Compound as adenosine a2a receptor antagonist and pharmaceutical composition comprising same

Abstract

The present invention relates to a compound represented by formula 1 as an adenosine A2areceptor antagonist, stereoisomers thereof, pharmaceutically acceptable salts thereof, a method using the same, a medicinal use thereof, and a pharmaceutical composition including the same.

Description

[0001] DESCRIPTION Title of Invention COMPOUND AS ADENOSINE A2a RECEPTOR ANTAGONIST AND PHARMACEUTICAL COMPOSITION COMPRISING SAME Technical Field The present invention relates to a compound as an adenosine A2a receptor antagonist, stereoisomers thereof, pharmaceutically acceptable salts thereof, a medicinal use thereof, and a pharmaceutical composition including the same. Background Art Adenosine refers to a variety of biologically active modifiers in the cardiovascular system and the nervous system that regulate various functions through interactions with specific cell surface receptors. In addition, adenosine is an immunosuppressive metabolite produced at a high level in a tumor microenvironment, accumulates in tumors to promote the proliferation of the tumors, and also serves to mediate a tumor escape in the immune system by conferring resistance to the immune system, etc. The tumor microenvironment is one of the important regulators for immune functions that influence cancer progression and metastasis. In the tumor microenvironment, a high concentration of adenosine inhibits the responses of antitumor cytotoxic lymphocytes, and T cells inhibit actions thereof and express an adenosine A2a receptor (A2aR), which blocks the removal of tumors by immunity. The adenosine A2a receptor is one of A1, A2a, A2b and A3 receptors, which are four subtypes of a G-protein coupled receptor (GPCR) and is widely distributed in human tissues and highly expressed in striatum of the brain, immune cells, spleen, thymus, leukocytes, platelets, GABA-type neurons, olfactory bulbs and the like. At the same time, the adenosine A2a receptor is also expressed in other parts such as the heart, lungs, blood vessels, brain and the like, and exhibits high affinity for adenosine. The A2b receptor is also widely expressed, but mostly at a low level and less sensitive to adenosine. The A2a receptor has been a target of drugs for the treatment of Parkinson's disease and has recently been reported as a promising target for cancer immunotherapy. (J. Med. Chem.2020, 63, 21, 12196–12212) Basically, the immune cells of cancer patients develop resistance to cancer antigens and thus can recognize cancer cells, but are functionally inhibited, thus failing to effectively eliminate cancer cells. A key to immunotherapy is to wake up the immune cells that have fallen into resistance and induce them to become activated immune cells to destroy cancer cells. Such immunotherapy includes cytokine therapeutic agents such as interferon gamma, IL-2, etc., cancer vaccines using dendritic cells, cell therapy products using T cells, immune checkpoints of blocking immunosuppressive proteins, and the like. Immune checkpoint proteins are cell membrane proteins that inhibit the differentiation, proliferation, and activity of immune cells. This suggests that immune checkpoint proteins may be a good target for cancer treatment. Indeed, in several animal cancer models, it has been confirmed that blocking of CTLA4, PD1 and PDL1 with antibodies inhibits cancer growth and increases a survival rate. Such therapeutic effect is based on a mechanism by which an inhibitory signal of the immune checkpoint proteins is blocked and thus cancer-specific T cells are activated. Based on animal test results, many clinical trials have been designed and conducted, and it is known that a much higher therapeutic effect is shown than that of conventional anticancer drugs (Leone and Emens, Journal for ImmunoTherapy of Cancer (2018) 6:57). It is known that an A2a receptor antagonist may inhibit a key immunosuppressive pathway in the tumor microenvironment of certain cancers. It has been found that adenosine is more highly distributed in the tumor microenvironment of the certain cancers, unlike other normal tissues, and it has been announced that such overexpressed adenosine acts to weaken the core immune system centering on T cells (Cancer Cell, 2015 Apr 13:27(4): 435-436). According to a recent study, among the receptors of adenosine, the A2a receptor is particularly known as a major factor in influencing the overexpression of adenosine in the tumor microenvironment of certain cancers, and thus it has been reported that selective and appropriate blocking of this receptor may create a great synergy in anti-PD-1 immunotherapy (Cancer Immunol Res; 3 (5) May 2015; 506– 517). As such, blocking of the adenosine signaling pathway of the A2a receptor may reduce an inhibitory effect on the immune system and enhance the immune functions of T cells, and thus the adenosine A2a receptor antagonist is a promising negative mechanism capable of inhibiting tumor growth. Accordingly, the present inventors have invented a novel compound structure as an A2a receptor antagonist which selectively inhibits the adenosine A2a receptor, and have used the same to inhibit or treat adenosine A2a receptor-associated diseases, thereby completing the present invention. Related Art References Non-Patent Documents J. Med. Chem.2020, 63, 21, 12196–12212 Leone and Emens Journal for ImmunoTherapy of Cancer (2018) 6:57 Cancer Cell, 2015 Apr 13: 27 (4), 435-436 Cancer Immunol Res; 3 (5); 506–517 Disclosure of the Invention Technical Problem An object of the present invention is to provide a compound as an A2a receptor antagonist, stereoisomers thereof or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a pharmaceutical composition including a compound as an A2a receptor antagonist, stereoisomers thereof or pharmaceutically acceptable salts thereof. Still another object of the present invention is to provide a composition for treating or preventing adenosine A2a receptor-associated diseases, including a compound as an A2a receptor antagonist, stereoisomers thereof or pharmaceutically acceptable salts thereof. Still another object of the present invention is to provide a composition for treating or preventing cancer or inflammatory diseases, including a compound as an A2a receptor antagonist, stereoisomers thereof or pharmaceutically acceptable salts thereof. Still another object of the present invention is to provide a method for treating or preventing adenosine A2a receptor-associated diseases, including administering a therapeutically effective amount of said compound or the pharmaceutical composition including the compound. Still another object of the present invention is to provide a use for treating or preventing adenosine A2a receptor-associated diseases or a use of said compound for preparing a medicament. Technical Solution to Problem Hereinafter, the present invention will be described in more detail. In other words, all the combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited to the specific description below. Compound represented by formula 1 According to the objects, the compounds provided in the present invention may be as shown in (1) to (6) below. The present invention may provide a compound represented by formula 1 below, stereoisomers thereof or pharmaceutically acceptable salts thereof: (1) A compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof: [Formula 1] in formula 1, W1 is O or S; W2is N or CH; Z1 is CH or N; Z2is C or N; Z3 is N, O or S; and each independently represent a single bond or a double bond (when is a double bond, is a single bond, and when is a single bond, is a double bond); Q is C-R4 or N; R1 is H or -CH3; R2is H or C1-C5 alkyl, R3is H or -La-Ra, or R2and R3are linked to form a ring, in which La is a single bond or C1-C3 alkylene, Ra is C1-C5 alkyl, C3-C6 cycloalkyl, (a and b are each independently 1 or 2, W3is CH or N, W4is CH2 or O, in which if W3 is CH, then W4 is not CH2), phenyl or -phenylen-O-benzyl, and if Ra is C1-C5 alkyl or phenyl, then at least one of each H may be substituted with -OH or C1-C5 alkoxy; a ring formed by linking R2and R3is a 4- to 6-membered N-containing heterocycloalkyl (in which at least one H of the N-containing heterocycloalkyl may be each independently substituted with C1-C5 alkyl or OH), or a 6- to 8-membered N- containing spiroheterocycloalkyl; R4 is H or C1-C5 alkyl; R5is -NH-(CH2)y-Rb (in which y is any one integer of 1 to 3, and Rb is a 5- or 6- membered heterocycloalkyl including any one of O and N); (in which n is 0 or 1, and Rc, Rd, Re, Rfand Rgare each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rf and Rg may be linked to form CH2or CH2-CH2); (in which m and q are each independently anyone integer of 0 to 3, m and q may not be 0 at the same time, and Rjis H or halogen); (in which r, s, t and u are each independently 1 or 2);

[0002] in above R5, L1is a single bond or C1-C3 alkylene; L2 is a single bond, -C(=O)-, -C(=O)NH-, -C(=O)-N(C1-C5 alkyl)-, -C(=O)- NH(C1-C5 alkylene)-, -S(=O)2- or -S(=O)2-(C1-C3 alkylene)-; Rh is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C5 alkylene)-phenyl, -phenylen-O-(C1-C5 alkyl), -phenylen- C(=O), -phenylen-piperazinyl, 4- to 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N, O and S, 5- to 10-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N, O, and S, or -NR6R7; R6and R7are each independently C1-C5 alkyl or C1-C5 haloalkyl; and at least one H of Rh may be each independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen. In above formula 1, if Z2 is C, then and may not be a double bond at the same time, and may not be a single bond at the same time. In above formula 1, may be expressed as if is a double bond, but may be explicitly viewed as substantially the same as the structure expressed as considering a definition of a resonance structure. In above formula 1, if Z2 is C, the compounds represented by formulas 1a and 1b below may mean substantially the same compound. [Formula 1a] [Formula 1b] In above formula 1, a compound in which R2and R3are linked to form a ring may be represented by formula 1c below. [Formula 1c] In above formula 1c, Q represents C-R4 or N and a ring including Q and N represents a 4- to 6-membered N-containing heterocycloalkyl (in which at least one H of the N-containing heterocycloalkyl may be each independently substituted with C1- C5 alkyl or OH) or a 6- to 8-membered N-containing spiroheterocycloalkyl. In the present invention, “alkyl” may mean a straight or branched saturated hydrocarbon group unless otherwise specified and, for example, “C1-C5 alkyl” may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n- pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl, etc. In the present invention, “alkylene” may mean a divalent functional group derived from the above-defined alkyl (including both straight and branched) unless otherwise specified and, for example, “C1-C3 alkylene” may include methylene (-CH2-), ethylene(-CH2CH2-), n-propylene(-CH2CH2CH2-), isopropylene(-CH(CH3)-CH2-) etc. In the present invention, "hetero" may refer to a heteroatom or a heteroatomic group (that is, an atomic group containing a heteroatom) unless otherwise specified and may mean, for example, atoms such as oxygen (O), nitrogen (S), sulfur (S) and / or the like and an atomic group containing such a hetero atom. In the present invention, “heteroaryl” may mean a heterocycle in which at least one carbon of an aromatic functional group is substituted with a heteroatom unless otherwise specified and the heteroatom may be O, N or S. For example, heteroaryl may include furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, imidazolyl, triazolyl, triazinyl, pyridazinyl, pyrazinyl or the like, but is not limited thereto. In the present invention, "heterocycloalkyl" may mean a cyclic alkyl group in which at least one carbon constituting a ring is substituted with a heteroatom unless otherwise specified. The heteroatom may be, for example, O, N or S. For example, heterocycloalkyl may include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc., but is not limited thereto. In the present invention, “spiroheterocycloalkyl” may be a double ring including two rings sharing only one carbon, in which at least one of the two rings includes a heteroatom. The heteroatom may be, for example, O, N or S. When one of the two rings is an x-angled shape and the other is an y-angled shape (in which x and y are each an integer of 3 or more), it may be referred to as a (x+y-1)-membered spiroheterocycloalkyl. For example, spiroheterocycloalkyl may be a 7-membered 5- azaspiro[2,4]heptanyl. In the present invention, “haloalkyl” may mean a functional group in which at least one hydrogen is substituted with halogen in the alkyl group defined above. Examples of haloalkyl may include CF3, CF2H, CH2F, CH2CH2F, CH2CF3, C(CH3)2CF3, etc. In the present invention, “halogen” may be F, Cl, Br or I unless otherwise specified. (2) The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to above (1): In formula 1, W1, W2, Z1, Z2, Z3, Q, R1, R2, R3, R4, and are each the same as defined above, if W1is O, then W2is CH; if W1 is S, then W2 is N; R5 is -NH-(CH2)y-Rb(in which y is any one integer of 1 to 3, and Rbis a 5- or 6- membered heterocycloalkyl including O); in above R5, L1, L2 and Rh are each the same as defined above. (3) The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to above (1) or (2): In formula 1, W1, W2, Z1, Z2, Z3, and are each the same as defined above; Q is C-R4; R1 and R2 are each H; R3 is H or -La-Ra (in which La is a single bond or C1-C3 alkylene; Ra is C1-C5 alkyl, C3-C6 cycloalkyl, (a and b are each independently 1 or 2, W3 is CH or N, W4is CH2or O, in which if W3is CH, then W4is not CH2), phenyl or - phenylen-O-benzyl, and if Ra is C1-C5 alkyl or phenyl, then at least one of each H may be substituted with -OH or C1-C5 alkoxy; R4 is H or C1-C5 alkyl; R5is (in which n is 0 or 1, and Rc, Rd, Re, Rfand Rgare each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rf and Rg may be linked to form CH2or CH2-CH2); (in which m and q are each independently any one integer of 0 to 3, and Rj is H or halogen); (in which r, s, t and u are eachindependently 1 or 2); in above R5, L1 is a single bond or C1-C3 alkylene; L2is a single bond, -C(=O)- or -S(=O)2-; Rh is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C3-C6 cycloalkyl, phenoxy, phenyl, 5- or 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N and O, or 5- or 6-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N and S; and at least one H of Rhmay be each independently substituted with C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen. (4) The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to any one of above (1), (2), and (3): In formula 1, W1, W2, Z1, Z2, Z3, R1, and are each the same as defined above, Q is C-R4 or N; R2 and R3 are linked with each other to form 4- to 6-membered N-containing heterocycloalkyl (in which at least one H of the N-containing heterocycloalkyl may be each independently substituted with C1-C5 alkyl or OH), or a 6- to 8-membered N- containing spiroheterocycloalkyl; R4 is H or C1-C5 alkyl; R5is -NH-(CH2)y-Rb (in which y is any one integer of 1 to 3, and Rb is a 5- or 6- membered heterocycloalkyl including O); (in which n is 0 or 1, and Rc, Rd, Re, Rfand Rgare each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rf and Rg may be linked to form CH2 or CH2-CH2); (in which m and q are each independently anyone integer of 0 to 3, m and q may not be 0 at the same time, and Rj is H or halogen); (in which r, s, t and u are eachindependently 1 or 2); in above R5, L1is a single bond or C1-C3 alkylene; L2 is a single bond, -C(=O)-, -C(=O)NH-, -C(=O)-N(C1-C5 alkyl)-, -C(=O)- NH(C1-C5 alkylene)-, -S(=O)2- or -S(=O)2-(C1-C3 alkylene)-; Rh is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C3 alkylene)-phenyl, -phenylen-O-(C1-C5 alkyl), -phenylen- C(=O)-, -phenylen-piperazinyl, 4- to 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N, O and S, 5- to 10-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N, O, and S, , or -NR6R7; R6and R7are each independently C1-C5 alkyl or C1-C5 haloalkyl; and at least one H of Rh may be each independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen. (5) The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to any one of above (1), (2), (3), and (4), in which the compound may be at least one compound selected from the compounds shown in the table 1 below.

Table 1

[0003] (6) The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to any one of above (1), (2), (3), (4), and (5), in which the compound represented by above formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof may include example compounds 25, 26, 48, 90, 111, 223, 224, 294, 303, 353 or 371. In one embodiment, the compound represented by above formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof may include example compounds 4, 6, 10, 11, 13, 14, 17, 18, 32, 77, 123, 149, 150, 163, 164, 165, 166, 167 or 169. The present invention may provide a compound as an A2a receptor antagonist, stereoisomers thereof or pharmaceutically acceptable salts thereof may be at least one compound selected from the compounds shown in the table 1 above. In the present invention, “pharmaceutically acceptable salts” may mean the salts conventionally used in a pharmaceutical industry, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium and the like; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid and the like; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but types of salts meant in the present invention are not limited to those listed salts. In the present invention, “stereoisomer” may include a diastereomer and an optical isomer (enantiomer), in which the optical isomer may include not only an enantiomer, but also a mixture of the enantiomer and even a racemate. Such isomer may be separated by being split according to the related art, for example, column chromatography, HPLC or the like. Alternatively, a stereoisomer of each of the compound represented by formula 1 may be stereospecifically synthesized by using a known array of optically pure starting materials and / or reagents. In the present invention, the compound as an A2a receptor antagonist may be the same as the compound list in this specification, but also include a pharmaceutically acceptable isotopic-labeled compound in which at least one may be replaced with an atom having the same atomic number, but having an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes which may be included in the compound of the present invention may include:2H,3H, isotopes of hydrogen;11C,13C,14C, isotopes of carbon;36Cl, an isotope of chlorine;18F, an isotope of fluorine;123I,125I, isotopes of iodine;13N,15N, isotopes of nitrogen;15O,17O,18O, isotopes of oxygen;32P, an isotope of phosphorus;35S, an isotope of sulfur; and the like. A certain isotopic-labeled compound of the present invention, for example, a compound with radioactive isotopes incorporated, may be useful in studying drugs and / or a distribution of substrate tissues (e.g., assays). A radioactive isotope tritium, that is,3H, and carbon-14, that is,14C may be useful in view of ease of incorporation and means of immediate detection. Substitution with heavier isotopes, for example, substitution of hydrogen (1H) with deuterium (2H), may exhibit an excellent therapeutic effect on diseases by enhancing metabolic stability, such as increasing a half-life in vivo or reducing a dosage. Substitution with positron- emitting isotopes, for example,11C,15F,18F,15O,13N, etc., may be useful in studying positron emission tomography (PET) to examine a substrate receptor occupancy. An isotopic-labeled compound of the present invention may be generally prepared by conventional techniques known to those skilled in the art, by processes similar to those described in the reaction formulas and / or examples and preparation examples described in this specification, using an appropriate isotopic-labeled reagent instead of the non-labeled reagent as used in this specification. Compounds represented by formula 1 and compounds exemplified in this specification, may include isotopic- labeled compounds of these compounds, such as, but not limited to, compounds including deuterated and tritiated isotopes and all other isotopes discussed above. Method for preparing compound represented by formula 1 The present invention may provide a method for preparing a compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof. The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof may be prepared according to any one method of reaction formulas 1 to 10, which may be modified to a level apparent to those skilled in the art. In reaction formulas 1 to 10 below, R1to R7, Z1to Z3, W1to W4, Q, La, Ra to Rh, a, b, m, n, q, r, t, s, u, y, L1 and L2 may be each substantially the same as defined in formula 1, unless particularly defined. The “PG” may mean a protecting group and may include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or the like. [Reaction formula 1] According to above reaction formula 1, a compound of formula 1-1-1 (R5-H) may be reacted with formula 1-1-2 to prepare a compound of formula 1-1-3, after which a protecting group (PG) may be removed therefrom to prepare a compound of formula 1-1-4, which may be then subjected to a substitution reaction with a compound of formula 1-1-5, thereby preparing a compound of formula 1-1-6. In the present invention, examples of the compounds prepared according to the same method as shown in above reaction formula 1 may include example compounds 1 to 3, 7 to 16, 19, 20, 26 to 29, 37, 40, 41, 48, 55, 57 to 60, 65, 67, 78 to 81, 84, 87, 90 to 98, 107 to 110, 112 to 114, 118 to 128, 134 to 151, 162 to 178, 187 to 195, 199 to 203, 207 to 222, 231 to 236, 238 to 243, 246 to 251, 264, 281, 300 to 310, 321, 336, 338, 339, 346, 349 to 352, 361, 367, 375, 385 to 399, 401 or the like. [Reaction formula 2]

[0004] Above reaction formula 2 may show a synthesis method of a pyrazolidin-1- carboxamide compound, in which a compound of formula 1-1-1 and formula 1-2-1 may be subjected to a reaction to prepare a compound of formula 1-2-2, after which a protecting group may be removed therefrom, so as to prepare a compound of formula 1-2-3. After that, a compound of formula 1-2-4 may be prepared through a substitution reaction with a compound of formula 1-1-5. In the present invention, a compound prepared by the same method as shown in above reaction formula 2 may include example compound 353, etc. [Reaction formula 3] ĨIn above reaction formula 3, Ra may represent .) According to above reaction formula 3, a compound of formula 1-3-1 may be subjected to a methane sulfonylation reaction to obtain a compound of formula 1-3-2, which may be then subjected to a substitution reaction to prepare a compound of formula 1-3-3, after which a protecting group may be removed therefrom, so as to prepare a compound of formula 1-3-4. After that, a compound of formula 1-3-5 may be prepared through a substitution reaction with a compound of formula 1-1-5. In the present invention, the compounds prepared by the same method as shown in above reaction formula 3 may include example compounds 272, 273, etc. A compound of formula 1-1-1 represented by R5-H in each of above reaction formulas 1 and 2 may be prepared according to the methods described in reaction formulas 4a to 4c below and reaction formulas 5a, 5b, and 6 to 8 below. In other words, a compound of formula 1-1 represented by R5-H in each of above reaction formulas 1 and 2 may be a compound of formulas 1-4-7, 1-4-8, or 1-4-9 below, or may be a compound of formulas 1-5-5, 1-5-6, 1-6-3, 1-7-4, 1-7-5, or 1-8-3. [Reaction formula 4a] [Reaction formula 4b]

[0005] [Reaction formula 4c] According to reaction formulas 4a to 4c, a substituent (-L1-L2-Rh) may be introduced into a compound of formula 1-4-1, 1-4-2 or 1-4-3 to prepare a compound of formula 1-4-4, 1-4-5 or 1-4-6, after which a protecting group (PG, Boc) may be removed therefrom, so as to prepare a compound of formula 1-4-7, 1-4-8 or 1-4-9 as a compound of formula 1-1-1(R5-H). In the present invention, examples of compounds which may be synthesized according to a method as shown in above reaction formula 1 or 2 by using R5-H prepared by the same method as shown above reaction formulas 4a to 4c may include example compounds 30 to 32, 42, 44, 49 to 52, 56, 73 to 77, 85, 86, 88, 129, 152 to 161, 179 to 184, 185, 196, 197, 204 to 206, 223 to 230, 237, 244, 252 to 263, 265 to 271, 274 to 280, 287 to 299, 311 to 320, 323 to 329, 333 to 335, 337, 340 to 345, 347, 348, 354 to 360, 362 to 366, 368 to 373, 376 to 381, 383, 384, 392 to 394, 396 to 398, 403, 404 or the like. A substituent (-L1-L2-Rh) included in R5 in each of above reaction formulas 4a to 4c may be introduced into a ring including N by using a coupling reaction with a compound having a halide compound such as acid chloride, oxalyl chloride, sulfonyl chloride, carbonyl chloride, etc., or a leaving group such as o-toluenesulfonyl fluoride, etc., a Buchwald-Hartwig reaction, a ring opening reaction through amide coupling and epoxide hydrolysis, a reductive amidation reaction, etc. For example, an introduction may be made into a ring including N by an alkylation or arylation reaction using a halide compound having a structure of X-L1-L2-Rh (in which X is halogen). [Reaction formula 5a] [Reaction formula 5b] (Rx in above reaction formulas 5a and 5b may be each independently -C1-C7 alkylene-, and alkylene of Rx may mean a divalent substituent of straight or branched alkyl.) According to above reaction formulas 5a and 5b, a substituent may be introduced into a compound of formula 1-4-1 or 1-4-3 to prepare a hydroxy compound of formula 1-5-1 or 1-5-2, which may be then subjected to a fluorination reaction to prepare a compound of formula 1-5-3 or 1-5-4, after which a protecting group (PG, Boc) may be removed therefrom, so as to prepare a compound of formula 1-5-5 or 1-5-6 as a compound of formula 1-1-1 (R5-H). In the present invention, examples of compounds with R5 substituted as prepared by the same method as shown in above reaction formula 5a or 5b may include example compounds 43, 245, 322, 332, 374, 382, 395 or the like. [Reaction formula 6] According to above reaction formula 6, a substituent may be introduced into a compound of formula 1-4-1 to prepare an amide compound of formula 1-6-1, which may be then subjected to a reduction reaction to prepare a compound of formula 1-6- 2. A protecting group may be removed from the compound of formula 1-6-2 to prepare a compound of formula 1-6-3 as a compound of formula 1-1-1 (R5-H). In the present invention, examples of compounds which may be synthesized according to a method of above reaction formula 1 or 2 using R5-H prepared by the same method as shown in above reaction formula 6 may include example compounds 282 to 286, 330, 389 or the like. [Reaction formula 7] According to above reaction formula 7, amide may be introduced into a compound of formula 1-7-1 to prepare a compound of formula 1-7-2, which may be then subjected to a reduction reaction to prepare a compound of formula 1-7-3. A protecting group may be removed from the compound of formula 1-7-3, so as to prepare a compound of formula 1-7-4 as a compound of formula 1-1-1 (R5-H). And, a protecting group may be removed from the compound of formula 1-7-2, so as to prepare a compound of formula 1-7-5 as a compound of formula 1-1-1 (R5-H). In the present invention, examples of compounds which may be synthesized according to a method of above reaction formula 1 or 2 using R5-H prepared by the same method as shown in above reaction formula 7 may include example compounds 131 to 133, 331, 402, 406 or the like. [Reaction formula 8] According to above reaction formula 8, a compound of formula 1-8-2 may be prepared through a reductive amination reaction to a compound of formula 1-8-1. A protecting group (Boc) may be removed from a compound of formula 1-8-2, so as to prepare a compound of formula 1-8-3. In the present invention, examples of compounds which may be synthesized according to a method of above reaction formula 1 or 2 using R5-H prepared by the same method as shown in above reaction formula 8 may include example compounds 186, 390, 391, 400, 405 or the like. [Reaction formula 9] In above reaction formula 9, a compound of formula 1-9-1 and formula 1-9-2 may be subjected to a reaction to prepare a compound of formula 1-9-3, after which a protecting group (Cbz) may be removed from N of piperazine, so as to prepare a compound of formula 1-9-4. A substituent may be introduced into the compound of formula 1-9-4 to prepare a compound of formula 1-9-5, after which a protecting group (PG) may be removed from N of amine, so as to prepare a compound of formula 1-9- 6. After that, a compound of formula 1-1-6 may be prepared through a substitution reaction with a compound of formula 1-1-5. In the present invention, the compounds prepared by above reaction formula 9 may include example compounds 4 to 6, 17, 18, 21 to 25, 45 to 47, 61 to 64, 66, 68 to 72, 82, 89, 99 to 106, 111, 115 to 117, etc. [Reaction formula 10] In above reaction formula 10, a compound of formula 1-10-1 may be introduced into a compound of formula 1-1-5 to obtain a compound of formula 1-10-2, after which the compound of formula 1-10-2 and a compound of formula 1-10-3 may be subjected to a reaction, thereby preparing a compound of formula 1-1-6. In the present invention, the compounds prepared by above reaction formula 10 may include example compounds 53, 54, etc. Composition including compound represented by formula 1, use thereof and therapeutic method using the same The present invention may provide a pharmaceutical composition including a compound represented by above formula 1, compounds exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. In addition, the present invention may provide a pharmaceutical composition for treating or preventing A2a receptor-associated diseases, including a compound represented by above formula 1, compounds exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. The A2a receptor-associated diseases may be cancer or inflammatory diseases. The cancer may be at least one selected from lung cancer, stomach cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, kidney cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, head and neck cancer, blood cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, lymphoma, leukemia, myeloma, sarcoma and virus-associated cancer. The inflammatory disease may be at least one selected from rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, graft-versus-host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin-dependent diabetes. For administration, a pharmaceutical composition of the present invention may further include at least one type of a pharmaceutically acceptable carrier, in addition to the compound represented by above formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable carrier to be used herein may include saline solution, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and a mixture of at least one ingredient thereof, and with the addition of other conventional additives such as antioxidants, buffer solutions, bacteriostatic agents, etc., if needed. In addition, diluents, dispersing agents, surfactants, binders and lubricants may be further added to formulate injectable dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Thus, the composition of the present invention may be patches, liquid medicines, pills, capsules, granules, tablets, suppositories, etc. The preparations may be prepared according to a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and the composition may be formulated into various preparations depending on each disease or ingredient. The composition of the present invention may be orally or parenterally administered (for example, applied intravenously, hypodermically, intraperitoneally or locally) according to a targeted method, in which a dosage thereof may vary in a range thereof depending on a patient’s weight, age, gender, health condition and diet, an administration time, an administration method, an excretion rate, a severity of a disease and the like. The compound represented by formula 1 of the present invention may be administered once or several times a day by dividing the daily dosage of the compound, but is not necessarily limited thereto. In addition to the compound represented by above formula 1, the compound exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further include at least one ingredient which may exhibit the same or similar medicinal effects or may bring synergy to medicinal effects in combination. The present invention may provide a method for treating or preventing adenosine A2a receptor-associated diseases, including administering a therapeutically effective amount of the compound represented by above formula 1, the compound exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof; or a pharmaceutical composition including the same as an effective ingredient into a subject in need thereof. As used herein, the term “therapeutically effective amount” may refer to an amount of the compound, the compound exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof, which are effective in treating or preventing adenosine A2a receptor-associated diseases. The adenosine A2a receptor-associated diseases may be cancer or inflammatory diseases. In the present invention, the term “subject” may refer to mammals including humans, and the term “administration” may refer to providing a predetermined material to a subject through any appropriate method. It is apparent to those skilled in the art that the therapeutically effective dosage and the number of administration for effective ingredient of the present invention may vary depending on a desired effect. In the present invention, the term “prevention” may refer to a delay of occurrence of disease, disorder or condition. If the occurrence of disease, disorder or condition is delayed for an expected period of time, the prevention may be considered as complete. In the present invention, the term “treatment” may refer to the one that partially or completely reduces, ameliorates, alleviates, inhibits or delays the occurrence of a certain disease, disorder and / or condition, reduces a severity thereof, or reduces the occurrence of at least one symptom or property thereof. The present invention may also provide a use of the compound represented by formula 1, the compound exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof; or a pharmaceutical composition including the same as an effective ingredient for treating or preventing adenosine A2a receptor- associated diseases. The adenosine A2a receptor-associated diseases may be cancer or inflammatory diseases. The present invention may also provide a use of the compound represented by formula 1, the compound exemplified in this specification, stereoisomers thereof or pharmaceutically acceptable salts thereof; or a pharmaceutical composition including the same as an effective ingredient in preparing a medicament for treating or preventing adenosine A2a receptor-associated diseases. The adenosine A2a receptor- associated diseases may be cancer or inflammatory diseases. Matters mentioned in the composition, therapeutic method and use of the present invention are equally applied, if not contradictory to each other. Advantageous Effects of Invention A compound of the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof can exhibit an effective antagonistic activity against adenosine A2a receptors and can be advantageously used for treatment or prevention of adenosine A2a receptor-associated diseases. Mode for Invention Hereinafter, the present invention will be described in more detail through preparation examples and exemplary examples. However, the following preparation examples and exemplary examples are provided for the purpose of illustrating the present invention, and thus the present invention is not limited to the preparation examples and exemplary examples. Preparation of compound represented by formula 1 Each of the compounds according to the present invention was synthesized as follows. In order to prepare compounds according to the present invention, each of the reaction compounds used in each reaction was purchased from Sigma Aldrich (company name), etc., or was synthesized by using an organic synthesis method obvious to those skilled in the chemistry field, and was used without a separate purification process. The compounds of each example were identified through1H- NMR (Bruker, avance II 400) and Mass (Waters, SQD2) analysis. Example 1: Synthesis of compound 1, (S)-2-((7-amino-2-(furan-2-yl)- [1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-1-(4-methylpiperazin-1-yl)-3- phenylpropan-1-one [Step 1] Synthesis of tert-butyl (S)-(1-(4-methylpiperazin-1-yl)-1-oxo-3- phenylpropan-2-yl)carbamate (Tert-butoxycarbonyl)-L-phenylalanine (10.000 g, 37.692 mmol), 1- methylpiperazine (8.390 mL, 75.384 mmol), [dimethylamino(triazolo[4,5-b]pyridin- 3-yloxy)methylidene]-dimethylazanium, hexafluorophosphate (28.664 g, 75.384 mmol) and N,N-diisopropylethylamine (13.130 mL, 75.384 mmol) were dissolved in N,N-dimethylformamide (200 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which water was poured into the resulting concentrate and an organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 120 g cartridge; methanol / dichloromethane = 0 to 10%) and concentrated to obtain a title compound (10.000 g, 76.4%) as a white solid of a foam type. [Step 2] Synthesis of (S)-2-amino-1-(4-methylpiperazin-1-yl)-3- phenylpropan-1-one Tert-butyl (S)-(1-(4-methylpiperazin-1-yl)-1-oxo-3-phenylpropan-2- yl)carbamate (9.000 g, 25.902 mmol) prepared in step 1 and 2,2,2-trifluoroacetic acid (9.911 mL, 129.511 mmol) were dissolved in methanol (100 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Aqueous solution of 2N-sodium hydroxide was poured into the reaction mixture and an organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 3.500 g, 54.6%, white solid). [Step 3] Synthesis of (S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5- a][1,3,5]triazin-5-yl)amino)-1-(4-methylpiperazin-1-yl)-3-phenylpropan-1-one 2-(Furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7- amine (3.500 g, 12.488 mmol) prepared in step 2, (S)-2-amino-1-(4-methylpiperazin- 1-yl)-3-phenylpropan-1-one (3.089 g, 12.488 mmol) and triethylamine (3.481 mL, 24.977 mmol) were dissolved in dimethylsulfoxide (60 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and an organic layer was extracted with ethyl acetate. The organic layer was washed with water, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0 to 8%) and concentrated to obtain a title compound (3.000 g, 53.7%) as a white solid form. 1H NMR (400 MHz, Chloroform-d) δ 9.34 (s, 1H), 8.47 – 8.36 (m, 1H), 7.62 (s, 1H), 7.31 – 7.08 (m, 6H), 6.59 (s, 1H), 6.30 – 6.25 (m, 1H), 5.72 – 5.65 (m, 1H), 3.81 – 3.38 (m, 4H), 3.11 – 3.05 (m, 2H), 2.39 – 2.31 (m, 2H), 2.21 (s, 3H), 2.17 – 2.13 (m, 1H), 1.83 – 1.79 (m, 1H), 1.33 (s, 1H), 1.28 (s, 1H); LRMS (ES) m / z 488.4 Examples 2, 3, 13, 19, 20, 28 and 191 Example compounds 2, 3, 13, 19, 20, 28 and 191 were each prepared through substantially the same synthesis method as a synthesis method of example compound 1 except for using the compounds of the following table instead of 1-methylpiperazine as R5-H of above reaction formula 1 in step 1 of a synthesis method of example 1.

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

[0006] Example 303: Synthesis of compound 303, (S)-2-((7-amino-2-(furan- 2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-1-(4-(2-fluoro-2- methylpropyl)piperazin-1-yl)-3-methoxypropan-1-one [Step 1] tert-butyl (S)-(1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3- methoxy-1-oxopropan-2-yl)carbamate 1-(2-Fluoro-2-methylpropyl)piperazine (0.500 g, 3.120 mmol), N-(tert- butoxycarbonyl)-O-methyl-L-serine (1.368 g, 6.241 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 2.373 g, 6.241 mmol) and N,N-diisopropylethylamine (2.717 mL, 15.602 mmol) were dissolved in dichloromethane (15 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which saturated aqueous solution of sodium hydrogen carbonate solution was poured into the resulting concentrate and an organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 1.000 g, 88.7%, brown oil). [Step 2] (S)-2-amino-1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3- methoxypropan-1-one Tert-butyl (S)-(1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3-methoxy-1- oxopropan-2-yl)carbamate (0.200 g, 0.553 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in dioxane, 1.383 mL, 5.533 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which an obtained product was used without an additional purification process (title compound, 0.100 g, 69.2%, brown oil). [Step 3] (S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin- 5-yl)amino)-1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3-methoxypropan-1-one (S)-2-Amino-1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3- methoxypropan-1-one (0.100 g, 0.383 mmol) prepared in step 2, 2-(furan-2-yl)-5- (methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.054 g, 0.191 mmol) and sodium hydrogen carbonate (0.096 g, 1.148 mmol) were dissolved in acetonitrile (10 mL) at room temperature, after which the resulting solution was stirred at 70°C for 18 hours to complete the reaction by lowering a temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified via column chromatography (SiO2, 4 g cartridge; methanol / ethyl acetate = 0 to 10%) and concentrated to obtain a title compound (0.015 g, 8.5%) as a white solid form.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 7.88 (s, 1H), 7.46 (dd, J = 53.9, 8.2 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.68 (dd, J = 3.2, 1.7 Hz, 1H), 5.09 (dd, J = 14.2, 6.3 Hz, 1H), 3.73 – 3.39 (m, 6H), 3.27 (s, 3H), 2.62 – 2.34 (m, 6H), 1.32 (d, J = 21.5 Hz, 6H); LRMS (ES) m / z 462.5 (M++ 1). Examples 304, 305, 306, 399 and 401 Example compounds 304, 305, 306, 399 and 401 were each prepared through substantially the same synthesis method as a synthesis method of example compound 303 except for using the compounds of the following table instead of 1-(2- fluoro-2-methylpropyl)piperazine as R5-H of above reaction formula 1 in step 1.

Table 19

Table 20

Table 21

[0007] Examples 30 and 31 Example compounds 30 and 31 were each synthesized through substantially the same synthesis method as a synthesis method of example compound 44 except for using the compounds of the following table instead of tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-carboxylate of step 1 and using (tert-butoxycarbonyl)-L- alanine instead of (tert-butoxycarbonyl)-L-proline of step 3.

Table 22

Table 23

Table 24

Table 25

[0008] Example 277: Synthesis of compound 277, (S)-(1-(7-amino-2-(furan-2- yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)(4-(pyrimidin-2-yl)-1,4- diazepan-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(pyrimidin-2-yl)-1,4-diazepan-1- carboxylate 2-Chloropyrimidine (0.229 g, 1.999 mmol), tert-butyl 1,4-diazepan-1- carboxylate (0.400 g, 1.999 mmol) and potassium carbonate (0.829 g, 5.998 mmol) were dissolved in acetonitrile (10 mL) at room temperature, after which the resulting solution was stirred at 80°C for 18 hours to complete the reaction by lowering a temperature to room temperature. Water was poured into the reaction mixture and an organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium chloride, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0 to 30%) and concentrated to obtain a title compound (0.556 g, 99.9%) as a light yellow liquid form. [Step 2] Synthesis of 1-(pyrimidin-2-yl)-1,4-diazepane hydrochloride Tert-butyl 4-(pyrimidin-2-yl)-1,4-diazepain-1-carboxylate (0.556 g, 1.997 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 1.997 mL, 7.990 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for five hours. Solvent was removed from the reaction mixture under reduced pressure, after which an obtained product was used without an additional purification process (title compound, 0.215 g, 50.1%, white solid). [Step 3] Synthesis of tert-butyl (S)-2-(4-(pyrimidin-2-yl)-1,4-diazepan-1- carbonyl)pyrrolidin-1-carboxylate 1-(Pyrimidin-2-yl)-1,4-diazepane hydrochloride (0.214 g, 0.997 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.215 g, 0.997 mmol), 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 0.914 mL, 1.495 mmol) and N,N-diisopropylethylamine (0.694 mL, 3.987 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Aqueous solution of N-sodium hydrogen carbonate was poured into the reaction mixture, and then an organic layer was extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 0.3750 g, 100.0%, light yellow liquid). [Step 4] Synthesis of (S)-1-prolyl-4-(pyrimidin-2-yl)-1,4-diazepane hydrochloride Tert-butyl (S)-2-(4-(pyrimidin-2-yl)-1,4-diazepan-1-carbonyl)pyrrolidin-1- carboxylate (0.375 g, 0.999 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which an obtained product was used without an additional purification process (title compound, 0.311 g, 99.9%, white solid). [Step 5] Synthesis of (S)-(1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5- a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)(4-(pyrimidin-2-yl)-1,4-diazepan-1- yl)methanone (S)-1-Prolyl-4-(pyrimidin-2-yl)-1,4-diazepane hydrochloride (0.311 g, 0.997 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5- a][1,3,5]triazin-7-amine (0.280 g, 0.997 mmol) and sodium hydrogen carbonate (0.251 g, 2.992 mmol) were dissolved in acetonitrile (5 mL) at room temperature, after which the resulting solution was stirred at 70°C for 18 hours to complete the reaction by lowering a temperature to room temperature. The reaction mixture was filtered via a celite pad to remove a solid therefrom, after which solvent was removed from the resulting filtrate without the solid under reduced pressure. Then, the resulting concentrate was purified via column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol= 0 to 30%) and concentrated to obtain a title compound (0.109 g, 23.0%) as a white solid form. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 1.7, 0.8 Hz, 1H), 7.46 (brs, 2H), 7.06 (dd, J = 3.4, 0.6 Hz, 1H), 6.67 (dd, J = 3.4, 1.8 Hz, 1H), 5.59 (brs, 1H), 4.96 (brs, 1H), 3.79 – 3.38 (m, 5H), 2.79 (t, J = 14.1 Hz, 3H), 2.64 – 2.36 (m, 4H), 2.24 (s, 1H), 2.06 – 1.77 (m, 3H), 1.66 (t, J = 19.1 Hz, 3H); LRMS (ES) m / z 461.5 (M++ 1). Examples 328, 329 and 384 Example compounds 328, 329 and 384 were each synthesized through substantially the same synthesis method as a synthesis method of example compound 277 except for using the starting material 1 of the table below instead of 2- chloropyrimidine in step 1, using the starting material 2 of the table below instead of tert-butyl 1,4-diazepan-1-carboxylate, and using (S)-1-(tert-butoxycarbonyl)azetidin- 2-carboxylic acid instead of (tert-butoxycarbonyl)-L-proline in step 3.

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

[0009] Examples 376, 377, 378, 379, 393 and 394 Example compounds 376, 377, 378, 379, 393 and 394 were each synthesized through substantially the same synthesis method as a synthesis method of example compound 223 except for using 2,2-difluoroethyl trifluoromethanesulfonate of step 1 or starting material 1 of the table below, using (tert-butoxycarbonyl)-L-proline or Boc- protected amino acid of the table below, and using 2-(furan-2-yl)-7-(methylsulfonyl)- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine instead of 2-(furan-2-yl)-5-(methylsulfonyl)- [1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

Table 34

Table 35

[0010] Example 73: Synthesis of compound 73, 1-(4-((7-amino-2-(furan-2- yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)piperazin-1-yl)-3,3,3- trifluoropropan-1-one [Step 1] Synthesis of tert-butyl 4-(3,3,3-trifluoropropanoyl)piperazin-1- carboxylate 3,3,3-Trifluoropropanoic acid (0.500 g, 3.905 mmol) and N,N- dimethylformamide (0.003 mL, 0.039 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which oxalyl dichloride (0.335 mL, 3.905 mmol) was added into the resulting solution and stirred at the same temperature for one hour. To the resulting mixture, a solution obtained by dissolving tert-butyl piperazin-1- carboxylate (0.636 g, 3.413 mmol) and triethylamine (0.951 mL, 6.826 mmol) in dichloromethane (10 mL) at room temperature, was added and stirred at the same temperature for one hour. Water was poured into the reaction mixture and an orngaic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous solution of ammonium chloride, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 1.000 g, 98.9%, white solid). [Step 2] Synthesis of 3,3,3-trifluoro-1-(piperazin-1-yl)propan-1-one Tert-butyl 4-(3,3,3-trifluoropropanoyl)piperazin-1-carboxylate (1.000 g, 3.375 mmol) prepared in step 1 and hydrochloric acid (0.615 g, 16.875 mmol) were dissolved in dichloromethane (10 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which an obtained product was used without an additional purification process (title compound, 0.500 g, 75.5%, white solid). [Step 3] Synthesis of tert-butyl (S)-2-(4-(3,3,3- trifluoropropanoyl)piperazin-1-carbonyl)pyrrolidin-1-carboxylate 3,3,3-Trifluoro-1-(piperazin-1-yl)propan-1-one (0.500 g, 2.549 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (1.097 g, 5.098 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium; hexafluorophosphate (1.938 g, 5.098 mmol) and N,N-diisopropylethylamine (1.776 mL, 10.195 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and an organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 0.500 g, 49.9%, brown oil). [Step 4] (S)-3,3,3-trifluoro-1-(4-prolylpiperazin-1-yl)propan-1-one Tert-butyl (S)-2-(4-(3,3,3-trifluoropropanoyl)piperazin-1- carbonyl)pyrrolidin-1-carboxylate (0.200 g, 0.508 mmol) prepared in step 3 and hydrochloric acid (0.093 g, 2.542 mmol) were dissolved in dichloromethane (5 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which an obtained product was used without an additional purification process (title compound, 0.120 g, 80.5%, brown solid). [Step 5] 1-(4-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin- 5-yl)-L-prolyl)piperazin-1-yl)-3,3,3-trifluoropropan-1-one 2-(Furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7- amine (0.050 g, 0.178 mmol) prepared in step 4, (S)-3,3,3-trifluoro-1-(4- prolylpiperazin-1-yl)propan-1-one (0.105 g, 0.357 mmol) and triethylamine (0.099 mL, 0.714 mmol) were dissolved in dimethylsulfoxide (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified via chromatography (SiO2 plate, 20x20x1 mm; methanol / ethyl acetate = 10%) and concentrated to obtain a title compound (0.020 g, 22.7%) as a yellow solid form. 1H NMR (400 MHz, DMSO-d6) δ 8.64 – 8.09 (m, 1H), 7.87 (ddd, J = 5.5, 1.8, 0.8 Hz, 1H), 7.09 – 7.01 (m, 1H), 6.68 (ddd, J = 5.6, 3.4, 1.8 Hz, 1H), 5.09 – 4.92 (m, 1H), 3.88 – 3.39 (m, 12H), 2.36 – 2.19 (m, 1H), 2.04 – 1.78 (m, 3H); LRMS (ES) m / z 494.5 (M++ 1). Examples 74 to 77, 85 and 86 Example compounds 74 to 77, 85 and 86 were each synthesized through substantially the same synthesis method as a synthesis method of example compound 73 except for using the starting materials shown in the table below instead of 3,3,3- trifluoropropanoic acid in step 1.

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

[0011] Example 45: Synthesis of compound 45 Example compound 45 was synthesized through substantially the same synthesis method as a synthesis method of example compound 18 except for using tert- butyl (S)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate instead of tert-butyl (S)-(1- oxo-3-phenyl-1-(piperazin-1-yl)propan-2-yl)carbamate. Example 47: Synthesis of compound 47 Example compound 47 was synthesized through substantially the same synthesis method as a synthesis method of example compound 111 except for using tert-butyl (S)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate instead of tert-butyl (S)-2-(piperazin-1-carbonyl)azetidin-1-carboxylate. Example 66: Synthesis of compound 66 Example compound 66 was synthesized through substantially the same synthesis method as a synthesis method of example compound 111 except for using tert-butyl (S)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate instead of tert-butyl (S)-2-(piperazin-1-carbonyl)azetidin-1-carboxylate and using (1-bromoethyl)benzene instead of 1-bromobutane. Example 101: Synthesis of compound 101 Example compound 101 was synthesized through substantially the same synthesis method as a synthesis method of example compound 111 except for using tert-butyl (R)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate instead of tert-butyl (S)-2-(piperazin-1-carbonyl)azetidin-1-carboxylate. Analysis data of each of the compounds prepared as described above are shown in the table below.

Table 53

[0012] Example 61: Synthesis of compound 61, 4-((7-amino-2-(furan-2-yl)- [1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)-N-(m-tolyl)piperazin-1- carboxamide [Step 1] Tert-butyl (S)-2-(4-(m-tolylcarbamoyl)piperazin-1- carbonyl)pyrrolidin-1-carboxylate Tert-butyl (S)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate (0.300 g, 1.059 mmol) prepared in step 1 of example 64 and 1-isocyanato-3-methylbenzene (0.141 g, 1.059 mmol) were dissolved in diethyl ether (2 mL) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and then an organic layer was extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0 to 5%) and concentrated to obtain a title compound (0.198 g, 44.9%) as a white solid form. [Step 2] Synthesis of (S)-4-prolyl-N-(m-tolyl)piperazin-1-carboxamide Tert-butyl (S)-2-(4-(m-tolylcarbamoyl)piperazin-1-carbonyl)pyrrolidin-1- carboxylate (0.198 g, 0.475 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 0.594 mL, 2.377 mmol) were mixed, after which the resulting mixture was stirred at room temperature and stirred at the same temperature for 18 hours. Saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and then an organic layer was extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. An obtained product was used without an additional purification process (title compound, 0.098 g, 65.2%, light brown oil). [Step 3] Synthesis of 4-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5- a][1,3,5]triazin-5-yl)-L-prolyl)-N-(m-tolyl)piperazin-1-carboxamide 2-(Furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7- amine (0.050 g, 0.178 mmol) prepared in step 2, (S)-4-prolyl-N-(m-tolyl)piperazin-1- carboxamide (0.056 g, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) were dissolved in dimethylsulfoxide (1 mL) at room temperature, after which the resulting solution was stirred for 18 hours at the same temperature. Water was poured into the reaction mixture, and then an organic layer was extracted with dichloromethane, filtered via a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0 to 5%) and concentrated to obtain a title compound (0.017 g, 18.4%) as a white solid form. 1H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.45 (m, 1H), 7.27 – 7.20 (m, 1H), 7.21 – 7.11 (m, 3H), 7.08 – 6.91 (m, 1H), 6.90 – 6.83 (m, 1H), 6.55 – 6.47 (m, 1H), 6.10 (s, 0H), 5.03 – 4.81 (m, 1H), 3.97 – 3.36 (m, 10H), 2.32 (d, J = 8.8 Hz, 4H), 2.28 – 2.11 (m, 1H), 2.08 – 1.85 (m, 2H); LRMS (ES) m / z 517.2 (M++ 1). Example 100: Synthesis of compound 100 Example compound 100 was synthesized through substantially the same synthesis method as a synthesis method of example compound 61 except for using tert- butyl (R)-2-(piperazin-1-carbonyl)pyrrolidin-1-carboxylate instead of tert-butyl (S)-2- (piperazin-1-carbonyl)pyrrolidin-1-carboxylate and using isocyanatobenzene instead of 1-isocyanato-3-methylbenzene. Examples 62, 115, 116 and 117 Example compounds 62, 115, 116 and 117 were each synthesized through substantially the same synthesis method as a synthesis method of example compound 61 except for using the compounds of the following table instead of 1-isocyanato-3- methylbenzene as a starting material.

Table 54

Table 55

Table 56

Table 57

Table 58

Claims

WHAT IS CLAIMED IS:

1. A compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof: [Formula 1] wherein, W1 is O or S; W2is N or CH; Z1 is CH or N; Z2is C or N; Z3 is N, O or S; and each independently represent a single bond or a double bond (when is a double bond, is a single bond, and when is a single bond, is a double bond); Q is C-R4or N; R1 is H or -CH3; R2is H or C1-C5 alkyl, R3is H or -La-Ra, or R2and R3are linked to form a ring, in which La is a single bond or C1-C3 alkylene, Ra is C1-C5 alkyl, C3-C6 cycloalkyl, (a and b are each independently 1 or 2, W3is CH or N, W4is CH2 or O, in which if W3 is CH, then W4 is not CH2), phenyl or -phenylen-O-benzyl, and if Ra is C1-C5 alkyl or phenyl, then at least one of each H may be substituted with -OH or C1-C5 alkoxy; a ring formed by linking R2and R3is a 4- to 6-membered N-containing heterocycloalkyl (in which at least one H of the N-containing heterocycloalkyl may be each independently substituted with C1-C5 alkyl or OH), or a 6- to 8-membered N-containing spiroheterocycloalkyl; R4is H or C1-C5 alkyl; R5 is -NH-(CH2)y-Rb (in which y is any one integer of 1 to 3, and Rb is a 5- or 6- membered heterocycloalkyl including any one of O and N);(in which n is 0 or 1, and Rc, Rd, Re, Rf and Rg are each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rfand Rgmay be linked to form CH2 or CH2-CH2);(in which m and q are each independently anyone integer of 0 to 3, m and q may not be 0 at the same time, and Rj is H or halogen);(in which r, s, t and u are eachindependently 1 or 2);in above R5, L1 is a single bond or C1-C3 alkylene; L2is a single bond, -C(=O)-, -C(=O)NH-, -C(=O)-N(C1-C5 alkyl)-, -C(=O)- NH(C1-C5 alkylene)-, -S(=O)2- or -S(=O)2-(C1-C3 alkylene)-;Rh is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C5 alkylene)-phenyl, -phenylen-O-(C1-C5 alkyl), -phenylen- C(=O), -phenylen-piperazinyl, 4- to 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N, O and S, 5- to 10-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N, O, and S,or -NR6R7;R6and R7are each independently C1-C5 alkyl or C1-C5 haloalkyl; and at least one H of Rh may be each independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen.

2. The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein in formula 1, W1, W2, Z1, Z2, Z3, Q, R1, R2, R3, R4, and are each same as defined in claim 1; if W1is O, then W2is CH; if W1 is S, then W2 is N; R5is -NH-(CH2)y-Rb (in which y is any one integer of 1 to 3, and Rb is a 5- or 6- membered heterocycloalkyl including O);are each independently H or C1-C5 alkyl) or(in which m and q are each independently anyone integer of 0 to 3, m and q may not be 0 at the same time, and Rjis H or halogen);(in which r, s, t and u are eachindependently 1 or 2);in above R5, L1, L2and Rhare same as defined in claim 1.

3. The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein in formula 1, W1, W2, Z1, Z2, Z3, and are each same as defined in claim 1; Q is C-R4; R1and R2are each H; R3 is H or -La-Ra (in which La is a single bond or C1-C3 alkylene; Ra is C1-C5 alkyl, C3-C6 cycloalkyl, (a and b are each independently 1 or 2, W3 isCH or N, W4 is CH2 or O, in which if W3 is CH, then W4 is not CH2), phenyl or - phenylen-O-benzyl, and if Ra is C1-C5 alkyl or phenyl, at least one of each H may be substituted with -OH or C1-C5 alkoxy; R4 is H or C1-C5 alkyl; R5is(in which n is 0 or 1, and Rc, Rd, Re, Rf and Rg are each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rfand Rgmay be linked to form CH2 or CH2-CH2);(in which m and q are each independently anyone integer of 0 to 3, and Rj is H or halogen);(in which r, s, t and u are eachL1is a single bond or C1-C3 alkylene; L2 is a single bond, -C(=O)- or -S(=O)2-; Rhis H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C3-C6 cycloalkyl, phenoxy, phenyl, 5- or 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N and O, or 5- or 6-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N and S; and at least one H of Rhmay be each independently substituted with C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen.

4. The compound represented by formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1, wherein in formula 1, W1, W2, Z1, Z2, Z3, R1, and are each same as defined in claim 1; Q is C-R4or N; R2 and R3 are linked with each other to form 4- to 6-membered N-containing heterocycloalkyl (in which at least one H of the N-containing heterocycloalkyl may be each independently substituted with C1-C5 alkyl or OH), or a 6- to 8-membered N- containing spiroheterocycloalkyl; R4 is H or C1-C5 alkyl; R5is -NH-(CH2)y-Rb (in which y is any one integer of 1 to 3, and Rb is a 5- or 6- membered heterocycloalkyl including O);(in which n is 0 or 1, and Rc, Rd, Re, Rfand Rgare each independently H or C1-C5 alkyl, but two selected from Rc, Rd, Re, Rfand Rgmay be linked to form CH2 or CH2-CH2); (in which m and q are each independently anyone integer of 0 to 3, m and q may not be 0 at the same time, and Rj is H or halogen);(in which r, s, t and u are eachindependently 1 or 2);in above R5, L1is a single bond or C1-C3 alkylene; L2 is a single bond, -C(=O)-, -C(=O)NH-, -C(=O)-N(C1-C5 alkyl)-, -C(=O)- NH(C1-C5 alkylene)-, -S(=O)2- or -S(=O)2-(C1-C3 alkylene)-; Rh is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C3 alkylene)-phenyl, -phenylen-O-(C1-C5 alkyl), -phenylen- C(=O)-, -phenylen-piperazinyl, 4- to 6-membered heterocycloalkyl including 1 to 3 heteroatoms of at least one selected from N, O and S, 5- to 10-membered heteroaryl including 1 to 3 heteroatoms of at least one selected from N, O, and S,R6 and R7 are each independently C1-C5 alkyl or C1-C5 haloalkyl; and at least one H of Rh may be each independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen.

5. A compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound is any one selected from the group consisting of compounds below:

6. The compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 5, wherein the compound is any one selected from the group consisting of compounds below:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for treating or preventing adenosine A2a receptor- associated diseases.

9. The pharmaceutical composition according to claim 8, wherein the adenosine A2a receptor-associated diseases are cancer or inflammatory diseases.

10. The pharmaceutical composition according to claim 9, wherein the cancer is at least one selected from lung cancer, stomach cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, kidney cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, head and neck cancer, blood cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, lymphoma, leukemia, myeloma, sarcoma and virus-associated cancer.

11. The pharmaceutical composition according to claim 9, the inflammatory disease is at least one selected from rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, graft-versus-host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin-dependent diabetes.

12. A method for treating or preventing adenosine A2a receptor-associated diseases, the method administering an effective amount of the compound according to any one of claims 1 to 6, stereoisomers thereof or pharmaceutically acceptable salts thereof.

13. A use of the compound according to any one of claims 1 to 6, stereoisomersthereof or pharmaceutically acceptable salts thereof for treating or preventing adenosine A2a receptor-associated diseases.

14. A use of the compound according to any one of claims 1 to 6, stereoisomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for treating or preventing adenosine A2a receptor-associated diseases.

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