC-MS conditions: 40-85% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=13.223, LRMS ESI m / z 568.30 (M+1).

[0151] Example 20: 8-(6-{N-[3-(2-oxo-1-pyrrolidinyl)propyl](6-trifluoromethyl-3-pyridyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0152] In a 50 mL flask, Preparation D (0.150 g, 0.31 mmol) was combined with 6-(trifluoromethyl)nicotinoyl chloride (0.045 mL, 0.62 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the crude product was bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.1291 g, 0.20 mmol, yield 63.38%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=13.828, LRMS ESI m / z 657.35 (M+1).

[0153] Example 21: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](cyclopentyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0154] In a 50 mL flask, Preparation D (0.150 g, 0.31 mmol) was dissolved in dried pyridine (10 mL) and dried DCM (1.58 mL). Cyclopentane carbonyl chloride (0.151 mL, 1.24 mmol) was added, and the reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the crude product was bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.170 g, 0.29 mmol, yield 94.38%. HPLC-MS conditions: 40-85% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=13.684, LRMS ESI m / z 580.35 (M+1).

[0155] Example 22: 8-(6-{N-[3-(2-oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-3-(3-methoxypropyl)-1-propylxanthine

[0156] In a 50 mL flask, preparation H (0.1500 g, 0.31 mmol) was dissolved in dried pyridine (10 mL) and dried DCM (1.585 mL). 6-fluoronicotinoyl chloride (0.049 mL, 0.43 mmol) was added to this solution, and the reaction mixture was stirred at 40°C for 24 hours. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. Similar fractions were collected and dried under vacuum. Yield: 0.159 g, 0.26 mmol, yield 84.49%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.255, LRMS ESI m / z 607.40 (M+1).

[0157] Example 23: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](6-fluoro-3-pyridyl)carbonylamino}-3-pyridyl)-1-(2-acetylaminoethyl)-3-propylxanthine

[0158] In a 50 mL flask, Preparation I (0.1500 g, 0.31 mmol) was dissolved in dried pyridine (10 mL) and dried DCM (1.585 mL). 6-fluoronicotinoyl chloride (0.049 mL, 0.43 mmol) was added to this solution, and the reaction mixture was stirred at 40°C for 24 hours. Water was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. Similar fractions were collected and dried under vacuum. Yield: 0.107 g, 0.17 mmol, yield 85.75%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=10.192, LRMS ESI m / z 620.40 (M+1).

[0159] Example 24: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3-methoxyphenyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0160] In a 50 mL flask, preparation example G (0.150 g, 0.33 mmol) was combined with 3-methoxybenzoyl chloride (0.114 g, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting solid was dissolved in DCM / MeOH and bound to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 11.741, LRMS ESI m / z 584.25 (M+1).

[0161] Example 25: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](6-chloro-3-pyridyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0162] In a 50 mL flask, Preparation Example G (0.150 g, 0.33 mmol) was combined with 6-chloronicotinoyl chloride (0.114 g, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum. The resulting solid was dissolved in DCM / MeOH and bonded to silica for column chromatography. The column was eluted with 0-5% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: 0.114 g, 0.19 mmol, yield 58.09%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=11.123, LRMS ESI m / z 589.25 (M+1).

[0163] Example 26: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3-fluoro-4-methoxyphenyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0164] In a 50 mL flask, preparation example G (0.150 g, 0.33 mmol) was combined with 6-fluoronicotinoyl chloride (0.076 mL, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-7% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: 0.105 g, 0.18 mmol, yield 54.95%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 11.711, LRMS ESI m / z 602.30 (M+1).

[0165] Example 27: 8-(6-{N-[3-(2-oxo-1-pyrrolidinyl)propyl](6-chloro-3-pyridyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0166] In a 50 mL flask, Preparation D (0.150 g, 0.31 mmol) was combined with dried pyridine (10 mL), 6-chloronicotinyl chloride (0.114 g, 0.33 mmol), and dried DCM (2 mL). The reaction mixture was stirred at 40 °C for 24 hours. Pyridine was removed under vacuum, and the remaining residue was removed under high vacuum to remove any trace amounts of pyridine. The crude solid was dissolved in DCM / MeOH and deposited on silica for column chromatography. This was then purified using a silica column (26 g). The column was eluted with 0-8% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.154 g, 0.25 mmol, yield 79.68%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt=12.974, LRMS ESI m / z 623.30 (M+1).

[0167] Example 28: 8-(6-{N-[3-(2-oxo-1-pyrrolidinyl)propyl](6-chloro-3-pyridyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine

[0168] In a 50 mL flask, Preparation B (0.150 g, 0.32 mmol) was combined with 6-chloronicotinoyl chloride (0.112 g, 0.64 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction, and the solvent was removed under vacuum. The resulting solid was dissolved in DCM for column chromatography. The column was eluted with 0-5% MeOH in DCM. The same fraction was collected and dried. Yield: 0.120 g, 0.20 mmol, yield 63.49%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 12.290, LRMS ESI m / z 609.20 (M+1).

[0169] Example 29: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3-fluorophenyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0170] In a 50 mL flask, preparation example G (0.150 g, 0.33 mmol) was combined with 3-fluorobenzoyl chloride (0.081 mL, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-7% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.105 g. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 12.622, LRMS ESI m / z 572.25 (M+1).

[0171] Example 30: 8-(6-{[3-(2-oxo-1-pyrrolidinyl)propyl](3-fluorophenyl)carbonylamino}-3-pyridyl)-1-(2-methoxyethyl)-3-propylxanthine

[0172] In a 50 mL flask, Preparation B (0.150 g, 0.33 mmol) was combined with 3-fluorobenzoyl chloride (0.076 mL, 0.67 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-7% MeOH in DCM. The same fraction was collected and dried under vacuum. Yield: HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 13.928, LRMS ESI m / z 592.25 (M+1).

[0173] Example 31: 8-{6-[N-(ethyl)[6-fluoro-3-pyridyl]carbonylamino]-3-pyridyl}-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-propylxanthine

[0174] In a 50 mL flask, Preparation Example J (0.240 g, 0.43 mmol) was combined with 6-fluoronicotinoyl chloride (0.194 mL, 1.7 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. After confirming completion of the reaction by HPLC, the acid chloride was added. The reaction mixture was stirred at 45 °C for 8 hours. After confirming completion of the reaction by HPLC, the acid chloride was added. The reaction mixture was stirred at 45 °C for 72 hours. After confirming completion of the reaction by HPLC, the acid chloride was added. The reaction mixture was stirred at 45 °C for 8 hours. Once the reaction was complete by HPLC, the solvent was removed under vacuum, and the crude product was deposited on silica for column chromatography. The column was eluted with 0-7% MeOH in DCM, and the same fraction was collected and dried under vacuum. Yield: 0.240 g, 0.40 mmol, 79.23%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 13.157, LRMS ESI m / z 563.30 (M+1).

[0175] Example 32: 8-{6-[N-(ethyl)[4-fluorophenyl]carbonylamino]-3-pyridyl}-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-propylxanthine

[0176] In a 50 mL flask, Preparation Example J (0.240 g, 0.51 mmol) was combined with 4-fluorobenzoyl chloride (0.243 mL, 2.04 mmol) in dried pyridine (10 mL) and dried DCM (1.58 mL). The reaction mixture was stirred at 40 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added. The reaction mixture was stirred at 45 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added. The reaction mixture was stirred at 45 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting crude product was deposited onto silica using DCM / EtOH for column chromatography. The column was eluted with 0-7% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.243 g, 0.41 mmol, 80.22%. HPLC-MS conditions: 40%-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 14.481, LRMS ESI m / z 562.30 (M+1).

[0177] Example 33: 8-(6-{[(1-methyl-5-oxo-3-pyrrolidinyl)methyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-1-(3-methoxypropyl)-3-propylxanthine

[0178] In a 50 mL flask, Preparation Example K (0.150 g, 0.32 mmol) was combined with 4-fluorobenzoyl chloride (0.151 mL, 1.28 mmol) in dried pyridine (10 mL) and dried DCM (1.585 mL). The reaction mixture was stirred at 40 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added. The reaction mixture was stirred at 45 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added. The reaction mixture was stirred at 45 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting crude material was deposited onto silica using DCM / EtOH for column chromatography. The column was eluted with 0-7% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.145 g, 0.24 mmol, 76.59%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 13.918, LRMS ESI m / z 592.25 (M+1).

[0179] Example 34: 8-(6-{[(1-methyl-5-oxo-3-pyrrolidinyl)methyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-1-cyclopropyl-3-propylxanthine

[0180] In a 50 mL flask, preparation example L (0.150 g, 0.34 mmol) was combined with 4-fluorobenzoyl chloride (0.175 mL, 1.37 mmol) in dried pyridine (15 mL). The reaction mixture was stirred at 40 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. Water and pyridine were removed under vacuum, and the resulting oil was dissolved in DCM and purified by silica column chromatography. The column was eluted with 0-5% MeOH in DCM, and the same fraction was collected and dried under vacuum. Yield: 0.1533 g, 0.27 mmol, 79.90%. HPLC-MS conditions: 40-80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Hold for 5 minutes, Rt = 13.558, LRMS ESI m / z 560.30 (M+1).

[0181] Example 35: 8-(6-{[(1-methyl-5-oxo-3-pyrrolidinyl)methyl](4-fluorophenyl)carbonylamino}-3-pyridyl)-1,3-dicyclopropylxanthine

[0182] In a 50 mL flask, preparation example M (0.150 g, 0.43 mmol) was combined with 4-fluorobenzoyl chloride (0.194 mL, 1.7 mmol) in dried pyridine (10 mL) and dried DCM (1.585 mL). The reaction mixture was stirred at 40 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added. The reaction mixture was stirred at 45 °C for 24 hours. The completion of the reaction was confirmed by HPLC, and then the acid chloride was added again. The reaction mixture was stirred at 45 °C for 24 hours. Water (approximately 2 mL) was added to stop the reaction. The solvent was removed under vacuum, and the resulting crude material was deposited onto silica using DCM / EtOH for column chromatography. The column was eluted with 0-7% MeOH in DCM. A similar fraction was collected and dried under vacuum. Yield: 0.095 g, 0.16 mmol, 46.54%. HPLC-MS conditions: 40%~80% MeOH (0.1% formic acid) / H2O (0.1% formic acid) for 10 minutes. Retention for 5 minutes, Rt = 12.124, LRMS ESI m / z 558.25 (M+1).

[0183] Representative compounds described herein are A 2B Its activity as an antagonist was tested and demonstrated. The test compound was tested for A2B antagonism according to Cooper J, Hill SJ, Alexander SP. An endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK 293) cells. Br J Pharmacol. 1997 Oct;122(3):546-50. doi:10.1038 / sj.bjp.0701401. PMID:9351513;PMCID:PMC1564960.

[0184] Table 1: Inhibition rate (%) of NECA (5'-N-ethylcarboxamide adenosine) of representative compounds. At 100 nM or 111 nM 67%~100%=+++ 33%~67%=++ 1%~33%=+ [Table 3] TIFF0007862445000045.tif207162TIFF0007862445000046.tif198162TIFF0007862445000047.tif200162TIFF00078624450 00048.tif199162TIFF0007862445000049.tif206162TIFF0007862445000050.tif192162TIFF0007862445000051.tif138162

[0185] Further compounds described herein are shown in Table 2 below. These compounds can be prepared as compounds 1 to 35 described above.

[0186] [Table 4] TIFF0007862445000053.tif209162TIFF0007862445000054.tif219162TIFF0007862445000055.tif205162 TIFF0007862445000056.tif205162TIFF0007862445000057.tif206162TIFF0007862445000058.tif204162 TIFF0007862445000059.tif213162TIFF0007862445000060.tif207162TIFF0007862445000061.tif205162 TIFF0007862445000062.tif206162TIFF0007862445000063.tif203162TIFF0007862445000064.tif192162 TIFF0007862445000065.tif200162TIFF0007862445000066.tif208162TIFF0007862445000067.tif212162 TIFF0007862445000068.tif210162TIFF0007862445000069.tif214162TIFF0007862445000070.tif200162 TIFF0007862445000071.tif209162TIFF0007862445000072.tif207162TIFF0007862445000073.tif185162 TIFF0007862445000074.tif200162TIFF0007862445000075.tif205162TIFF0007862445000076.tif147162

[0187] All references listed herein are incorporated individually by reference in their entirety.

[0188] In consideration of the teachings described above, many modifications and variations of the present invention are possible. Therefore, it should be understood that the present invention may be carried out in ways other than those specifically described herein, within the scope of the appended claims.

Claims

1. Formula I: 【Chemistry 1】 A compound or stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein in the formula, n is selected from 2 to 4. Ring A is selected from phenyl, naphthyl, pyridyl, and pyrimidyl. R １ is selected from C １－６ alkyl, C ３－６ cycloalkyl, -(CH ２ ) ２ -OCH ３ , -(CH ２ ) ３ -OCH ３ , -(CH ２ ) ４ -OCH ３ , -(CH ２ ) ２ -NHC(O)CH ３ , and -C １－６ alkylene - 4- to 10-membered cyclic amide, R ２ C １－６ Alkyl and C ３－６ Selected from cycloalkyl groups, R ３ It is a 4-10 membered cyclic amide, R ４ H, F, Cl, Br, I, C １－６ Alkyl, OR ６ CF ３ Selected from, and OCF3, R ５ H, F, Cl, Br, I, C １－６ Selected from alkyl and OR6, R ６ These are H and C, independently. １－６ Selected from alkyl groups, Alternatively, R ４ and R ５ It does not exist, and ring A is CF ３ , and C ３－６ It is replaced by a group selected from cycloalkyl groups. Alternatively, -(CH ２ ) ｎ -R ３ is, -(CH ２ ) ２ - OCH ３ ,-(CH ２ ) ３ - OCH ３ , and - (CH ２ ) ４ - OCH ３ Selected from, however R １ (CH ２ ) ２ - NHC(O)CH ３ and -C １－６ An amide-containing group selected from alkylene-4 to 10-membered cyclic amides. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

2. n is selected from 2 to 4. Ring A is selected from phenyl, naphthyl, pyridyl, and pyrimidyl. R １ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -(CH ２ ) ２ - OCH ３ ,-(CH ２ ) ３ - OCH ３ ,-(CH ２ ) ４ - OCH ３ ,-(CH ２ ) ２ - NHC(O)CH ３ , 【Chemistry 2】 Selected from, R ２ However, C １－６ Alkyl and C ３－６ Selected from cycloalkyl groups, R ３ but, 【Transformation 3】 Selected from, R ４ But H, F, Cl, Br, I, C １－６ Alkyl, OR ６ CF ３ Selected from, and OCF3, R ５ But H, F, Cl, Br, I, C １－６ Selected from alkyl and OR6, R ６ However, independently, H and C １－６ Selected from alkyl groups, Alternatively, -(CH ２ ) ｎ -R ３ is selected from -(CH ２ ) ２ -OCH ３ , -(CH ２ ) ３ -OCH ３ , and -(CH ２ ) ４ -OCH ３ , provided that R １ is -(CH ２ ) ２ -NHC(O)CH ３ , 【Chemistry 4】 Selected from, The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

3. n is selected from 2 to 4. Ring A is selected from phenyl, pyridyl, and pyrimidyl. R １ is n-propyl, cyclopropyl, -(CH ２ ) ２ -OCH ３ , -(CH ２ ) ３ -OCH ３ , -(CH ２ ) ４ -OCH ３ , -(CH ２ ) ２ -NH(C(O)CH ３ , 【Transformation 5】 Selected from, R ２ However, it is selected from n-propyl and cyclopropyl, R ３ but, 【Transformation 6】 Selected from, R ４ However, H, F, Cl, C １－４ Alkyl, OR ６ CF ３ , and OCF ３ Selected from, R ５ However, H, F, Cl, C １－４ Selected from alkyl and OR6, R ６ However, independently, H and C １－４ Selected from alkyl groups, Alternatively, -(CH ２ ) ｎ -R ３ However, - (CH ２ ) ２ - OCH ３ ,-(CH ２ ) ３ - OCH ３ , and - (CH ２ ) ４ - OCH ３ Selected from, however R １ (CH ２ ) ２ - NHC(O)CH ３ , 【Transformation 7】 Selected from, The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

4. n is selected from 2 to 4. Ring A is selected from phenyl and pyridyl. R １ However, n-propyl, cyclopropyl, -(CH ２ ) ２ - OCH ３ ,-(CH ２ ) ３ - OCH ３ , 【Transformation 8】 Selected from, R ２ However, it is selected from n-propyl and cyclopropyl, R ３ but, 【Chemistry 9】 And, R ４ However, H, F, Cl, C １－４ Alkyl and OR ６ Selected from, R ５ However, selected from H and F, R ６ However, independently, H and C １－４ Selected from alkyl groups, Alternatively, -(CH ２ ) ｎ -R ３ However, - (CH ２ ) ２ - OCH ３ , and - (CH ２ ) ３ - OCH ３ Selected from, however R １ teeth, 【Chemistry 10】 Selected from, The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

5. n is selected from 2 to 3, Ring A is selected from phenyl and pyridyl. R １ However, n-propyl, cyclopropyl, -(CH ２ ) ２ - OCH ３ ,-(CH ２ ) ３ - OCH ３ , 【Chemistry 11】 Selected from, R ２ However, it is selected from n-propyl and cyclopropyl, R ３ but, 【Chemistry 12】 And, R ４ However, H, F, Cl, CH ３ cyclopropyl and OR ６ Selected from, R ５ However, selected from H and F, R ６ However, independently, H and CH ３ Selected from, Alternatively, -(CH ２ ) ｎ -R ３ However, - (CH ２ ) ２ - OCH ３ , and - (CH ２ ) ３ - OCH ３ Selected from, however R １ teeth, 【Chemistry 13】 Selected from, The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

6. R ３ but, 【Chemistry 14】 A compound according to claim 2, or a stereoisomer thereof or a pharmaceutically acceptable salt, selected from the above.

7. R ３ but, 【Chemistry 15】 A compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

8. R ３ but 【Chemistry 16】 The compound according to claim 4, or its stereoisomer or a pharmaceutically acceptable salt thereof.

9. R ３ but 【Chemistry 17】 The compound according to claim 5, or its stereoisomer or a pharmaceutically acceptable salt thereof.

10. Table 1: Table 1 A compound selected from the compounds, or its stereoisomer or a pharmaceutically acceptable salt thereof.

11. Table 2: Table 2 A compound selected from the compounds, or its stereoisomer or a pharmaceutically acceptable salt thereof.

12. Table 3: Table 3 A compound selected from the compounds, or its stereoisomer or a pharmaceutically acceptable salt thereof.

13. Table 4: Table 4 A compound selected from the compounds, or its stereoisomer or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. In the subject, adenosine A ２Ｂ A composition for use in treating receptor-associated conditions, comprising a compound according to any one of claims 1 to 13 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. The adenosine A ２Ｂ The composition according to claim 15, wherein the receptor-associated condition is selected from asthma, bronchoconstriction, chronic obstructive pulmonary disease, angiogenesis, pulmonary fibrosis, emphysema, allergy, allergic disease, autoimmune disease, inflammation, atherosclerosis, hypertension, congestive heart failure, retinopathy, diarrheal disease, insulin resistance, type 1 diabetes, type 2 diabetes, obesity, fatty liver, pain, wound healing, inflammatory gastrointestinal disorder, sickle cell disease, cancer, heart attack, diabetic retinopathy, hyperbaric oxygen-induced retinopathy, inhibition of angiogenesis in neoplastic tissue, gastrointestinal disorders, immune disorders, hypersensitivity disorders, neuropathy, and cardiovascular diseases resulting from both cell overgrowth and apoptosis.

17. The adenosine A ２Ｂ The composition according to claim 15, wherein the receptor-associated state is selected from asthma, insulin resistance, atherosclerosis, fatty liver disease, bladder cancer, and breast cancer.

18. The adenosine A ２Ｂ The composition according to claim 17, wherein the receptor-associated state is the human cell line MDA-MB-231 breast cancer.

19. An analgesic adjuvant comprising a compound or stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is administered in combination with an analgesic to a subject in need of pain relief.

20. The analgesic adjuvant according to claim 19, wherein the analgesic is an opioid or a nonsteroidal anti-inflammatory drug.

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