Compounds as adenosine A2a receptor antagonists and pharmaceutical compositions containing the same

Abstract

The present invention relates to compounds of formula 1 as adenosine A2a receptor antagonists, their stereoisomers, their pharma- ceutically acceptable salts, their methods of use, their medicinal uses and pharmaceutical compositions containing them. <Chemical formula 1> JPEG2024515739000466.jpg29150

Description

[Technical field]

[0001] The present invention relates to compounds as adenosine A2a receptor antagonists, their stereoisomers, their pharma- ceutically acceptable salts, their medical use and pharmaceutical compositions containing them. [Background technology]

[0002] Adenosine is a versatile physiological regulator of the cardiovascular and nervous systems, regulating various functions through interaction with specific cell surface receptors. Adenosine is also an immunosuppressive metabolite produced at high levels in the tumor microenvironment, which accumulates in tumors to promote tumor growth, while also mediating tumor evasion by conferring resistance to the immune system. The tumor microenvironment is one of the key regulators of immune function that influences cancer progression and metastasis. High adenosine concentrations in the tumor microenvironment suppress the response of antitumor cytotoxic lymphocytes, and T cells express adenosine A2a receptors (A2aR), which inhibit their action and block tumor elimination by the immune system.

[0003] Adenosine A2a receptors are one of the four subtypes of G protein-coupled receptors (GPCRs), A1, A2a, A2b and A3 receptors. They are widely distributed in human tissues and are highly expressed in the striatum, immune cells, spleen, thymus, leukocytes, platelets, GABA-type neurons and olfactory bulbs. At the same time, adenosine A2a receptors are also expressed in the heart, lungs, blood vessels and brain, and show high affinity for adenosine. A2b receptors are also widely expressed, but most of them are at low levels and are not very sensitive to adenosine. A2a receptors are targeted by drugs to treat Parkinson's disease and have been reported as promising targets for cancer immunotherapy in recent years (J.Med.Chem.2020,63,21,12196-12212).

[0004] Basically, the immune cells of cancer patients have become resistant to cancer antigens, and although they can recognize cancer cells, they are functionally suppressed and cannot effectively remove the cancer cells. The core of immunotherapy is to awaken the resistant immune cells and induce them to become activated immune cells to destroy the cancer cells. Such immunotherapy includes cytokine therapeutics such as interferon-gamma and IL-2, cancer vaccines using dendritic cells, cell therapy using T cells, and immune checkpoints that block immunosuppressive proteins.

[0005] Immune checkpoint proteins, as cell membrane proteins, inhibit the differentiation, proliferation, and activity of immune cells. Therefore, it is suggested that immune checkpoint proteins may be good targets for cancer therapy. In fact, in several animal cancer models, it was confirmed that when CTLA4, PD1, and PDL1 were blocked with antibodies, cancer proliferation was suppressed and survival rates increased. These therapeutic effects are explained as a mechanism in which the inhibitory signals of immune checkpoint proteins are blocked and cancer-specific T cells are activated. Many clinical trials have been designed and conducted based on the results of such animal experiments, and it is known that they show a much higher therapeutic effect than conventional anticancer drug treatments (Leone and Emens, Journal for ImmunoTherapy of Cancer (2018) 6: 57).

[0006] It is known that A2a receptor antagonists can inhibit the main immunosuppressive pathway in the tumor microenvironment of certain cancers. It has been found that the distribution of adenosine is higher in the tumor microenvironment of certain cancers than in other normal tissues, and it has been reported that such overexpressed adenosine acts to weaken the core immune system, centered on T cells (Cancer Cell, 2015 Apr 13:27(4):435-436).

[0007] Recent studies have shown that adenosine receptors, particularly the A2a receptor, are known to be major factors influencing the overexpression of adenosine in the tumor microenvironment of certain cancers, and therefore selective and appropriate blocking of this receptor can produce significant synergistic effects in anti-PD-1 immunotherapy (Cancer Immunol Res;3(5) May 2015;506-517).

[0008] Thus, blocking the adenosine signaling pathway of the A2a receptor can reduce the suppressive effect on the immune system and improve the immune function of T cells, making adenosine A2a receptor antagonists a promising negative mechanism for suppressing tumor growth. Therefore, the inventors have invented a novel compound structure as an A2a receptor antagonist that selectively inhibits the adenosine A2a receptor, and have completed the present invention by using this to inhibit or treat adenosine A2a receptor-related diseases. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] J.Med.Chem.2020,63,21,12196-12212 [Non-Patent Document 2] Leone and Emens Journal for ImmunoTherapy of Cancer(2018)6:57 [Non-Patent Document 3] Cancer Cell,2015 Apr 13:27(4),435-436 [Non-Patent Document 4] Cancer Immunol Res;3(5);506-517 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a compound, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof as an A2a receptor antagonist. Another object of the present invention is to provide a pharmaceutical composition comprising a compound, its stereoisomer or a pharma- ceutically acceptable salt thereof as an A2a receptor antagonist.

[0011] Another object of the present invention is to provide a composition for treating or preventing adenosine A2a receptor-related diseases, comprising a compound as an A2a receptor antagonist, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

[0012] Another object of the present invention is to provide a composition for treating or preventing cancer or an inflammatory disease, comprising a compound as an A2a receptor antagonist, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

[0013] Another object of the present invention is to provide a method for the treatment or prevention of adenosine A2a receptor-associated diseases, comprising administering a therapeutically effective amount of said compound or a pharmaceutical composition containing said compound.

[0014] Another object of the present invention is to provide a use of said compounds for the treatment or prevention of adenosine A2a receptor related diseases or for the manufacture of a medicament. [Means for solving the problem]

[0015] The present invention will be described in more detail below. All combinations of the various elements disclosed in the present invention are within the scope of the present invention. In addition, the following specific description should not be construed as limiting the scope of the present invention.

[0016] Compound represented by chemical formula 1 In accordance with the above-mentioned object, the compounds provided by the present invention can be represented by the following (1) to (6). The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0017] (1) A compound represented by chemical formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] JPEG2024515739000002.jpg36150In the above Chemical Formula 1, W1 is O or S; W2 is N or CH; Z1 is CH or N; Z2 is C or N; Z3 is N, O or S; JPEG2024515739000003.jpg6150Each independently represents a single bond or a double bond. JPEG2024515739000004.jpg6150 is a single bond, JPEG2024515739000005.jpg6150 double bond); Q is C-R4 or N; R1 is H or -CH3; R2 is H or C1-C5 alkyl and R3 is H or -La-Ra, or R2 and R3 are linked to form a ring; Wherein, La is a single bond or C1-C3 alkylene, Ra is C1-C5 alkyl, C3-C6 cycloalkyl, JPEG2024515739000006.jpg21150 (a and b are each independently 1 or 2, W3 is CH or N, and W4 is CH2 or O, provided that when W3 is CH, W4 is not CH2), phenyl or -phenylene-O-benzyl, and when Ra is C1-C5 alkyl or phenyl, at least one or more of the H in each of these may be substituted with -OH or C1-C5 alkoxy; The ring formed by combining R2 and R3 is a 4- to 6-membered N-containing heterocycloalkyl (wherein at least one or more H of the N-containing heterocycloalkyl may be independently replaced by C1-C5 alkyl or OH), or a 6- to 8-membered N-containing spiroheterocycloalkyl; R4 is H or C1-C5 alkyl; R5 is, -NH-(CH2) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing either O or N; TIFF2024515739000007.tif3049 (where n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , R f and R g two selected from may be linked to form CH2 or CH2-CH2); TIFF2024515739000008.tif1951 (where m and q are each independently an integer between 0 and 3, and m and q are not both 0; R j is H or a halogen); TIFF2024515739000009.tif1958 (where r, s, t and u are each independently 1 or 2); TIFF2024515739000010.tif70150 In the R5, L1 is 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)-; R h represents H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C5 alkylene)-phenyl, -phenylene-O-(C1-C5 alkyl), -phenylene-C(=O), -phenylene-piperazinyl, 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms of one or more selected from N, O and S, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms of one or more selected from N, O and S, TIFF2024515739000011.tif26150 or -NR6R7; R6 and R7 are each independently C1-C5 alkyl or C1-C5 haloalkyl; R h One or more H may be independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH, or halogen. In the above formula 1, when Z2 is C, TIFF2024515739000012.tif6150It is never a double bond and a single bond at the same time.

[0018] In the above Chemical Formula 1, JPEG2024515739000013.jpg20150 JPEG2024515739000014.jpg20150By definition of resonance structure It is obvious that this can be regarded as being substantially similar to the structure shown in TIFF2024515739000015.tif1515.

[0019] In the above Chemical Formula 1, when Z2 is C, the compounds represented by the following Chemical Formulas 1a and 1b are substantially the same compounds. [Chemical formula 1a] TIFF2024515739000016.tif3674[Formula 1b] TIFF2024515739000017.tif3577 In Chemical Formula 1, a compound in which R2 and R3 are linked to form a ring can be represented by Chemical Formula 1c below. [Chemical formula 1c] TIFF2024515739000018.tif3078 In the above chemical formula 1c, Q represents C-R4 or N, and the ring containing Q and N represents a 4- to 6-membered N-containing heterocycloalkyl (wherein at least one or more H of the N-containing heterocycloalkyl may be independently replaced by C1-C5 alkyl or OH), or a 6- to 8-membered N-containing spiroheterocycloalkyl.

[0020] In the present invention, unless otherwise specified, "alkyl" means a straight or branched chain saturated hydrocarbon group, 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, and the like.

[0021] In the present invention, unless otherwise specified, "alkylene" means a divalent functional group derived from alkyl (including both straight and branched chains) as defined above, for example, "C1-C3 alkylene" may include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)-CH2-), etc.

[0022] In the present invention, unless otherwise specified, "hetero" refers to a heteroatom or a heteroatom group (i.e., an atomic group containing a heteroatom), and may refer to, for example, atoms such as oxygen (O), nitrogen (S) and / or sulfur (S), as well as atomic groups containing these heteroatoms.

[0023] In the present invention, unless otherwise specified, "heteroaryl" refers to a heterocycle in which at least one or more carbons of an aromatic functional group are replaced with a heteroatom, and the heteroatom may be O, N, or S. For example, heteroaryl includes, but is not limited to, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, imidazolyl, triazolyl, triazinyl, pyridazinyl, or pyrazinyl.

[0024] In the present invention, unless otherwise specified, "heterocycloalkyl" refers to a cyclic alkyl group in which at least one or more carbons forming the ring are replaced with a heteroatom. The heteroatom may be, for example, O, N or S. For example, heterocycloalkyl includes, but is not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0025] In the present invention, a "spiroheterocycloalkyl" is a bicyclic ring containing two rings that share only one carbon, and at least one of the two rings contains a heteroatom. The heteroatom may be, for example, O, N, or S. When one of the two rings is x-sided and the other is y-sided (where x and y are each an integer of 3 or more), it is called a (x+y-1)-membered spiroheterocycloalkyl. For example, the spiroheterocycloalkyl may be a 7-membered 5-azaspiro[2,4]heptanyl.

[0026] In the present invention, "haloalkyl" refers to a functional group in which at least one hydrogen in the alkyl group defined above is replaced with a halogen. Examples of haloalkyl include CF3, CF2H, CH2F, CH2CH2F, CH2CF3, and C(CH3)2CF3.

[0027] In the present invention, a "halogen" may be F, Cl, Br or I, unless otherwise specified.

[0028] (2) A compound represented by the chemical formula 1 according to (1), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: In Chemical Formula 1, W1, W2, Z1, Z2, Z3, Q, R1, R2, R3, R4, TIFF2024515739000019.tif13150, each of which is as defined above. When W1 is O, W2 is CH; When W1 is S, W2 is N; R5 is, -NH-(CH2) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing O; TIFF2024515739000020.tif26150 TIFF2024515739000021.tif32150 (where n is 0 or 1, R c , R e , R f and R g are each independently H or C1-C5 alkyl) or TIFF2024515739000022.tif2538; TIFF2024515739000023.tif1746 (where m and q are each independently an integer between 0 and 3, and m and q are not both 0; R j is H or a halogen); TIFF2024515739000024.tif2060 (where r, s, t and u are each independently 1 or 2); Could be TIFF2024515739000025.tif64150; In the above R5, L1, L2 and R h are the same as defined above.

[0029] (3) A compound represented by the chemical formula 1 according to (1) or (2), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: In Chemical Formula 1, W1, W2, Z1, Z2, Z3, TIFF2024515739000026.tif13150, each as defined above; Q is C-R4; R1 and R2 are each H; R3 is H or -La-Ra, where La is a single bond or C1-C3 alkylene; Ra is C1-C5 alkyl, C3-C6 cycloalkyl, TIFF2024515739000027.tif20150 (a and b are each independently 1 or 2, W3 is CH or N, and W4 is CH2 or O, provided that when W3 is CH, W4 is not CH2), phenyl, or -phenylene-O-benzyl, and when Ra is C1-C5 alkyl or phenyl, at least one or more of the H in each of these may be substituted with -OH or C1-C5 alkoxy); R4 is H or C1-C5 alkyl; R5 is, TIFF2024515739000028.tif2943 (where n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , Rf and R g two selected from may be linked to form CH2 or CH2-CH2); TIFF2024515739000029.tif1543 (where m and q are each independently an integer of 0 to 3, R j is H or a halogen); TIFF2024515739000030.tif1652 (where r, s, t and u are each independently 1 or 2); Could be TIFF2024515739000031.tif20150; In the above R5, L1 is a single bond or C1-C3 alkylene; L2 is a single bond, -C(=O)- or -S(=O)2-; R h is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C3-C6 cycloalkyl, phenoxy, phenyl, a 5- or 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N and O, or a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and S; R h At least one H may be independently substituted with C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen.

[0030] (4) A compound represented by formula 1 according to any one of (1), (2) and (3), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein the compound is In Chemical Formula 1, W1, W2, Z1, Z2, Z3, R1, TIFF2024515739000032.tif13150, each of which is as defined above. Q is C-R4 or N; R2 and R3 combine together to form a 4- to 6-membered N-containing heterocycloalkyl (wherein at least one or more H of said N-containing heterocycloalkyl may each be independently replaced with C1-C5 alkyl or OH), or a 6- to 8-membered N-containing spiroheterocycloalkyl; R4 is H or C1-C5 alkyl; R5 is, -NH-(CH2) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing O; TIFF2024515739000033.tif3046 (where n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , R f and R g two selected from may be linked to form CH2 or CH2-CH2); TIFF2024515739000034.tif1949 (where m and q are each independently an integer between 0 and 3, and m and q are not both 0; R j is H or a halogen); TIFF2024515739000035.tif1751 (where r, s, t and u are each independently 1 or 2); TIFF2024515739000036.tif64150 In the R5, L1 is 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)-; R h represents H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C3 alkylene)-phenyl, -phenylene-O-(C1-C5 alkyl), -phenylene-C(=O)-, -phenylene-piperazinyl, 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms of one or more selected from N, O and S, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms of one or more selected from N, O and S, TIFF2024515739000037.tif26150 or -NR6R7; R6 and R7 are each independently C1-C5 alkyl or C1-C5 haloalkyl; R h At least one H may be independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH, or halogen.

[0031] (5) A compound represented by chemical formula 1 according to any one of (1), (2), (3) and (4), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein the compound may be one or more compounds selected from the compounds shown in Table 1 below. [Table 1]

[0032] JPEG2024515739000039.jpg229158

[0033] JPEG2024515739000040.jpg212158

[0034] JPEG2024515739000041.jpg223158

[0035] JPEG2024515739000042.jpg223158

[0036] JPEG2024515739000043.jpg223158

[0037] JPEG2024515739000044.jpg220158

[0038] JPEG2024515739000045.jpg231158

[0039] JPEG2024515739000046.jpg217158

[0040] JPEG2024515739000047.jpg235158

[0041] JPEG2024515739000048.jpg217158

[0042] JPEG2024515739000049.jpg237158

[0043] JPEG2024515739000050.jpg223158

[0044] JPEG2024515739000051.jpg223158

[0045] JPEG2024515739000052.jpg223158

[0046] JPEG2024515739000053.jpg221158

[0047] JPEG2024515739000054.jpg223158

[0048] JPEG2024515739000055.jpg214158

[0049] JPEG2024515739000056.jpg199158

[0050] JPEG2024515739000057.jpg210158

[0051] JPEG2024515739000058.jpg199158

[0052] JPEG2024515739000059.jpg199158

[0053] JPEG2024515739000060.jpg227158

[0054] JPEG2024515739000061.jpg127158

[0055] (6) A compound represented by chemical formula 1 according to any one of (1), (2), (3), (4) and (5), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein the compound represented by chemical formula 1, a stereoisomer thereof or a pharma-ceutically acceptable salt thereof may include Example compounds 25, 26, 48, 90, 111, 223, 224, 294, 303, 353 or 371.

[0056] In one embodiment, the compound represented by Formula 1, its stereoisomer, or its pharma- ceutically acceptable salt may include Example compounds 4, 6, 10, 11, 13, 14, 17, 18, 32, 77, 123, 149, 150, 163, 164, 165, 166, 167, or 169.

[0057] The compound, stereoisomer or pharma- ceutically acceptable salt thereof as the A2a receptor antagonist of the present invention may be one or more compounds selected from the compounds shown in Table 1 above.

[0058] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt commonly used in the pharmaceutical industry, and includes, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc., inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid, etc., 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, asparagine, etc. Examples of suitable salts include organic acid salts produced from, for example, carboxylic acid, vanillic acid, hydroiodic acid, etc.; sulfonate salts produced from, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; amino acid salts produced from, for example, glycine, arginine, and lysine; and amine salts produced from, for example, trimethylamine, triethylamine, ammonia, pyridine, and picoline, but the types of salts meant in the present invention are not limited to these listed salts.

[0059] In the present invention, "stereoisomers" include partial stereoisomers and optical isomers, and optical isomers include not only enantiomers but also mixtures of enantiomers and racemates. These isomers can be separated by conventional techniques, such as resolution by column chromatography or HPLC. Alternatively, each stereoisomer of the compounds of formula 1 can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence.

[0060] The compounds of the present invention as A2a receptor antagonists include pharma- ceutically acceptable isotopically labeled compounds similar to those listed herein, but with at least one atom having the same atomic number but a different atomic mass or mass number from the naturally predominant atomic mass or mass number. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen. 2 H,3 H; an isotope of carbon 11 C. 13 C. 14 C; an isotope of chlorine 36 Cl; an isotope of fluorine 18 F; an isotope of iodine 123 I, 125 I; Nitrogen isotope 13 N, 15 N; an isotope of oxygen 15 O. 17 O. 18 O; isotope of phosphorus 32 P; and sulfur isotopes 35 Certain isotopically-labeled compounds of the invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution assays (e.g., assays). The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for its ease of incorporation and ready means of detection. Heavier isotopes, such as hydrogen ( 1 H) deuterium ( 2 H) can show excellent therapeutic effects by improving metabolic stability, such as extending the half-life in vivo and reducing the dosage. 11 C. 15 F, 18 F, 15 O. 13 Substitutions such as N are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of ordinary skill in the art or by processes similar to those described in the reaction schemes and / or examples and preparations herein, using appropriate isotopically labeled reagents instead of the non-labeled reagents used herein. In the present specification, the compounds represented by Chemical Formula 1 and the exemplified compounds include isotopically labeled compounds of these compounds, including, but not limited to, deuterated and tritiated isotopes, as well as all other isotopes mentioned above.

[0061] Method for producing the compound represented by formula 1 The present invention provides a process for preparing a compound represented by formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. The compound represented by Chemical Formula 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof may be prepared by any of the methods shown in Reaction Schemes 1 to 10, and Reaction Schemes 1 to 10 may be modified to a degree that would be obvious to a person skilled in the art.

[0062] In the following reaction formulas 1 to 10, unless otherwise defined, R1 to R7, Z1 to Z3, W1 to W4, Q, La, Ra to Rh, a, b, m, n, q, r, t, s, u, y, L1 and L2 are substantially the same as those defined in Chemical Formula 1. "PG" means a protecting group, and examples thereof include tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0063] [Reaction Scheme 1] According to Reaction Scheme 1, the compound of formula 1-1-1 (R5-H) is reacted with the compound of formula 1-1-2 to prepare the compound of formula 1-1-3, from which the protecting group (PG) is removed to prepare the compound of formula 1-1-4. The compound of formula 1-1-4 can then be subjected to a substitution reaction with the compound of formula 1-1-5 to prepare the compound of formula 1-1-6.

[0064] In the present invention, examples of the compound produced by the reaction formula 1 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, and 401.

[0065] [Reaction Scheme 2] TIFF2024515739000063.tif72149 The reaction scheme 2 is a method for synthesizing a pyrazolidine-1-carboxamide compound, in which a compound of formula 1-1-1 is reacted with a compound of formula 1-2-1 to prepare a compound of formula 1-2-2, and then a protecting group is removed to prepare a compound of formula 1-2-3. Then, a substitution reaction with a compound of formula 1-1-5 is carried out to prepare a compound of formula 1-2-4.

[0066] In the present invention, examples of the compound produced by the above reaction scheme 2 include Example compound 353. [Reaction Scheme 3] TIFF2024515739000064.tif75154 (In the above reaction formula 3, Ra is TIFF2024515739000065.tif2128.) According to Reaction Scheme 3, the compound of formula 1-3-1 is subjected to a methanesulfonylation reaction to obtain a compound of formula 1-3-2, which is then subjected to a substitution reaction to obtain a compound of formula 1-3-3, and the protecting group is then removed to obtain a compound of formula 1-3-4. The compound of formula 1-3-5 can then be produced by a substitution reaction with a compound of formula 1-1-5. In the present invention, examples of the compound produced by the above reaction scheme 3 include Example compounds 272 and 273.

[0067] The compound of chemical formula 1-1-1 represented by R5-H in each of the above reaction schemes 1 and 2 can be produced by the methods described in the following reaction schemes 4a to 4c, and the following reaction schemes 5a, 5b, and 6 to 8. That is, the compound of chemical formula 1-1 represented by R5-H in each of the above reaction schemes 1 and 2 may be a compound of the following chemical formula 1-4-7, 1-4-8, or 1-4-9, or a compound of chemical formula 1-5-5, 1-5-6, 1-6-3, 1-7-4, 1-7-5, or 1-8-3.

[0068] [Reaction Scheme 4a] TIFF2024515739000066.tif32134[Reaction 4b] TIFF2024515739000067.tif64123[Reaction 4c] According to reaction schemes 4a to 4c, the compounds of formula 1-4-1, 1-4-2, or 1-4-3 have a substituent (-L1-L2-R h ) to prepare a compound of formula 1-4-4, 1-4-5, or 1-4-6, and then the protecting group (PG, Boc) is removed to prepare a compound of formula 1-1-1 (R5-H), which is a compound of formula 1-4-7, 1-4-8, or 1-4-9.

[0069] In the present invention, examples of compounds that can be synthesized by the method of Reaction Scheme 1 or 2 using R5-H produced by Reaction Scheme 4a to 4c 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, 23 7, 244, 252-263, 265-271, 274-280, 287-299, 311-320, 323-329, 333-335, 337, 340-345, 347, 348, 354-360, 362-366, 368-373, 376-381, 383, 384, 392-394, 396-398, 403 or 404.

[0070] In each of the above reaction formulas 4a to 4c, the substituent contained in R5 (-L1-L2-R h ) can be introduced into the N-containing ring by coupling reactions using halide compounds such as acid chloride, oxalyl chloride, sulfonyl chloride, and carbonyl chloride, or compounds with leaving groups such as o-Toluenesulfonyl fluoride, Buchwald-Hartwig reactions, amide coupling and ring opening reactions by epoxide hydrolysis, reductive amination reactions, etc. For example, X-L1-L2-R h It can be introduced into the N-containing ring by alkylation or arylation reaction with a halide compound having the structure: (wherein X is a halogen).

[0071] [Reaction Scheme 5a] TIFF2024515739000069.tif22157[Reaction 5b] TIFF2024515739000070.tif16153 (Rx in the above reaction formulas 5a and 5b is each independently -C1-C7 alkylene-, and the alkylene of Rx means a divalent substituent of a linear or branched alkyl.) According to Reaction Schemes 5a and 5b, a substituent is 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 is then subjected to a fluorination reaction to prepare a compound of formula 1-5-3 or 1-5-4. The protecting group (PG, Boc) of the compound of formula 1-5-3 or 1-5-4 can then be removed to prepare a compound of formula 1-1-1 (R5-H), which is a compound of formula 1-5-5 or 1-5-6. In the present invention, examples of the compound having a substituted R5 group prepared by the above reaction scheme 5a or 5b include Example compounds 43, 245, 322, 332, 374, 382, ​​and 395.

[0072] [Reaction Scheme 6] TIFF2024515739000071.tif30153 According to Reaction Scheme 6, a substituent is introduced into a compound of formula 1-4-1 to prepare an amide compound of formula 1-6-1, and then a compound of formula 1-6-2 is prepared by reduction. The protective group of the compound of formula 1-6-2 can be removed to prepare a compound of formula 1-1-1 (R5-H) as a compound of formula 1-6-3. In the present invention, examples of compounds that can be synthesized by the method of Reaction Scheme 1 or 2 using R5-H produced by Reaction Scheme 6 include Example compounds 282 to 286, 330, and 389.

[0073] [Reaction Scheme 7] TIFF2024515739000072.tif56136 According to the reaction formula 7, an amide is introduced into a compound of formula 1-7-1 to produce a compound of formula 1-7-2, and then a compound of formula 1-7-3 is produced by a reduction reaction. A compound of formula 1-7-4 can be produced as a compound of formula 1-1-1 (R5-H) by removing a protective group of the compound of formula 1-7-3. Then, a compound of formula 1-7-5 can be produced as a compound of formula 1-1-1 (R5-H) by removing a protective group of the compound of formula 1-7-2. In the present invention, examples of compounds that can be synthesized by the method of Reaction Scheme 1 or 2 using R5-H produced by Reaction Scheme 7 include Example compounds 131 to 133, 331, 402, and 406.

[0074] [Reaction Scheme 8] According to Reaction Scheme 8, the compound of formula 1-8-1 is subjected to reductive amination to produce the compound of formula 1-8-2. The protecting group (Boc) of the compound of formula 1-8-2 is removed to produce the compound of formula 1-8-3. In the present invention, examples of the compounds that can be synthesized by the method of Reaction Scheme 1 or 2 using R5-H produced by Reaction Scheme 8 include Example compounds 186, 390, 391, 400, and 405.

[0075] [Reaction Scheme 9] TIFF2024515739000074.tif90153 In the above reaction scheme 9, the compound of formula 1-9-1 is reacted with the compound of formula 1-9-2 to produce the compound of formula 1-9-3, and then the protecting group (Cbz) of N of piperazine is removed to produce the compound of formula 1-9-4. A substituent is introduced into the compound of formula 1-9-4 to produce the compound of formula 1-9-5, and then the protecting group (PG) of N of amine is removed to produce the compound of formula 1-9-6. Then, the compound of formula 1-1-6 can be produced by a substitution reaction with the compound of formula 1-1-5. In the present invention, examples of the compound produced by Reaction Scheme 9 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, and 115 to 117.

[0076] [Reaction Scheme 10] TIFF2024515739000075.tif61150 In Reaction Scheme 10, a compound of formula 1-10-1 is introduced into a compound of formula 1-1-5 to obtain a compound of formula 1-10-2, and then the compound of formula 1-10-2 is reacted with a compound of formula 1-10-3 to produce a compound of formula 1-1-6. In the present invention, examples of the compound produced by the above reaction scheme 10 include Example compounds 53 and 54.

[0077] Compositions containing compounds represented by formula 1, uses thereof and treatment methods using same The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound represented by Chemical Formula 1, a compound exemplified in the present specification, a stereoisomer or a pharma- ceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition for treating or preventing an A2a receptor-related disease, comprising, as an active ingredient, a compound represented by Chemical Formula 1, a compound exemplified in the present specification, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. The A2a receptor-related disease may be cancer or an inflammatory disease.

[0078] The cancer may be one or more selected from lung cancer, gastric cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, pancreatic cancer, colon 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-related cancer.

[0079] The inflammatory disease may be one or more 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 mellitus.

[0080] The pharmaceutical composition of the present invention may further contain one or more pharma- ceutically acceptable carriers for administration in addition to the compound represented by Formula 1, its stereoisomers, or its pharma- ceutically acceptable salts. The pharma- ceutically acceptable carriers may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may contain other conventional additives such as antioxidants, buffers, bacteriostatic agents, etc., as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be further added to the composition to be formulated into injection forms such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets. Thus, the composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository, etc. These preparations may be prepared by conventional methods used in the art for formulation or methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and may be formulated into various preparations according to each disease or component.

[0081] The composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) depending on the desired method, and the dosage range varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease, etc. The compound represented by Chemical Formula 1 of the present invention may be administered once or several times a day, but is not necessarily limited thereto.

[0082] The pharmaceutical composition of the present invention may further contain, in addition to the compound represented by Chemical Formula 1, the compound exemplified in the present specification, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, one or more components that exhibit the same or similar pharmacological activity or that, when used in combination, produce a synergistic effect on the pharmacological activity.

[0083] The present invention can provide a method for treating or preventing an adenosine A2a receptor-related disease, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula 1, a compound exemplified in the present specification, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising the same as an active ingredient can be provided to a subject in need thereof.

[0084] The term "therapeutically effective amount" as used herein refers to an amount of a compound, a compound exemplified herein, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, that is effective for treating or preventing adenosine A2a receptor-related diseases. The adenosine A2a receptor-related disease may be cancer or an inflammatory disease.

[0085] In the present invention, "subject" refers to a mammal, including a human, and "administration" can refer to providing a given substance to a subject by any suitable method. It is obvious to those skilled in the art that the therapeutically effective amount and administration frequency of the active ingredient of the present invention can vary depending on the desired effect.

[0086] In the present invention, "prevention" may mean delaying the onset of a disease, disorder, or condition. Prevention can be considered to have been achieved if the onset of a disease, disorder, or condition is delayed beyond the expected period of time.

[0087] In the present invention, "treatment" may mean partially or completely reducing, ameliorating, alleviating, inhibiting or delaying the onset of a particular disease, disorder and / or condition, reducing its severity, or reducing the occurrence of at least one or more symptoms or characteristics thereof.

[0088] The present invention can provide the use of the compound represented by Chemical Formula 1, the compound exemplified in the present specification, its stereoisomer or its pharma- ceutically acceptable salt; or the use of a pharmaceutical composition comprising the compound as an active ingredient for treating or preventing adenosine A2a receptor-related diseases. The adenosine A2a receptor-related diseases may be cancer or inflammatory diseases.

[0089] The present invention can provide the use of the compound represented by Chemical Formula 1, the compound exemplified in the present specification, its stereoisomer or its pharma- ceutically acceptable salt; or the use of a pharmaceutical composition comprising the compound as an active ingredient in the manufacture of a medicament for treating or preventing adenosine A2a receptor-related diseases. The adenosine A2a receptor-related disease can be cancer or inflammatory disease.

[0090] All references to the compositions, methods of treatment and uses of the present invention apply equally unless they contradict each other. Effect of the Invention

[0091] The compound of the present invention, its stereoisomer or a pharma- ceutically acceptable salt thereof exhibits effective antagonistic activity against adenosine A2a receptors and is useful for treating or preventing adenosine A2a receptor-associated diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0092] The present invention will be described in more detail below using Production Examples and Examples. However, the following Production Examples and Examples are for illustrating the present invention, and the present invention is not limited to the following Production Examples and Examples.

[0093] Preparation of the compound represented by formula 1 Each of the compounds according to the invention was synthesized as follows. The reaction compounds used in each reaction to produce the compounds according to the present invention were either purchased from Sigma Aldrich (company name) or synthesized using organic synthesis methods obvious to those skilled in the art of chemistry, and were used as they were without further purification. 1 This was confirmed by H-NMR (Bruker, Avance II 400) and Mass (Waters, SQD2) analysis.

[0094] 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 TIFF2024515739000076.tif25105(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 stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and water was poured into the concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed water with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 120 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (10.000 g, 76.4%) as a white foamy solid.

[0095] [Step 2] Synthesis of (S)-2-amino-1-(4-methylpiperazin-1-yl)-3-phenylpropan-1-one TIFF2024515739000077.tif2571 A solution of 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) in methanol (100 mL) was stirred at room temperature for 18 hours. A 2N aqueous solution of sodium hydroxide was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained material was used as is without further purification (title compound, 3.500 g, 54.6%, white solid).

[0096] [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 TIFF2024515739000078.tif24152 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-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 dimethyl sulfoxide (60 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 8%) to give the title compound (3.000 g, 53.7%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ9.34(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),3.8 1-3.38(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 / z488.4 Examples 2, 3, 13, 19, 20, 28 and 191 Example compounds 2, 3, 13, 19, 20, 28 and 191 were prepared in substantially the same manner as in the synthesis of Example compound 1, except that in step 1 of the synthesis of Example compound 1, the compound in the table below was used instead of 1-methylpiperazine as R5-H in Reaction Scheme 1. [Table 2]

[0097] Example 26: Synthesis of compound 26, (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-(2-fluoro-2-methylpropyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(4-(2-fluoro-2-methylpropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000080.tif20107(tert-Butoxycarbonyl)-L-proline (2.000 g, 9.292 mmol), 1-(2-fluoro-2-methylpropyl)piperazine (2.978 g, 18.583 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate (7.066 g, 18.583 mmol), and N,N-diisopropylethylamine (6.474 mL, 37.166 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of ammonium chloride was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, filtered with anhydrous sodium sulfate to remove moisture, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (2.000 g, 60.2%) as a yellow solid.

[0098] [Step 2] Synthesis of (S)-1-(2-fluoro-2-methylpropyl)-4-prolylpiperazine TIFF2024515739000081.tif2088 A solution of tert-butyl (S)-2-(4-(2-fluoro-2-methylpropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.559 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 0.699 mL, 2.797 mmol) in dichloromethane (5 mL) / methanol (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.140 g, 97.2%, brown solid).

[0099] [Step 3] 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-(2-fluoro-2-methylpropyl)piperazin-1-yl)methanone JPEG2024515739000082.jpg23150 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 2, (S)-1-(2-fluoro-2-methylpropyl)-4-prolylpiperazine (0.046 g, 0.178 mmol), and triethylamine (0.050 mL, 0.357 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and the solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.013 g, 15.3%) as a brown solid. 1H NMR(400MHz,Chloroform-d)δ7.60-7.51(m,1H),7.24-7.13(m,1H),6.54(dd d,J=11.3,3.4,1.8Hz,1H),6.30(s,1H),6.14(s,1H),5.13-4.83(m,1H),3.9 5-3.39(m,6H),2.72(s,1H),2.57-2.38(m,4H),2.29(ddd,J=13.8,9.7,5.3H z,1H),2.16(dt,J=12.7,7.7Hz,1H),1.47-1.33(m,6H).LRMS(ES)m / z458.4(M + +1).

[0100] Example 48: Synthesis of compound 48, (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-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000083.tif20106(tert-Butoxycarbonyl)-L-proline (1.000 g, 4.646 mmol), 1-(2,2,2-trifluoroethyl)piperazine (0.781 g, 4.646 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate (3.533 g, 9.292 mmol), and N,N-diisopropylethylamine (1.618 mL, 9.292 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.700 g, 41.2%) as a yellow solid.

[0101] [Step 2] Synthesis of (S)-1-prolyl-4-(2,2,2-trifluoroethyl)piperazine TIFF2024515739000084.tif2092 A solution of tert-butyl (S)-2-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.547 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution dioxane, 1.368 mL, 5.473 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.140 g, 96.4%, white solid).

[0102] [Step 3] 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-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone JPEG2024515739000085.jpg20153The (S)-1-prolyl-4-(2,2,2-trifluoroethyl)piperazine (0.050 g, 0.188 mmol) prepared in step 2, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.053 g, 0.188 mmol), and triethylamine (0.053 mL, 0.377 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and the solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.015 g, 16.5%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.61-7.54(m,1H),7.27-7.13(m,1H),6.56(ddd,J=5.2,3.4,1.8Hz,1H),5.95(d,J=74.2Hz,2H),5.02(ddd,J=63.5,8.5,3. 0Hz,1H),3.99-3.71(m,4H),3.67-3.61(m,2H),3.09(p,J=9.5,9.1Hz,3H),2 .80-2.60(m,3H),2.38-2.08(m,2H),2.06-1.97(m,2H).LRMS(ES)m / z466.5(M + +1).

[0103] Example 90: Synthesis of compound 90, (S)-(1-(7-amino-2-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)methanone [Step 1] Synthesis of (S)-(1-(7-amino-2-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)methanone TIFF2024515739000086.tif20136 (S)-1-(2-fluoro-2-methylpropyl)-4-prolylpiperazine (0.087 g, 0.340 mmol) prepared in the synthesis step 2 of Example 26, 2-(5-methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.050 g, 0.170 mmol), and triethylamine (0.047 mL, 0.340 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water, removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 5%) to obtain the title compound (0.035 g, 43.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.27(m,2H),6.94(ddd,J=3.2,2.2,0.6Hz,1H),6.29(ddd,J=3.3,1.7,1.1Hz,1H),5.02-4.92(m,1H),3. 72-3.39(m,6H),2.72(m,1H),2.61-2.52(m,5H),2.48-2.18(m,4H),2.04-1.71(m,3H),1.39-1.26(m,6H);LRMS(ES)m / z472.6(M + +1). Examples 12, 16, 27, 55, 78-81, 113, 114, 120-128, 134-142, 145, 146, 149, 150, 151, 236, 239, 246, 247, 265, 266, 281, 301, 302, 309, 310 and 321 In step 1 of the synthesis method of Example compound 26, except that the compound in the table below was used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H in the reaction formula 1, Example compounds 12, 16, 27, 55, 78 to 81, 113, 114, 120 to 128, 134 to 142, 145, 146, 149, 150, 151, 236, 239, 246, 247, 265, 266, 281, 301, 302, 309, 310 and 321 were prepared by substantially the same method as the synthesis method of Example compound 26, respectively. [Table 3]

[0104] JPEG2024515739000088.jpg235156

[0105] JPEG2024515739000089.jpg49156

[0106] Example 15: Synthesis of Compound 15 Example compound 15 was synthesized in a manner substantially similar to that for example compound 16, except that (tert-butoxycarbonyl)glycine was used instead of (tert-butoxycarbonyl)-L-proline.

[0107] Example 37: Synthesis of Compound 37 Example compound 37 was synthesized in a manner substantially similar to that of Example compound 12, except that (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0108] Example 385: Synthesis of Compound 385 Example compound 385 was synthesized in a manner substantially similar to that of Example compound 48, except that (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0109] Example 386: Synthesis of Compound 386 Example compound 386 was synthesized in a manner substantially similar to that of Example compound 26, except that (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0110] Example 387: Synthesis of Compound 387 Example compound 387 was synthesized in a manner substantially similar to that of Example compound 48, except that (S)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0111] Example 388: Synthesis of Compound 388 Example compound 388 was synthesized in a manner substantially similar to that of Example compound 26, except that (tert-butoxycarbonyl)glycine was used instead of (tert-butoxycarbonyl)-L-proline.

[0112] Examples 65, 107, 108, 109, 110, 112, 242, 264 and 350 Example compound 108 was synthesized in a manner substantially similar to that of Example compound 26, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline. In addition, Example compounds 65, 107, 109, 110, 112, 242, 264 and 350 were prepared by substantially the same method as that for synthesis of Example compound 26, except that the compounds in the table below were used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H in Reaction Scheme 1. [Table 4]

[0113] Example 29: Synthesis of Compound 29 Example compound 29 was synthesized in substantially the same manner as Example compound 16, except that (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0114] Examples 92, 93, 94, 95, 96, 97 and 98 Example compounds 92, 93, 94, 95, 96, 97 and 98 were prepared by substantially the same method as the synthesis method of Example compound 26, except that the compound in the table below was used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H in Reaction Scheme 1, and tert-butoxycarbonyl-D-proline was used instead of (tert-butoxycarbonyl)-L-proline. [Table 5]

[0115] Example 7: Synthesis of Compound 7 Example compound 7 was synthesized in a manner substantially similar to that of Example compound 12, except that (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0116] Example 14: Synthesis of Compound 14 Example compound 14 was synthesized in a manner substantially similar to that of Example compound 16, except that (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0117] Example 190: Synthesis of Compound 190 Example compound 190 was synthesized in a manner substantially similar to that of Example compound 191, except that (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of (tert-butoxycarbonyl)-L-phenylalanine.

[0118] Example 195: Synthesis of Compound 195 Example compound 195 was synthesized in a manner substantially similar to that of Example compound 26, except that (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0119] Examples 171, 241 and 249 Example compound 171 was synthesized in a manner substantially similar to that of Example compound 12, except that (S)-2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid.

[0120] In addition, Example compounds 241 and 249 were each produced by substantially the same method as the synthesis method of Example compound 171, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 6]

[0121] Examples 8 and 231-235 Example compound 8 was synthesized in a manner substantially similar to that of Example compound 12, except that (tert-butoxycarbonyl)-L-serine was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid. In addition, Example compounds 231 to 235 were each produced by a method substantially similar to the synthesis method of Example compound 8, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 7]

[0122] Examples 9, 118, 119, 240, 251 and 349 Example compound 9 was synthesized in a manner substantially similar to that of Example compound 8, except that (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-serine. In addition, Example compounds 118, 119, 240, 251 and 349 were each produced by a method substantially similar to the synthesis method of Example compound 9, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 8]

[0123] Examples 10, 57-60, 143, 144, 351 and 367 Example compound 10 was synthesized by a method substantially similar to the synthesis method of Example compound 8, except that (tert-butoxycarbonyl)-L-valine was used instead of (tert-butoxycarbonyl)-L-serine. In addition, Example compounds 57 to 60, 143, 144, 351 and 367 were each produced by a method substantially similar to the synthesis method of Example compound 10, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 9]

[0124] Examples 162 to 167 Example compounds 162 to 167 were each produced by substantially the same method as that for synthesizing Example compound 9, except that the compounds in the table below were used as N-protected amino acids instead of (tert-butoxycarbonyl)-L-alanine. [Table 10]

[0125] Examples 172 to 175 Example compounds 172 to 175 were each produced by substantially the same method as the synthesis method of Example compound 143, except that the compound in the table below was used as the N-protected amino acid instead of (tert-butoxycarbonyl)-L-valine. [Table 11]

[0126] Examples 211 to 215 Example compounds 211 to 215 were each produced by substantially the same method as the synthesis method of Example compound 144, except that the compound in the table below was used as the N-protected amino acid instead of (tert-butoxycarbonyl)-L-valine. [Table 12]

[0127] Examples 248, 338 and 346 Example compound 338 was prepared in a manner substantially similar to the synthesis method of Example compound 240, except that (S)-2-((tert-butoxycarbonyl)amino)butanoic acid was used instead of (tert-butoxycarbonyl)-L-alanine. In addition, Example compounds 248 and 346 were each prepared by a method substantially similar to the synthesis method of Example compound 338, except that the compound in the table below was used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H. [Table 13]

[0128] Examples 11, 147, 148, 187 and 188 Example compound 11 was synthesized in a manner substantially similar to that of Example compound 12, except that (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid. In addition, Example compounds 147, 148, 187 and 188 were each produced by a method substantially similar to the synthesis method of Example compound 11, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 14]

[0129] Examples 168, 176, 216 and 339 Example compound 168 was synthesized in a manner substantially similar to that of Example compound 11, except that (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid. Example compounds 176, 216 and 339 were prepared by substantially the same method as that for synthesizing Example compound 168, except that the compounds in the table below were used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 15]

[0130] Examples 169 and 177 Example compound 169 was synthesized in a manner substantially similar to that of Example compound 11, except that (S)-2-((tert-butoxycarbonyl)amino)-2-cyclobutylacetic acid was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid. Moreover, Example compound 177 was synthesized in a manner substantially similar to that of Example compound 169, except that 1-butylpiperazine was used instead of 1-(2,4-difluorophenyl)piperazine.

[0131] Examples 170, 178 and 217 Example compound 170 was synthesized in a manner substantially similar to that of Example compound 11, except that (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid. In addition, Example compounds 178 and 217 were each synthesized by a method substantially similar to the method for synthesizing Example compound 170, except that the compound in the table below was used instead of 1-(2,4-difluorophenyl)piperazine as R5-H. [Table 16]

[0132] Examples 40, 87, 89, 91, 189, 198, 199, 200, 201, 202, 203 and 300 Example compounds 40, 87, 89, 91, 189, 198, 199, 200, 201, 202, 203 and 300 were synthesized by substantially the same method as that for Example compound 90, except that the compound in the table below was used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H. [Table 17]

[0133] Examples 207 to 210 and 218 to 222 Example compounds 207 to 210 and 218 to 222 were synthesized by substantially the same method as that for Example compound 90, except that the compounds in the table below were used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H, and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline. [Table 18]

[0134] 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 TIFF2024515739000105.tif221031-(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 and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the material used as is without further purification (title compound, 1.000 g, 88.7%, brown oil).

[0135] [Step 2] (S)-2-Amino-1-(4-(2-fluoro-2-methylpropyl)piperazin-1-yl)-3-methoxypropan-1-one TIFF2024515739000106.tif25104 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) in dichloromethane (10 mL) were stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.100 g, 69.2%, brown oil).

[0136] [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 TIFF2024515739000107.tif21145The (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 bicarbonate (0.096 g, 1.148 mmol) were dissolved in acetonitrile (10 mL) at room temperature and stirred at 70 ° C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / ethyl acetate = 0% to 10%) to give the title compound (0.015 g, 8.5%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.32(s,2H),7.88(s,1H),7.46(dd,J=53.9,8.2Hz,1H),7.08(d,J=3.2Hz,1H),6.68(dd,J=3.2,1.7Hz,1H ),5.09(dd,J=14.2,6.3Hz,1H),3.73-3.39(m,6H),3.27(s,3H),2.62-2.34(m,6H),1.32(d,J=21.5Hz,6H);LRMS(ES)m / z462.5(M + +1).

[0137] Examples 304, 305, 306, 399 and 401 In step 1, the compounds in the table below were used instead of 1-(2-fluoro-2-methylpropyl)piperazine as R5-H in the above reaction scheme 1, but the compounds in the table below were prepared in a manner substantially similar to the synthesis method of the compound 303. [Table 19]

[0138] Example 307: Synthesis of Compound 307 Example compound 307 was synthesized in a manner substantially similar to that of Example compound 304, except that N-(tert-butoxycarbonyl)-O-ethyl-L-serine was used instead of N-(tert-butoxycarbonyl)-O-methyl-L-serine.

[0139] Example 308: Synthesis of Compound 308 Example compound 308 was synthesized in a manner substantially similar to that of Example compound 306, except that N-(tert-butoxycarbonyl)-O-ethyl-L-serine was used instead of N-(tert-butoxycarbonyl)-O-methyl-L-serine.

[0140] Example 352: Synthesis of Compound 352 Example compound 352 was synthesized by a synthetic method substantially similar to the production method of Example compound 26, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine in step 3.

[0141] Examples 336 and 361: Synthesis of Compounds 336 and 361 Example compounds 336 and 361 were synthesized in a manner substantially similar to that of Example compound 352, except that 1-(2-methoxyethyl)piperazine and 1-butylpiperazine were used instead of 1-(2,4-difluorophenyl)piperazine as R5-H.

[0142] Example 375: Synthesis of Compound 375 Example compound 375 was synthesized by substantially the same method as that for synthesis of Example compound 119, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0143] Example 41: Synthesis of Compound 41 Example compound 41 was synthesized by substantially the same method as that for synthesizing example compound 16, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrooxazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0144] Example 238: Synthesis of Compound 238 Example compound 238 was synthesized by substantially the same method as that for Example compound 48, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0145] Example 243: Synthesis of Compound 243 Example compound 243 was synthesized by substantially the same method as that for synthesis of Example compound 189, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0146] Example 192: Synthesis of Compound 192 Example compound 192 was synthesized by a method substantially similar to the synthesis method of example compound 48, except that phenyl(piperazin-1-yl)methanone was used instead of 1-(2,2,2-trifluoroethyl)piperazine, and 5-(methylsulfonyl)-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0147] Example 193: Synthesis of Compound 193 Example compound 193 was synthesized by a method substantially similar to the synthesis method of example compound 48, except that 1-benzylpiperazine was used instead of 1-(2,2,2-trifluoroethyl)piperazine, and 5-(methylsulfonyl)-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0148] Example 194: Synthesis of Compound 194 Example compound 194 was synthesized by substantially the same method as that for synthesizing example compound 9, except that 5-(methylsulfonyl)-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0149] Example 250: Synthesis of Compound 250 Example compound 250 was synthesized by substantially the same method as that for synthesizing example compound 148, except that 5-(methylsulfonyl)-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0150] Example 67: Synthesis of Compound 67 Example compound 67 was synthesized by substantially the same method as that for synthesizing example compound 12, except that 5-(methylsulfonyl)-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0151] Example 84: Synthesis of Compound 84 Example compound 84 was synthesized by substantially the same method as that for synthesizing example compound 139, except that 2-(5-methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine, and 1-cyclohexylpiperazine was used instead of 1-cyclopropylpiperazine.

[0152] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 20]

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[0219] Example 353: Synthesis of compound 353, (2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrazolidin-1-yl)(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone [Step 1] tert-Butyl 2-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)pyrazolidine-1-carboxylate TIFF2024515739000176.tif24132 tert-Butyl pyrazolidine-1-carboxylate (1.000 g, 5.806 mmol), 1,1′-carbonyldiimidazole (CDI, 1.412 g, 8.709 mmol), and N,N-diisopropylethylamine (3.034 mL, 17.419 mmol) were dissolved in dichloromethane (20 mL) at room temperature, to which 1-(2,2,2-trifluoroethyl)piperazine (1.953 g, 11.612 mmol) was added and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed water with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.500 g, 23.5%) as a white foamy solid.

[0220] [Step 2] Synthesis of pyrazolidin-1-yl(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone TIFF2024515739000177.tif22116 A solution of tert-butyl 2-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)pyrazolidine-1-carboxylate (0.400 g, 1.092 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 2.729 mL, 10.917 mmol) in dichloromethane (5 mL) / methanol (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.250 g, 86.0%, brown oil).

[0221] [Step 3] Synthesis of (2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrazolidin-1-yl)(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone TIFF2024515739000178.tif22150 A solution of pyrazolidin-1-yl(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone (0.200 g, 0.751 mmol) prepared in step 2, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.105 g, 0.376 mmol), and sodium bicarbonate (0.189 g, 2.253 mmol) in acetonitrile (10 mL) at room temperature was stirred at 70 °C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / ethyl acetate = 0% to 10%), and the resulting material was purified and concentrated again by chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / dichloromethane = 10%) to give the title compound (0.020 g, 5.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.40(m,2H),7.88(dd,J=1.7,0.8Hz,1H),7.08(dd,J=3.4,0.7Hz,1H),6.69(dd,J=3.4,1.8Hz,1 H),3.73(t,J=7.1Hz,2H),3.43(m,6H),3.30-3.10(m,2H),2.73-2.58(m,4H),2.12-1.94(m,2H);LRMS(ES)m / z467.19(M + +1).

[0222] Example 272: Synthesis of compound 272, (2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrazolidin-1-yl)(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (S)-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate TIFF2024515739000179.tif301291-(2,4-difluorophenyl)piperazine (10.000 g, 50.449 mmol), (tert-butoxycarbonyl)-L-serine (20.705 g, 100.898 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 38.364 g, 100.898 mmol), and N,N-diisopropylethylamine (43.936 mL, 252.245 mmol) were dissolved in dichloromethane (500 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of ammonium chloride was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, filtered with anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 120 g cartridge; ethyl acetate / hexane = 0% to 45%) to obtain the title compound (18.000 g, 92.6%) as a white foamy solid.

[0223] [Step 2] Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl methanesulfonate TIFF2024515739000180.tif30127 tert-Butyl (S)-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate (18.000 g, 46.704 mmol) prepared in step 1, methanesulfonyl chloride (3.976 mL, 51.374 mmol), and triethylamine (13.019 mL, 93.407 mmol) were dissolved in dichloromethane (500 mL) at room temperature and stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 20.000 g, 92.4%, yellow oil).

[0224] [Step 3] Synthesis of tert-butyl (S)-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)-1-oxo-3-(piperidin-1-yl)propan-2-yl)carbamate TIFF2024515739000181.tif36123 (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl methanesulfonate (1.000 g, 2.157 mmol) prepared in step 2, cesium carbonate (1.406 g, 4.315 mmol), and piperidine (0.426 mL, 4.315 mmol) were dissolved in acetonitrile (10 mL) at room temperature and stirred at 90 ° C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, removed moisture with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.450 g, 46.1%) as a colorless oil.

[0225] [Step 4] Synthesis of (S)-2-amino-1-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-(piperidin-1-yl)propan-1-one TIFF2024515739000182.tif37104 tert-Butyl (S)-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)-1-oxo-3-(piperidin-1-yl)propan-2-yl)carbamate (0.200 g, 0.442 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in dioxane, 1.105 mL, 4.419 mmol) in dichloromethane (5 mL) were stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.100 g, 64.2%, brown oil).

[0226] [Step 5] 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-(2,4-difluorophenyl)piperazin-1-yl)-3-(piperidin-1-yl)propan-1-one TIFF2024515739000183.tif35148 Step 4 (S)-2-amino-1-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-(piperidin-1-yl)propan-1-one (0.100 g, 0.284 mmol), 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.080 g, 0.284 mmol), and sodium bicarbonate (0.048 g, 0.567 mmol) were dissolved in acetonitrile (5 mL) at room temperature and stirred at 70 ° C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / ethyl acetate = 0% to 10%) to obtain the title compound (0.020 g, 12.8%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.31(m,2H),7.87(s,1H),7.45(dd,J=37.2,7.0Hz,1H),7.26-6.89(m,4H),6.68(dd,J=3.3,1.8Hz,1H ),5.12-4.95(m,1H),3.65(m,5H),3.22(m,1H),3.08-2.78(m,4H),2.68-2.56(m,2H),2.37(m,2H),1.42(m,4H),1.35(m,2H).

[0227] Example 273: Synthesis of Compound 273 Example compound 273 was synthesized in a manner substantially similar to that of Example compound 272, except that (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl methanesulfonate obtained in Step 2 was used and morpholine was used instead of piperidine. 1 H NMR(400MHz,DMSO-d6)δ8.47-8.00(m,2H),7.87(s,1H),7.50(dd,J=32.6,7.7Hz,1H),7.29-6.92(m,4H),6.68(dd,J=3.2,1.8H z,1H),5.11-4.95(m,1H),3.95-3.58(m,4H),3.55(d,J=13.7Hz,4H),3.30-3.13(m,2H),3.11-2.79(m,4H),2.70-2.48(m,4H).

[0228] Example 44: Synthesis of compound 44, ((S)-1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)((1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone [Step 1] Synthesis of tert-butyl (1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate TIFF2024515739000184.tif14106tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (10.000 g, 50.436 mmol), 1-(bromomethyl)-2,4-difluorobenzene (6.406 mL, 50.436 mmol), and potassium carbonate (27.882 g, 201.745 mmol) were dissolved in N,N-dimethylformamide (80 mL) at room temperature and stirred for 18 hours at the same temperature. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (16.000 g, 97.8%) as a white solid.

[0229] [Step 2] Synthesis of (1S,4S)-2-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane TIFF2024515739000185.tif1289A solution of tert-butyl (1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (12.000 g, 36.995 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 92.487 mL, 369.948 mmol) in dichloromethane (100 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 8.000 g, 96.4%, white solid).

[0230] [Step 3] Synthesis of tert-butyl (S)-2-((1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000186.tif32120A solution of (1S,4S)-2-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane (0.500 g, 2.230 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.960 g, 4.459 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate (1.696 g, 4.459 mmol), and N,N-diisopropylethylamine (0.777 mL, 4.459 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hours at the same temperature. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.200 g, 21.3%) as a white solid.

[0231] [Step 4] Synthesis of (1S,4S)-2-(L-prolyl)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane TIFF2024515739000187.tif3092 A solution of tert-butyl (S)-2-((1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.475 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in dioxane, 1.186 mL, 4.745 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.150 g, 98.4%, white solid).

[0232] [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)((1S,4S)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone TIFF2024515739000188.tif22146 (1S,4S)-2-(L-prolyl)-5-(2,4-difluorobenzyl)-2,5-diazabicyclo[2.2.1]heptane (0.200 g, 0.622 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.087 g, 0.311 mmol), and triethylamine (0.173 mL, 1.245 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 10%) to obtain the title compound (0.040 g, 12.3%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.33(m,1H),7.90-7.44(m,2H),7.18(m,1H),7.12-6.87(m,2H),6.67(m,1H),4.66 (m,2H),4.13-3.37(m,7H),3.29-2.74(m,2H),2.47-2.20(m,2H),2.14-1.64(m,5H);LRMS(ES)m / z522.4(M + +1).

[0233] Examples 49, 50, 51 and 52 Example compounds 49, 50, 51 and 52 were synthesized in substantially the same manner as Example compound 44, except that the compound in the table below was used instead of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in Step 1. [Table 21]

[0234] Examples 30 and 31 Example compounds 30 and 31 were synthesized in a manner substantially similar to that of Example compound 44, except that the compound in the table below was used instead of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in step 1, and (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline in step 3. [Table 22]

[0235] Example 32: Synthesis of Compound 32 Example compound 32 was synthesized in a manner substantially similar to that of Example compound 44, except that ((tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0236] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 23]

[0237] TIFF2024515739000192.tif154156

[0238] TIFF2024515739000193.tif223156

[0239] Example 157: Synthesis of compound 157, (3-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone [Step 1] Synthesis of tert-butyl 8-benzoyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF2024515739000194.tif19112tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.319 g, 1.503 mmol), benzoyl chloride (0.175 mL, 1.503 mmol), and triethylamine (0.314 mL, 2.254 mmol) in dichloromethane (5 mL) were stirred at room temperature for 18 hours. The reaction mixture was poured into an aqueous solution of sodium bicarbonate N, the organic layer was extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.474 g, 99.7%, pale yellow oil).

[0240] [Step 2] Synthesis of (3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone hydrochloride TIFF2024515739000195.tif21102 A solution of tert-butyl 8-benzoyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.474 g, 1.498 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 1.498 mL, 5.992 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.378 g, 99.8%, pale yellow oil).

[0241] [Step 3] Synthesis of tert-butyl (2S)-2-(8-benzoyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000196.tif27130A solution of (3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone hydrochloride (0.378 g, 1.496 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.322 g, 1.496 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 1.334 mL, 2.243 mmol), and N,N-diisopropylethylamine (0.782 mL, 4.487 mmol) in dichloromethane (8 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into an aqueous solution of sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 5%) to give the title compound (0.424 g, 68.6%) as a clear oil.

[0242] [Step 4] Synthesis of (3-(L-prolyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone hydrochloride TIFF2024515739000197.tif26117A solution of tert-butyl (2S)-2-(8-benzoyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyrrolidine-1-carboxylate (0.424 g, 1.025 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.025 mL, 4.101 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.358 g, 99.8%, pale yellow oil).

[0243] [Step 5] Synthesis of (3-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone TIFF2024515739000198.tif23157A solution of (3-(L-prolyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone hydrochloride (0.358 g, 1.023 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.287 g, 1.023 mmol), and sodium bicarbonate (0.258 g, 3.070 mmol) in cyclopentyl methyl ether (CPME, 5 mL) was stirred at 50 °C for 18 h, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 5%) to give the title compound (0.309 g, 58.9%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.69-7.33(m,5H),7.24-7.09(m,1H),6.51(td,J=3.7,1.7 Hz,1H),6.31(s,1H),5.18-4.69(m,2H),4.16(dd,J=78.6,54.6Hz,2H),3.92-3.49(m,3H ),3.42-2.78(m,1H),2.61(s,1H),2.53-2.26(m,1H),2.26-2.09(m,2H),2.00(dp,J=17. 5,7.3,6.1Hz,3H),1.92-1.83(m,1H),1.74(dd,J=15.6,8.1Hz,1H).LRMS(ES)m / z514.5(M + +1).

[0244] Examples 158, 159, 160 and 161 Example compounds 158 to 161 were each synthesized in a manner substantially similar to that of Example compound 157, except that the compound in the table below was used as a starting material instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in step 1. [Table 24]

[0245] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 25]

[0246] TIFF2024515739000201.tif160158

[0247] TIFF2024515739000202.tif122158

[0248] 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-diazepane-1-carboxylate TIFF2024515739000203.tif191182-Chloropyrimidine (0.229 g, 1.999 mmol), tert-butyl 1,4-diazepane-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 and stirred at 80 °C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to obtain the title compound (0.556 g, 99.9%) as a pale yellow liquid.

[0249] [Step 2] Synthesis of 1-(pyrimidin-2-yl)-1,4-diazepane hydrochloride TIFF2024515739000204.tif1998 A solution of tert-butyl 4-(pyrimidin-2-yl)-1,4-diazepane-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) in dichloromethane (5 mL) was stirred at room temperature for 5 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.215 g, 50.1%, white solid).

[0250] [Step 3] Synthesis of tert-butyl (S)-2-(4-(pyrimidin-2-yl)-1,4-diazepane-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000205.tif23130A solution of 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) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into an aqueous solution of sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as it was without further purification (title compound, 0.3750g, 100.0%, pale yellow liquid).

[0251] [Step 4] Synthesis of (S)-1-Prolyl-4-(pyrimidin-2-yl)-1,4-diazepane hydrochloride TIFF2024515739000206.tif25115A solution of tert-butyl (S)-2-(4-(pyrimidin-2-yl)-1,4-diazepane-1-carbonyl)pyrrolidine-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) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.311 g, 99.9%, white solid).

[0252] [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 TIFF2024515739000207.tif22149A solution of (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 bicarbonate (0.251 g, 2.992 mmol) in acetonitrile (5 mL) at room temperature was stirred at 70 °C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was subjected to reduced pressure to remove the solvent. The concentrate was then purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to give the title compound (0.109 g, 23.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.86(dd,J=1.7,0.8Hz,1H),7.46(brs,2H),7.06(dd,J=3.4,0.6Hz,1H),6.67(dd,J=3.4,1.8Hz,1H),5.59(brs,1H),4.96(b rs,1H),3.79-3.38(m,5H),2.79(t,J=14.1Hz,3H),2.64-2.36(m,4H),2.2 4(s,1H),2.06-1.77(m,3H),1.66(t,J=19.1Hz,3H).LRMS(ES)m / z461.5(M + +1).

[0253] Examples 328, 329 and 384 Example compounds 328, 329 and 384 were synthesized in a manner substantially similar to that of Example compound 277, except that starting material 1 in the table below was used instead of 2-chloropyrimidine in step 1, starting material 2 in the table below was used instead of tert-butyl 1,4-diazepane-1-carboxylate, and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline in step 3. [Table 26]

[0254] Example 265: Synthesis of Compound 265 Example compound 265 was synthesized in a manner substantially similar to that of Example compound 328, except that (tert-butoxycarbonyl)-L-proline was used instead of (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid.

[0255] Example 266: Synthesis of Compound 266 Example compound 266 was synthesized in a manner substantially similar to that of Example compound 329, except that (tert-butoxycarbonyl)-L-proline was used instead of (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid.

[0256] Example 380: Synthesis of Compound 380 Example compound 380 was synthesized in a manner substantially similar to that of Example compound 329, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0257] Example 383: Synthesis of Compound 383 Example compound 383 was synthesized in a manner substantially similar to that of Example compound 328, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0258] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 27] TIFF2024515739000210.tif186158 TIFF2024515739000211.tif196158 TIFF2024515739000212.tif154158

[0259] Example 229: Synthesis of compound 229, 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-hydroxy-3-methylbutan-1-one [Step 1] Synthesis of tert-butyl 4-(3-hydroxy-3-methylbutanoyl)piperazine-1-carboxylate A solution of 2-hydroxy-3-methylbutanoic acid (0.315 mL, 2.500 mmol), tert-butyl piperazine-1-carboxylate (0.466 g, 2.500 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.959 g, 5.000 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 0.338 g, 2.500 mmol), and N,N-diisopropylethylamine (1.306 mL, 7.500 mmol) in dichloromethane (8 mL) at room temperature was stirred at the same temperature for 18 h. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as it was without further purification (title compound, 0.715 g, 99.9%, white solid).

[0260] [Step 2] Synthesis of 3-hydroxy-3-methyl-1-(piperazin-1-yl)butan-1-one hydrochloride TIFF2024515739000214.tif19105A solution of tert-butyl 4-(3-hydroxy-3-methylbutanoyl)piperazine-1-carboxylate (0.715 g, 2.497 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 3.121 mL, 12.484 mmol) in dichloromethane (6 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.555 g, 99.8%, white solid).

[0261] [Step 3] Synthesis of tert-butyl (S)-2-(4-(3-hydroxy-3-methylbutanoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000215.tif24136A solution of 3-hydroxy-3-methyl-1-(piperazin-1-yl)butan-1-one hydrochloride (0.555 g, 2.492 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.536 g, 2.492 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.955 g, 4.984 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 0.337 g, 2.492 mmol), and N,N-diisopropylethylamine (1.302 mL, 7.476 mmol) in dichloromethane (8 mL) was stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.890 g, 93.1%) as a colorless oil.

[0262] [Step 4] Synthesis of (S)-3-hydroxy-3-methyl-1-(4-prolylpiperazin-1-yl)butan-1-one hydrochloride TIFF2024515739000216.tif25118 A solution of tert-butyl (S)-2-(4-(3-hydroxy-3-methylbutanoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.890 g, 2.321 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.321 mL, 9.283 mmol) in dichloromethane (5 mL) was stirred at 40° C. for 2 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was subjected to removal of the solvent under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.740 g, 99.7%, white solid).

[0263] [Step 5] Synthesis of 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-hydroxy-3-methylbutan-1-one TIFF2024515739000217.tif20157The (S)-3-hydroxy-3-methyl-1-(4-prolylpiperazin-1-yl)butan-1-one hydrochloride (0.150 g, 0.469 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.131 g, 0.469 mmol), and sodium bicarbonate (0.079 g, 0.938 mmol) were dissolved in acetonitrile (2 mL) at room temperature and stirred at 50 °C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%), and the obtained material was purified and concentrated again by chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / dichloromethane = 10%) to give the title compound (0.117 g, 51.8%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.63-8.00(m,2H),7.91-7.84(m,1H),7.10-7.01(m,1H),6.72-6.64(m,1H),5.09-4.94(m,1H),4.88-4. 72(m,1H),3.89-3.38(m,10H),2.61-2.53(m,2H),2.35-2.17(m,1H),1.98-1.77(m,3H),1.27-1.13(m,6H);LRMS(ES)m / z484.3(M + +1).

[0264] Examples 230 and 237 Example compounds 230 and 237 were each synthesized in a manner substantially similar to that of Example compound 229, except that the starting material in the table below was used instead of 3-hydroxy-3-methylbutanoic acid in Step 1. [Table 28]

[0265] Example 262: Synthesis of Compound 262 Example compound 262 was synthesized in a manner substantially similar to that of Example compound 268, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in step 5.

[0266] Example 263: Synthesis of Compound 263 Example compound 263 was synthesized in a manner substantially similar to that of Example compound 229, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrooxazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine in step 5.

[0267] Example 267: Synthesis of Compound 267 Example compound 267 was synthesized in a manner substantially similar to that of Example compound 229, except that 2-hydroxy-2-methylpropanoic acid was used instead of 3-hydroxy-3-methylbutanoic acid in step 1, and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0268] Example 268: Synthesis of Compound 268 Example compound 268 was synthesized in a manner substantially similar to that of Example compound 229, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0269] Example 274: Synthesis of compound 274 Example compound 274 was synthesized in a manner substantially similar to that of Example compound 229, except that 2-hydroxy-2-methylpropanoic acid was used instead of 3-hydroxy-3-methylbutanoic acid in step 1.

[0270] Example 275: Synthesis of Compound 275 Example compound 275 was synthesized in a manner substantially similar to that of Example compound 268, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in step 5.

[0271] Example 290: Synthesis of Compound 290 Example compound 290 was synthesized in a manner substantially similar to that of Example compound 229, except that tert-butyl 4,4′-bipiperidine-1-carboxylate was used instead of tert-butyl piperazine-1-carboxylate in Step 1.

[0272] Example 327: Synthesis of Compound 327 Example compound 327 was synthesized in a manner substantially similar to that of Example compound 290, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0273] Example 292: Synthesis of Compound 292 Example compound 292 was synthesized in a manner substantially similar to that of Example compound 229, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine in step 5.

[0274] Example 315: Synthesis of Compound 315 Example compound 315 was synthesized in a manner substantially similar to that of Example compound 268, except that 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in step 5.

[0275] Example 340: Synthesis of Compound 340 Example compound 340 was synthesized in a manner substantially similar to that for synthesizing example compound 262, except that (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline.

[0276] Examples 368, 369 and 370 Example compounds 368, 369 and 370 were each synthesized in a manner substantially similar to that of Example compound 229, except that the compound in the table below was used as the N-protected amino acid instead of (tert-butoxycarbonyl)-L-proline in step 3. [Table 29]

[0277] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 30]

[0278] TIFF2024515739000221.tif191158

[0279] TIFF2024515739000222.tif223158

[0280] TIFF2024515739000223.tif138158

[0281] TIFF2024515739000224.tif170158

[0282] TIFF2024515739000225.tif197158

[0283] Example 276: Synthesis of compound 276, (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-(2,4-difluorophenyl)-1,4-diazepan-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2,4-difluorophenyl)-1,4-diazepane-1-carboxylate TIFF2024515739000226.tif191101-Bromo-2,4-difluorobenzene (0.386 g, 2.000 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.401 g, 2.000 mmol), chloro(2-dicyclohexylphosphino-2′,6′-diisopropyl-1,1′-diphenyl)[2-(2′-amino-1,1′-diphenyl)]palladium(II, 0.155 g, 0.200 mmol), and cesium carbonate (1.955 g, 6.000 mmol) in tetrahydrofuran (10 mL) at room temperature were stirred at 80° C. for 18 hours, and the reaction was stopped by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to obtain the title compound (0.624 g, 99.9%) as a pale yellow liquid.

[0284] [Step 2] Synthesis of 1-(2,4-difluorophenyl)-1,4-diazepane hydrochloride TIFF2024515739000227.tif21100 A solution of tert-butyl 4-(2,4-difluorophenyl)-1,4-diazepane-1-carboxylate (0.624 g, 1.998 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 1.998 mL, 7.991 mmol) in dichloromethane (5 mL) was stirred at room temperature for 5 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.248 g, 49.9%, white solid).

[0285] [Step 3] Synthesis of tert-butyl (S)-2-(4-(2,4-difluorophenyl)-1,4-diazepane-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000228.tif25124A solution of 1-(2,4-difluorophenyl)-1,4-diazepane hydrochloride (0.497 g, 1.998 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.430 g, 1.998 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 1.833 mL, 2.998 mmol), and N,N-diisopropylethylamine (1.392 mL, 7.994 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into an aqueous solution of N-sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as it was without further purification (title compound, 0.409 g, 50.0%, pale yellow liquid).

[0286] [Step 4] Synthesis of (S)-1-(2,4-difluorophenyl)-4-prolyl-1,4-diazepane hydrochloride TIFF2024515739000229.tif25104 A solution of tert-butyl (S)-2-(4-(2,4-difluorophenyl)-1,4-diazepane-1-carbonyl)pyrrolidine-1-carboxylate (0.409 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) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.345 g, 99.9%, white solid).

[0287] [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-(2,4-difluorophenyl)-1,4-diazepan-1-yl)methanone TIFF2024515739000230.tif24143 Step 4: (S)-1-(2,4-difluorophenyl)-4-prolyl-1,4-diazepane hydrochloride (0.345 g, 0.998 mmol), 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.280 g, 0.998 mmol), Then, (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-(2,4-difluorophenyl)-1,4-diazepan-1-yl)methanone (1.525 g, 2.993 mmol) was dissolved in acetonitrile (5 mL) at room temperature and stirred at 70° C. for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was removed from the solvent under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to obtain the title compound (0.011 g, 2.1%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.54-8.06(m,2H),7.87(s,1H),7.22-6.83(m,4H),6.68(ddd,J=5.2,3.5,1.6Hz ,1H),5.03-4.91(m,1H),3.87-3.37(m,10H),2.34-2.09(m,2H),1.97-1.78(m,4H).LRMS(ES)m / z510.5(M + +1).

[0288] Example 42: Synthesis of compound 42, (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-(2-ethyl-2-hydroxybutyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2-ethyl-2-hydroxybutyl)piperazine-1-carboxylate TIFF2024515739000231.tif14108tert-Butyl piperazine-1-carboxylate (2.000 g, 10.738 mmol), 2,2-diethyloxirane (2.151 g, 21.475 mmol), and potassium carbonate (5.936 g, 42.951 mmol) were mixed in ethanol (10 mL) / water (2 mL) at room temperature and heated at 110° C. for 1 hour by microwave irradiation, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated by removing the solvent under reduced pressure, and water was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, removed water with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained material was used as it was without further purification (title compound, 2.800 g, 91.0%, white solid).

[0289] [Step 2] Synthesis of 3-(piperazin-1-ylmethyl)pentan-3-ol TIFF2024515739000232.tif1578A solution of tert-butyl 4-(2-ethyl-2-hydroxybutyl)piperazine-1-carboxylate (0.600 g, 2.095 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 5.237 mL, 20.948 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.300 g, 76.9%, white solid).

[0290] [Step 3] Synthesis of tert-butyl (S)-2-(4-(2-ethyl-2-hydroxybutyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000233.tif22106 3-(piperazin-1-ylmethyl)pentan-3-ol (0.500 g, 2.684 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (1.155 g, 5.368 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate (2.041 g, 5.368 mmol), and N,N-diisopropylethylamine (0.935 mL, 5.368 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.200 g, 19.4%) as a white solid.

[0291] [Step 4] Synthesis of (S)-1-(2-ethyl-2-hydroxybutyl)-4-prolylpiperazine TIFF2024515739000234.tif24100 A solution of tert-butyl (S)-2-(4-(2-ethyl-2-hydroxybutyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.501 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in dioxane, 1.252 mL, 5.006 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.140 g, 93.4%, white solid).

[0292] [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-(2-ethyl-2-hydroxybutyl)piperazin-1-yl)methanone TIFF2024515739000235.tif22150 (S)-1-(2-ethyl-2-hydroxybutyl)-4-prolylpiperazine (0.200 g, 0.706 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.099 g, 0.353 mmol), and triethylamine (0.197 mL, 1.411 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, removed water with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 10%) to obtain the title compound (0.006 g, 1.8%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.54-8.06(m,2H),7.87(s,1H),7.06(d,J=3.1Hz,1H),6.68(d,J=3.3Hz,1H),5.03-4.91(m,1H),3.92-3.79(m,1H), 3.72-3.39(m,6H),2.89-2.55(m,2H),2.43-2.14(m,5H),2.01-1.75(m,3H),1.57-1.26(m,4H),0.80(t,J=7.0Hz,6H);LRMS(ES)m / z484.4(M + +1). Example 88: Synthesis of Compound 88 Example compound 88 was synthesized in a manner substantially similar to that of Example compound 42, except that 2-(5-methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in step 5.

[0293] Example 185: Synthesis of Compound 185 Example compound 185 was synthesized in a manner substantially similar to that of Example compound 42, except that (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0294] Example 347: Synthesis of Compound 347 Example compound 347 was synthesized in a manner substantially similar to that of Example compound 42, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0295] Example 348: Synthesis of Compound 348 Example compound 348 was synthesized in a manner substantially similar to that of Example compound 42, except that (tert-butoxycarbonyl)-L-valine was used instead of (tert-butoxycarbonyl)-L-proline in step 3.

[0296] Example 244: Synthesis of Compound 244 Example compound 244 was synthesized in a manner substantially similar to that of Example compound 42, except that tert-butyl[4,4′-bipiperidine]-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate in step 1, and 2,2-dimethyloxirane was used instead of 2,2-diethyloxirane.

[0297] Example 333: Synthesis of Compound 333 Example compound 333 was synthesized in a manner substantially similar to that of Example compound 244, except that (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline.

[0298] Example 373: Synthesis of Compound 373 Example compound 373 was synthesized in a manner substantially similar to that of Example compound 244, except that tert-butyl (R)-2-methylpiperazine-1-carboxylate was used instead of tert-butyl piperazine-1-carboxylate.

[0299] Example 381: Synthesis of Compound 381 Example compound 333 was synthesized in a manner substantially similar to that of Example compound 244, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0300] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 31]

[0301] TIFF2024515739000237.tif165158

[0302] TIFF2024515739000238.tif154158

[0303] TIFF2024515739000239.tif149158

[0304] TIFF2024515739000240.tif128158

[0305] Example 223: Synthesis of compound 223, (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-(2,2-difluoroethyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2,2-difluoroethyl)piperazine-1-carboxylate TIFF2024515739000241.tif131092,2-Difluoroethyl trifluoromethanesulfonate (95.00% solution 0.279mL, 1.899mmol), tert-butyl piperazine-1-carboxylate (0.354g, 1.899mmol), and N,N-diisopropylethylamine (0.331mL, 1.899mmol) were dissolved in tetrahydrofuran (5mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and an aqueous solution of N-ammonium chloride was poured into the concentrate. The organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 20%) to give the title compound (0.411 g, 86.1%) as a white solid.

[0306] [Step 2] Synthesis of 1-(2,2-difluoroethyl)piperazine hydrochloride TIFF2024515739000242.tif1581 A solution of tert-butyl 4-(2,2-difluoroethyl)piperazine-1-carboxylate (0.250 g, 0.999 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.186 g, 99.8%, white solid).

[0307] [Step 3] Synthesis of tert-butyl (S)-2-(4-(2,2-difluoroethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000243.tif22123A solution of 1-(2,2-difluoroethyl)piperazine hydrochloride (3.614 g, 19.365 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (4.168 g, 19.365 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 17.767 mL, 29.048 mmol), and N,N-diisopropylethylamine (10.119 mL, 58.095 mmol) in dichloromethane (130 mL) was stirred at room temperature for 18 hours. Aqueous N-sodium bicarbonate solution was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, and then water was removed with anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified and concentrated using column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol) to obtain the title compound (5.360 g, 79.7%) as a yellow liquid.

[0308] [Step 4] Synthesis of (S)-1-(2,2-difluoroethyl)-4-prolylpiperazine hydrochloride TIFF2024515739000244.tif22102 tert-Butyl (S)-2-(4-(2,2-difluoroethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (5.360 g, 15.428 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 15.428 mL, 61.714 mmol) in dichloromethane (65 mL) was stirred at 40° C. for 5 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was subjected to removal of the solvent under reduced pressure, and the resulting material was used as is without further purification (title compound, 4.377 g, 100.0%, white solid).

[0309] [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-(2,2-difluoroethyl)piperazin-1-yl)methanone TIFF2024515739000245.tif22155The (S)-1-(2,2-difluoroethyl)-4-prolylpiperazine hydrochloride (4.377 g, 15.426 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (4.323 g, 15.426 mmol), and sodium bicarbonate (3.887 g, 46.277 mmol) were dissolved in acetonitrile (90 mL) at room temperature and stirred at 80 °C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was subjected to reduced pressure to remove the solvent. The concentrate was then purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 20%) to give the title compound (4.240 g, 61.4%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.33(d,J=126.9Hz,2H),7.90-7.84(m,1H),7.06(ddd,J=7.7,3.4,0.9Hz,1H) ,6.68(dt,J=3.4,1.6Hz,1H),6.40-6.02(m,1H),4.99(ddd,J=12.5,8.6,3.1Hz,1H),4.12(q,J=5.3Hz ,1H),3.70-3.49(m,5H),3.17(d,J=5.1Hz,2H),2.82(tdd,J=17.4,10.3,4.2Hz,3H),2.58(d,J=9.2Hz ,1H),2.48-2.37(m,1H),2.26(ddd,J=12.2,8.1,3.8Hz,1H),1.96-1.79(m,3H).LRMS(ES)m / z448.3(M + +1).

[0310] Example 224: Synthesis of compound 224, (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-(2,2-difluoropropyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2,2-difluoropropyl)piperazine-1-carboxylate TIFF2024515739000246.tif141092,2-Difluoropropyl trifluoromethanesulfonate (0.456 g, 1.999 mmol), tert-butyl piperazine-1-carboxylate (0.372 g, 1.999 mmol), and N,N-diisopropylethylamine (0.348 mL, 1.999 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and N-ammonium chloride aqueous solution was poured into the concentrate. The organic layer was extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 20%) to obtain the title compound (0.423 g, 80.1%) as a white solid.

[0311] [Step 2] Synthesis of 1-(2,2-difluoropropyl)piperazine hydrochloride TIFF2024515739000247.tif1580A solution of tert-butyl 4-(2,2-difluoropropyl)piperazine-1-carboxylate (0.264 g, 0.999 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.200 g, 99.8%, white solid).

[0312] [Step 3] Synthesis of tert-butyl (S)-2-(4-(2,2-difluoropropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000248.tif20114A solution of 1-(2,2-difluoropropyl)piperazine hydrochloride (6.000 g, 29.901 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (6.436 g, 29.901 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 27.434 mL, 44.852 mmol), and N,N-diisopropylethylamine (15.624 mL, 89.704 mmol) in dichloromethane (150 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and an aqueous solution of N-sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then water was removed with anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to obtain the title compound (8.030 g, 74.3%) as a pale yellow liquid.

[0313] [Step 4] Synthesis of (S)-1-(2,2-difluoropropyl)-4-prolylpiperazine hydrochloride TIFF2024515739000249.tif2093 A solution of tert-butyl (S)-2-(4-(2,2-difluoropropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (8.030 g, 22.217 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 22.217 mL, 88.869 mmol) in dichloromethane (100 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 6.615 g, 100.0%, pale yellow solid).

[0314] [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-(2,2-difluoropropyl)piperazin-1-yl)methanone TIFF2024515739000250.tif21156 (S)-1-(2,2-difluoropropyl)-4-prolylpiperazine hydrochloride (5.000 g, 16.791 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (4.706 g, 16.791 mmol), and sodium bicarbonate (4.232 g, 50.374 mmol) were dissolved in acetonitrile (95 mL) at room temperature and stirred at 70 °C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was subjected to removal of the solvent under reduced pressure. The concentrate was then purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to give the title compound (2.920 g, 37.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.33(d,J=124.7Hz,2H),7.88(s,1H),7.06(s,1H),6.68(s,1H),4.98(t,J=10.6Hz,1H),3.63(t,J=9.8Hz,5H),3.17(d ,J=5.0Hz,1H),2.80(td,J=13.9,7.5Hz,3H),2.60(s,1H),2.46-2.19(m,2H),2.00-1.77(m,3H),1.66(t,J=19.1Hz,3H).LRMS(ES)m / z462.4(M + +1).

[0315] Example 294: Synthesis of compound 294, (S)-(1-(5-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)pyrrolidin-2-yl)(4-(2,2-difluoropropyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2,2-difluoropropyl)piperazine-1-carboxylate TIFF2024515739000251.tif14128tert-Butyl piperazine-1-carboxylate (0.559 g, 3.000 mmol), 2,2-difluoropropyl trifluoromethanesulfonate (0.447 mL, 3.000 mmol), and potassium carbonate (0.829 g, 6.000 mmol) were dissolved in acetonitrile (8 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was removed under reduced pressure to obtain a concentrate, which was poured into water, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane=1%) to obtain the title compound (0.790 g, 99.6%) as a white solid.

[0316] [Step 2] Synthesis of 1-(2,2-difluoropropyl)piperazine hydrochloride TIFF2024515739000252.tif1595A solution of tert-butyl 4-(2,2-difluoropropyl)piperazine-1-carboxylate (0.790 g, 2.989 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 5.978 mL, 23.910 mmol) in dichloromethane (6 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.599 g, 99.9%, white solid).

[0317] [Step 3] Synthesis of tert-butyl (S)-2-(4-(2,2-difluoropropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000253.tif20124A solution of 1-(2,2-difluoropropyl)piperazine hydrochloride (0.201 g, 1.000 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.215 g, 1.000 mmol), triethylamine (0.348 mL, 2.500 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 0.707 mL, 1.200 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane=1.5%) to obtain the title compound (0.360 g, 99.6%) as a colorless oil.

[0318] [Step 4] Synthesis of (S)-1-(2,2-difluoropropyl)-4-prolylpiperazine hydrochloride TIFF2024515739000254.tif20101 A solution of tert-butyl (S)-2-(4-(2,2-difluoropropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.360 g, 0.996 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.494 mL, 5.976 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.227 g, 76.4%, white solid).

[0319] [Step 5] Synthesis of (S)-(1-(5-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)pyrrolidin-2-yl)(4-(2,2-difluoropropyl)piperazin-1-yl)methanone TIFF2024515739000255.tif19148 (S)-1-(2,2-difluoropropyl)-4-prolylpiperazine hydrochloride (0.227 g, 0.761 mmol) prepared in step 4, 7-chloro-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (0.179 g, 0.761 mmol), and sodium bicarbonate (0.192 g, 2.284 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred at 100 ° C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%), and the resulting material was purified and concentrated again by chromatography (SiO2, 12 g cartridge; acetone / dichloromethane = 10% to 100%) to give the title compound (0.055 g, 15.8%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.86(dd,J=1.7,0.8Hz,1H),7.46(brs,2H),7.06(dd,J=3.4,0.6Hz,1H),6.67(dd,J=3.4,1.8Hz,1H),5.59(brs,1H),4.96(b rs,1H),3.79-3.38(m,5H),2.79(t,J=14.1Hz,3H),2.64-2.36(m,4H),2.2 4(s,1H),2.06-1.77(m,3H),1.66(t,J=19.1Hz,3H).LRMS(ES)m / z461.5(M + +1).

[0320] Example 371: Synthesis of compound 371, ((S)-1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)((R)-4-(2,2-difluoroethyl)-2-methylpiperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (R)-4-(2,2-difluoroethyl)-2-methylpiperazine-1-carboxylate TIFF2024515739000256.tif19133 tert-Butyl (R)-2-methylpiperazine-1-carboxylate (0.507 g, 2.531 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.542 g, 2.531 mmol), and potassium carbonate (1.050 g, 7.594 mmol) were dissolved in acetonitrile (10 mL) at room temperature and stirred for 18 hours at the same temperature. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was removed under reduced pressure to remove the solvent. The material obtained was used as is without further purification (title compound, 0.668 g, 99.8%, clear liquid).

[0321] [Step 2] Synthesis of (R)-1-(2,2-difluoroethyl)-3-methylpiperazine hydrochloride TIFF2024515739000257.tif1583 A solution of tert-butyl (R)-4-(2,2-difluoroethyl)-2-methylpiperazine-1-carboxylate (0.668 g, 2.527 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 2.527 mL, 10.109 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.507 g, 100.0%, white solid).

[0322] [Step 3] Synthesis of tert-butyl (S)-2-((R)-4-(2,2-difluoroethyl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000258.tif20105A solution of (R)-1-(2,2-difluoroethyl)-3-methylpiperazine hydrochloride (0.507 g, 2.527 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.544 g, 2.527 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 2.232 mL, 3.790 mmol), and N,N-diisopropylethylamine (1.320 mL, 7.580 mmol) in dichloromethane (10 mL) was stirred at room temperature. Pour N-sodium bicarbonate aqueous solution into the reaction mixture, and extract the organic layer with dichloromethane. Wash the organic layer with saturated sodium chloride aqueous solution, remove moisture with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained material was used as it is without further purification (title compound, 1.028g, 98.9%, pale yellow liquid).

[0323] [Step 4] Synthesis of (R)-1-(L-prolyl)-4-(2,2-difluoroethyl)-2-methylpiperazine hydrochloride TIFF2024515739000259.tif2090 A solution of tert-butyl (S)-2-((R)-4-(2,2-difluoroethyl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.903 g, 2.498 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in 1,4-dioxane, 2.498 mL, 9.994 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.743 g, 99.9%, white solid).

[0324] [Step 5] ((S)-1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrrolidin-2-yl)((R)-4-(2,2-difluoroethyl)-2-methylpiperazin-1-yl)methanone TIFF2024515739000260.tif19149 Step 4 (R)-1-(L-prolyl)-4-(2,2-difluoroethyl)-2-methylpiperazine hydrochloride (0.743 g, 2.495 mmol), 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.699 g, 2.495 mmol), and sodium bicarbonate (0.629 g, 7.486 mmol) were dissolved in acetonitrile (15 mL) at room temperature and stirred at 75 ° C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was subjected to removal of the solvent under reduced pressure. The concentrate was then purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 30%) to give the title compound (0.509 g, 44.2%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.56-7.93(m,2H),7.90-7.83(m,1H),7.06(dd,J=8.5,3.3Hz,1H),6.67 (ddd,J=6.4,3.3,1.6Hz,1H),6.39-5.95(m,1H),4.96(dddd,J=35.1,26.4,8.5,2.6Hz,1H),4.3 3(d,J=100.5Hz,1H),4.15-3.76(m,1H),3.70-3.53(m,2H),2.96-2.64(m,5H),2.48-2.00(m,3H ),1.98-1.69(m,3H),1.49(dd,J=15.8,6.6Hz,2H),1.13(d,J=6.8Hz,1H).LRMS(ES)m / z462.4(M + +1).

[0325] Example 258: Synthesis of Compound 258 Example compound 258 was synthesized in a manner substantially similar to that of Example compound 223, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in the synthesis method of Example compound 223.

[0326] Example 259: Synthesis of Compound 259 Example compound 259 was synthesized in a manner substantially similar to that of Example compound 224, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine in the synthesis method of Example compound 224.

[0327] Example 260: Synthesis of Compound 260 Example compound 260 was synthesized by a method substantially similar to the synthesis method of Example compound 223, except that in the synthesis method of Example compound 223, 1,1,2,2-tetrafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0328] Example 261: Synthesis of Compound 261 Example compound 261 was synthesized by a method substantially similar to the synthesis method of Example compound 223, except that in the synthesis method of Example compound 223, 1,1,1,2,2-pentafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0329] Example 269: Synthesis of Compound 269 Example compound 269 was synthesized in a manner substantially similar to that of Example compound 223, except that 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrooxazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine in the synthesis method of Example compound 223.

[0330] Example 270: Synthesis of Compound 270 Example compound 270 was synthesized by a method substantially similar to the synthesis method of example compound 223, except that in the synthesis method of example compound 223, 2,2-difluoro-1-((trifluoromethyl)sulfonyl)butane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrooxazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine.

[0331] Example 271: Synthesis of Compound 271 Example compound 271 was synthesized by a method substantially similar to the synthesis method of Example compound 223, except that in the synthesis method of Example compound 223, 1,1,2,2-tetrafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrooxazolo[5,4-d]pyrimidin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0332] Example 293: Synthesis of Compound 293 Example compound 293 was synthesized in a manner substantially similar to that of Example compound 223, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine in the synthesis method of Example compound 223.

[0333] Example 295: Synthesis of Compound 295 Example compound 295 was synthesized by a method substantially similar to the synthesis method of example compound 223, except that in the synthesis method of example compound 223, 2,2-difluoro-1-((trifluoromethyl)sulfonyl)butane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0334] Example 296: Synthesis of Compound 296 Example compound 296 was synthesized by a method substantially similar to the synthesis method of Example compound 223, except that in the synthesis method of Example compound 223, 1,1,1,2,2-pentafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0335] Examples 316, 317, 318 and 319 In the synthesis method of each of the example compounds 258, 259, 260 and 261, (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline, and 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-3a,7a-dihydrothiazolo[5,4-d]pyrimidin-7-amine. Except for this, example compounds 316, 317, 318 and 319 were synthesized by substantially the same method as each of the synthesis methods.

[0336] Example 320: Synthesis of Compound 320 Example compound 320 was synthesized by substantially the same method as that for synthesizing example compound 223, except that in the synthesis method for example compound 223, 1,1,1,2,2,3,3-heptafluoro-4-((trifluoromethyl)sulfonyl)butane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline.

[0337] Examples 323, 324, 325 and 326 Example compounds 323, 324, 325 and 326 were synthesized by substantially the same method as the synthesis method of each of Example compounds 316, 317, 318 and 319, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-alanine and tert-butyl[4,4′-bipiperidine]-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate.

[0338] Examples 334 and 335 Example compounds 334 and 335 were synthesized by substantially the same methods as those for synthesizing example compounds 316 and 317, except that tert-butyl[4,4′-bipiperidine]-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate.

[0339] Examples 252, 253, 255, 256, and 257 Example compounds 252, 253, 255, 256 and 257 were synthesized by substantially the same method as the synthesis method of example compounds 316, 317, 318 and 319, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-alanine.

[0340] Example 254: Synthesis of Compound 254 Example compound 254 was synthesized by substantially the same synthesis method as Example compound 225, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of tert-butoxycarbonyl-D-proline.

[0341] Examples 204, 205, 206, 225, 226, 227, 228, 278, 362, 363, 364, 365, 287, 288, 289, 337, 341, 342, 343 and 345 Example compounds 204, 205, 206, 225, 226, 227, 228, 278, 362, 363, 364, 365, 287, 288, 289, 337, 341, 342, 343 and 345 were synthesized in substantially the same manner as the synthesis method of example compound 224, except that starting material 1 in the table below was used instead of tert-butyl piperazine-1-carboxylate and starting material 2 in the table below was used instead of difluoropropyl trifluoromethanesulfonate in step 1 of the synthesis method of example compound 224. [Table 32]

[0342] TIFF2024515739000262.tif161153

[0343] Example 196: Synthesis of Compound 196 Example compound 196 was synthesized by a method substantially similar to the synthesis method of Example compound 205, except that in the synthesis method of Example compound 205, 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0344] Example 197: Synthesis of Compound 197 Example compound 197 was synthesized in a manner substantially similar to that of Example compound 196, except that tert-butyl (R)-2-methylpiperazine-1-carboxylate was replaced with tert-butyl [4,4′-bipiperidine]-1-carboxylate.

[0345] Example 279: Synthesis of Compound 279 Example compound 279 was synthesized by substantially the same method as that for synthesis of Example compound 223, except that 1,1,2,2-tetrafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0346] Example 280: Synthesis of Compound 280 Example compound 280 was synthesized by substantially the same method as that for synthesis of Example compound 223, except that 1,1,1,2,2-pentafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0347] Example 297: Synthesis of Compound 297 Example compound 297 was synthesized by substantially the same method as that for synthesizing example compound 223, except that 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0348] Example 298: Synthesis of Compound 298 Example compound 298 was synthesized by a method substantially similar to the synthesis method of example compound 223, except that 1,1,2,2-tetrafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0349] Example 299: Synthesis of Compound 299 Example compound 299 was synthesized by a method substantially similar to the synthesis method of example compound 223, except that 1,1,1,2,2-pentafluoro-3-((trifluoromethyl)sulfonyl)propane was used instead of 2,2-difluoroethyl trifluoromethanesulfonate, and 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0350] Example 311: Synthesis of Compound 311 Example compound 311 was synthesized by substantially the same method as that for synthesizing example compound 223, except that 2-(methylfuran-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine.

[0351] Example 312: Synthesis of Compound 312 Example compound 312 was synthesized in a manner substantially similar to that of Example compound 298, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of tert-butoxycarbonyl-D-proline.

[0352] Example 313: Synthesis of Compound 313 Example compound 313 was synthesized in a manner substantially similar to that of Example compound 299, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of tert-butoxycarbonyl-D-proline.

[0353] Example 314: Synthesis of Compound 314 Example compound 314 was synthesized in a manner substantially similar to that of Example compound 311, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of tert-butoxycarbonyl-D-proline.

[0354] Examples 354, 355, 356, 357, 358, 359 and 360 Example compounds 354, 355, 356, 357, 358, 359 and 360 were synthesized in substantially the same manner as the synthesis method of example compound 223, except that starting material 1 in the table below was used instead of 2,2-difluoroethyl trifluoromethanesulfonate in step 1, and a Boc-protected amino acid in the table below was used instead of (tert-butoxycarbonyl)-L-proline. [Table 33]

[0355] Examples 376, 377, 378, 379, 393 and 394 Using 2,2-difluoroethyl trifluoromethanesulfonate in step 1 or starting material 1 in the table below, (tert-butoxycarbonyl)-L-proline or a Boc-protected amino acid in the table below, and using 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine instead of 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the example compounds 376, 377, 378, 379, 393 and 394 were synthesized by substantially the same method as the synthesis method of example compound 223, respectively. [Table 34]

[0356] Example 366: Synthesis of Compound 366 Example compound 366 was synthesized in substantially the same manner as in the synthesis of Example compound 365, except that (tert-butoxycarbonyl)-L-alanine was used instead of (tert-butoxycarbonyl)-L-proline.

[0357] Example 396: Synthesis of Compound 396 Example compound 396 was synthesized in a manner substantially similar to that of Example compound 223, except that N-(tert-butoxycarbonyl)-O-methyl-L-serine was used instead of (tert-butoxycarbonyl)-L-proline.

[0358] Example 397: Synthesis of Compound 397 Example compound 397 was synthesized in a manner substantially similar to that of Example compound 224, except that N-(tert-butoxycarbonyl)-O-methyl-L-serine was used instead of (tert-butoxycarbonyl)-L-proline.

[0359] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below.

Table 35

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[0390] 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)piperazine-1-carboxylate TIFF2024515739000296.tif161143,3,3-Trifluoropropanoic acid (0.500g, 3.905mmol) and N,N-dimethylformamide (0.003mL, 0.039mmol) were dissolved in dichloromethane (10mL) at room temperature, to which oxalyl dichloride (0.335mL, 3.905mmol) was added and stirred at the same temperature for 1 hour. tert-Butyl piperazine-1-carboxylate (0.636g, 3.413mmol) and triethylamine (0.951mL, 6.826mmol) were dissolved in dichloromethane (10mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, and the moisture was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The resulting material was used as is without further purification (title compound, 1.000 g, 98.9%, white solid).

[0391] [Step 2] Synthesis of 3,3,3-trifluoro-1-(piperazin-1-yl)propan-1-one TIFF2024515739000297.tif1997 A solution of tert-butyl 4-(3,3,3-trifluoropropanoyl)piperazine-1-carboxylate (1.000 g, 3.375 mmol) prepared in step 1 and hydrochloric acid (0.615 g, 16.875 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting material was used as is without further purification (title compound, 0.500 g, 75.5%, white solid).

[0392] [Step 3] tert-Butyl (S)-2-(4-(3,3,3-trifluoropropanoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000298.tif271263,3,3-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 and stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the material used as is without further purification (title compound, 0.500 g, 49.9%, brown oil).

[0393] [Step 4] (S)-3,3,3-trifluoro-1-(4-prolylpiperazin-1-yl)propan-1-one TIFF2024515739000299.tif27103 A solution of tert-butyl (S)-2-(4-(3,3,3-trifluoropropanoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.508 mmol) prepared in step 3 and hydrochloric acid (0.093 g, 2.542 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.120 g, 80.5%, brown solid).

[0394] [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 TIFF2024515739000300.tif24142A solution of 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) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 18 h. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / ethyl acetate = 10%) to obtain the title compound (0.020 g, 22.7%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.64-8.09(m,1H),7.87(ddd,J=5.5,1.8,0.8Hz,1H),7.09-7.01(m,1H),6.68(ddd,J=5.6, 3.4,1.8Hz,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 / z494.5(M + +1).

[0395] Examples 74 to 77, 85 and 86 Example compounds 74 to 77, 85, and 86 were each synthesized in a manner substantially similar to that of Example compound 73, except that the starting materials shown in the table below were used instead of 3,3,3-trifluoropropanoic acid in step 1. [Table 36]

[0396] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 37]

[0397] TIFF2024515739000303.tif186158

[0398] Example 56: Synthesis of Compound 56, (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-(4,4-difluorocyclohexyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(4,4-difluorocyclohexyl)piperazine-1-carboxylate TIFF2024515739000304.tif201114,4-Difluorocyclohexan-1-one (0.402 g, 3.000 mmol), tert-butyl piperazine-1-carboxylate (0.559 g, 3.000 mmol), and sodium triacetoxyborohydride (0.954 g, 4.500 mmol) in dichloromethane (10 mL) were stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.910 g, 99.7%, pale yellow oil).

[0399] [Step 2] Synthesis of 1-(4,4-difluorocyclohexyl)piperazine hydrochloride TIFF2024515739000305.tif2593 tert-Butyl 4-(4,4-difluorocyclohexyl)piperazine-1-carboxylate (0.910 g, 2.990 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.990 mL, 11.959 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature for 5 hours. The precipitated solid was filtered, washed with dichloromethane and dried to obtain the title compound (0.710 g, 98.7%) as a white solid.

[0400] [Step 3] Synthesis of tert-butyl (S)-2-(4-(4,4-difluorocyclohexyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000306.tif25124A solution of 1-(4,4-difluorocyclohexyl)piperazine hydrochloride (0.710 g, 2.949 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (0.698 g, 3.244 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 1.131 g, 5.899 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 0.399 g, 2.949 mmol), and N,N-diisopropylethylamine (1.541 mL, 8.848 mmol) in dichloromethane (10 mL) at room temperature was stirred at the same temperature for 18 hours. The reaction mixture was poured into water, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as is without further purification (title compound, 1.180 g, 99.6%, pale yellow oil).

[0401] [Step 4] Synthesis of (S)-1-(4,4-difluorocyclohexyl)-4-prolylpiperazine hydrochloride TIFF2024515739000307.tif25110 A solution of tert-butyl (S)-2-(4-(4,4-difluorocyclohexyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (1.180 g, 2.939 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.939 mL, 11.756 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.990 g, 99.7%, pale yellow solid).

[0402] [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-(4,4-difluorocyclohexyl)piperazin-1-yl)methanone TIFF2024515739000308.tif23157 (S)-1-(4,4-difluorocyclohexyl)-4-prolylpiperazine hydrochloride (0.338 g, 1.000 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, 1.000 mmol), and triethylamine (0.418 mL, 3.000 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature and stirred for 18 hours at the same temperature. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and the solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%), and then the obtained material was stirred in dichloromethane (2 mL). The precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.131 g, 26.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.61-7.99(m,2H),7.92-7.82(m,1H),7.10-6.98(m,1H),6.73-6.61(m,1H),5.16-4.91(m,1H),3.99-3.53(m,5H) ,3.51-3.36(m,2H),2.95-2.65(m,1H),2.44-2.15(m,3H),2.15-1.70(m,9H),1.66-1.44(m,2H),1.39-1.16(m,1H);LRMS(ES)m / z502.6(M + +1).

[0403] Examples 152 to 156, 392 and 403 Example compounds 152 to 156, 392 and 403 were each synthesized in a manner substantially similar to that of Example compound 56, except that in step 1 of the synthesis method of Example compound 56, the starting material shown in the table below was used instead of 4,4-difluorocyclohexane-1-one. [Table 38]

[0404] Example 344: Synthesis of Compound 344 Example compound 344 was synthesized in a manner substantially similar to that of Example compound 56, except that cyclohexanone was used instead of 4,4-difluorocyclohexan-1-one in step 1, and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate was used instead of tert-butyl piperazine-1-carboxylate.

[0405] Example 398: Synthesis of Compound 398 Example compound 398 was synthesized in a manner substantially similar to that of Example compound 56, except that N-(tert-butoxycarbonyl)-O-methyl-L-serine was used instead of (tert-butoxycarbonyl)-L-proline.

[0406] Example 404: Synthesis of Compound 404 Example compound 404 was synthesized by substantially the same method as that for example compound 403, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0407] Example 291: Synthesis of Compound 291 Example compound 291 was synthesized in a manner substantially similar to that of Example compound 56, except that 4,4,4-trifluorobutanal was used instead of 4,4-difluorocyclohexan-1-one in step 1, and tert-butyl[4,4′-bipiperidine]-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate.

[0408] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 39]

[0409] TIFF2024515739000311.tif149156

[0410] TIFF2024515739000312.tif197156

[0411] TIFF2024515739000313.tif218156

[0412] TIFF2024515739000314.tif85156

[0413] Example 129: Synthesis of compound 129, (2S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)propan-1-one [Step 1] Synthesis of tert-butyl 3,5-dimethyl-4-(morpholine-4-carbonyl)piperazine-1-carboxylate TIFF2024515739000315.tif19117tert-Butyl 3,5-dimethylpiperazine-1-carboxylate (0.321 g, 1.500 mmol), N,N-diisopropylethylamine (0.261 mL, 1.500 mmol), and morpholine-4-carbonyl chloride (0.175 mL, 1.500 mmol) in acetonitrile (5 mL) were stirred at room temperature for 18 h. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0%~5%) to give the title compound (0.205 g, 41.7%) as a white solid.

[0414] [Step 2] Synthesis of (2,6-dimethylpiperazin-1-yl)(morpholino)methanone hydrochloride TIFF2024515739000316.tif20107A solution of tert-butyl 3,5-dimethyl-4-(morpholine-4-carbonyl)piperazine-1-carboxylate (0.205 g, 0.626 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.626 mL, 2.504 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.165 g, 99.9%, white solid).

[0415] [Step 3] Synthesis of tert-butyl ((2S)-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate TIFF2024515739000317.tif25123A solution of (2,6-dimethylpiperazin-1-yl)(morpholino)methanone hydrochloride (0.165 g, 0.626 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-alanine (0.130 g, 0.688 mmol), triethylamine (0.218 mL, 1.564 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 0.558 mL, 0.938 mmol) in dichloromethane (5 mL) was stirred at 40° C. for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as is without further purification (title compound, 0.249 g, 99.9%, pale yellow oil).

[0416] [Step 4] Synthesis of (2S)-2-amino-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)propan-1-one hydrochloride TIFF2024515739000318.tif25105 A solution of tert-butyl ((2S)-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (0.249 g, 0.625 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.625 mL, 2.499 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.209 g, 99.9%, white solid).

[0417] [Step 5] Synthesis of (2S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)propan-1-one TIFF2024515739000319.tif22155A solution of (2S)-2-amino-1-(3,5-dimethyl-4-(morpholine-4-carbonyl)piperazin-1-yl)propan-1-one hydrochloride (0.209 g, 0.624 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.175 g, 0.624 mmol), and sodium bicarbonate (0.210 g, 2.497 mmol) in cyclopentyl methyl ether (CPME, 4 mL) was stirred at 50° C. for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.069 g, 22.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.49-7.98(m,2H),7.90-7.82(m,1H),7.77-7.42(m,1H),7.06(dd,J=13.0,3.5Hz,1H),6.71-6.63(m ,1H),5.04-4.75(m,1H),3.89-3.36(m,11H),3.29-2.88(m,3H),1.36-1.24(m,3H),1.22-0.89(m,6H);LRMS(ES)m / z499.6(M + +1).

[0418] Example 179: Synthesis of Compound 179 Example compound 179 was synthesized in a manner substantially similar to that of Example compound 129, except that (tert-butoxycarbonyl)-L-proline was used instead of (tert-butoxycarbonyl)-L-alanine, and tert-butyl 3,5-dimethylpiperazine-1-carboxylate and morpholine-4-carbonyl chloride were used instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate and phenylcarbamic acid chloride, respectively.

[0419] Examples 180 to 184 Example compounds 180 to 184 were each synthesized in a manner substantially similar to that of Example compound 179, except that the compound in the table below was used as a starting material instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. [Table 40]

[0420] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 41]

[0421] TIFF2024515739000322.tif186158

[0422] TIFF2024515739000323.tif212158

[0423] Example 43: Synthesis of compound 43, (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-(2-ethyl-2-fluorobutyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(2-ethyl-2-fluorobutyl)piperazine-1-carboxylate TIFF2024515739000324.tif1496 tert-Butyl 4-(2-ethyl-2-hydroxybutyl)piperazine-1-carboxylate (3.000 g, 10.474 mmol) was dissolved in dichloromethane (300 mL), and dust (2.076 mL, 15.711 mmol) was added at 0 °C and stirred at the same temperature for 30 minutes, and then stirred at room temperature for another 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, and after removing moisture with anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 25%) to obtain the title compound (0.500 g, 16.6%) as a colorless oil.

[0424] [Step 2] Synthesis of 1-(2-ethyl-2-fluorobutyl)piperazine TIFF2024515739000325.tif1475A solution of tert-butyl 4-(2-ethyl-2-fluorobutyl)piperazine-1-carboxylate (0.500 g, 1.734 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution in dioxane, 4.334 mL, 17.336 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.320 g, 98.0%, brown solid).

[0425] [Step 3] tert-Butyl (S)-2-(4-(2-ethyl-2-fluorobutyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000326.tif22115 1-(2-ethyl-2-fluorobutyl)piperazine (0.500 g, 2.655 mmol) prepared in step 2, (tert-butoxycarbonyl)-L-proline (1.143 g, 5.311 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate (2.019 g, 5.311 mmol), and N,N-diisopropylethylamine (0.925 mL, 5.311 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.200 g, 19.5%) as a white solid.

[0426] [Step 4] Synthesis of (S)-1-(2-ethyl-2-fluorobutyl)-4-prolylpiperazine TIFF2024515739000327.tif25102 A solution of tert-butyl (S)-2-(4-(2-ethyl-2-fluorobutyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.200 g, 0.519 mmol) prepared in step 3 and hydrochloric acid (4.00 M solution in dioxane, 1.297 mL, 5.188 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.140 g, 94.6%, white solid).

[0427] [Step 5] (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-(2-ethyl-2-fluorobutyl)piperazin-1-yl)methanone TIFF2024515739000328.tif22149 (S)-1-(2-ethyl-2-fluorobutyl)-4-prolylpiperazine (0.150 g, 0.526 mmol) prepared in step 4, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.074 g, 0.263 mmol), and triethylamine (0.147 mL, 1.051 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, removed water with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 10%) to obtain the title compound (0.005 g, 2.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.64-8.08(m,2H),7.87(s,1H),7.09-7.01(m,1H),6.68(s,1H),5.05-4.92(m, 1H),3.77-3.36(m,6H),2.81-2.21(m,6H),2.03-1.58(m,8H),0.91-0.79(m,6H);LRMS(ES)m / z486.5(M + +1).

[0428] Example 245: Synthesis of Compound 245 Example compound 245 was synthesized in a manner substantially similar to that of Example compound 43, except that tert-butyl 1'-(2-ethyl-2-hydroxybutyl)-[4,4'-bipiperidine]-1-carboxylate was used instead of tert-butyl 4-(2-ethyl-2-hydroxybutyl)piperazine-1-carboxylate in step 1.

[0429] Examples 322 and 332 Example compounds 322 and 332 were synthesized in a manner substantially similar to that of Example compound 245, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid and (tert-butoxycarbonyl)-L-alanine were used instead of (tert-butoxycarbonyl)-L-proline, respectively.

[0430] Example 374: Synthesis of compound 374 Example compound 374 was synthesized in a manner substantially similar to that of Example compound 43, except that tert-butyl (R)-4-(2-hydroxy-2-methylpropyl)-2-methylpiperazine-1-carboxylate was used instead of tert-butyl 4-(2-ethyl-2-hydroxybutyl)piperazine-1-carboxylate in step 1.

[0431] Example 382: Synthesis of Compound 382 Example compound 382 was synthesized in a manner substantially similar to that of Example compound 322, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0432] Example 395: Synthesis of Compound 395 Example compound 395 was synthesized by substantially the same method as that for synthesis of Example compound 245, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0433] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 42] TIFF2024515739000330.tif175156 TIFF2024515739000331.tif186156 TIFF2024515739000332.tif96156

[0434] Example 282: Synthesis of Compound 282 [Step 1] Synthesis of tert-butyl 4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate TIFF2024515739000333.tif191133,3,3-Trifluoro-2,2-dimethylpropanoic acid (1.000 g, 6.406 mmol), oxalyl chloride (0.550 mL, 6.406 mmol), and N,N-dimethylformamide (0.049 mL, 0.641 mmol) were dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 18 hours. tert-Butyl piperazine-1-carboxylate (1.067 g, 5.729 mmol), and triethylamine (1.597 mL, 11.458 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of ammonium chloride was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the material used as is without further purification (title compound, 1.800 g, 96.9%, white oil).

[0435] [Step 2] Synthesis of tert-butyl 4-((1-(trifluoromethyl)cyclobutyl)methyl)piperazine-1-carboxylate TIFF2024515739000334.tif16102 tert-Butyl 4-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperazine-1-carboxylate (2.000 g, 6.166 mmol) prepared in step 2, boron trifluoride (45.00% solution in Et2O, 4.647 mL, 30.832 mmol), and sodium borohydride (0.467 g, 12.333 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed moisture with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 1.500 g, 78.4%, brown oil).

[0436] [Step 3] 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine TIFF2024515739000335.tif1497A solution of tert-butyl 4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate (1.500 g, 4.833 mmol) prepared in step 2 and hydrochloric acid (4.00 M solution in dioxane, 12.083 mL, 48.331 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.900 g, 88.6%, brown oil).

[0437] [Step 4] tert-Butyl (S)-2-(4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000336.tif22121 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine (1.000 g, 4.756 mmol) prepared in step 3, L-proline (1.095 g, 9.513 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.617 g, 9.513 mmol), and N,N-diisopropylethylamine (4.142 mL, 23.782 mmol) were dissolved in dichloromethane (20 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the material used as is without further purification (title compound, 1.500 g, 77.4%, brown oil).

[0438] [Step 5] (S)-1-Prolyl-4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine TIFF2024515739000337.tif24137 A solution of tert-butyl (S)-2-(4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.300 g, 0.736 mmol) prepared in step 5 and hydrochloric acid (0.268 g, 7.362 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.200 g, 88.4%, brown oil).

[0439] [Step 6] (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-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazin-1-yl)methanone TIFF2024515739000338.tif21148A solution of (S)-1-prolyl-4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine (0.200 g, 0.651 mmol) prepared in step 5, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.182 g, 0.651 mmol), and sodium bicarbonate (0.164 g, 1.952 mmol) in acetonitrile (5 mL) at room temperature was stirred at 70 °C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.010 g, 3.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.30(m,2H),7.87(ddd,J=2.6,1.8,0.8Hz,1H),7.06(ddd,J=6.5,3.4,0.8Hz,1H),6.69-6.61(m,1H),5.06- 4.90(m,1H),3.76-3.40(m,6H),2.77(m,1H),2.60-2.34(m,5H),2.26(m,1H),1.96-1.75(m,3H),1.11(m,6H);LRMS(ES)m / z508.5(M + +1). Examples 283, 284, 285, 286, 330 and 389 Example compounds 283, 284, 285, 286, 330 and 389 were each synthesized in a manner substantially similar to that of Example compound 282, except that the compounds in the table below were used as starting materials instead of 3,3,3-trifluoro-2,2-dimethylpropanoic acid. [Table 43]

[0440] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 44]

[0441] TIFF2024515739000341.tif218156

[0442] TIFF2024515739000342.tif128156

[0443] Example 130: Synthesis of compound 130, 1-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)-N-(3-fluorophenyl)piperidine-4-carboxamide [Step 1] Synthesis of tert-butyl 4-((3-fluorophenyl)carbamoyl)piperidine-1-carboxylate TIFF2024515739000343.tif241241-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (0.229 g, 1.000 mmol), 3-fluoroaniline (0.096 mL, 1.000 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 0.892 mL, 1.500 mmol), and N,N-diisopropylethylamine (0.523 mL, 3.000 mmol) in dichloromethane (5 mL) were stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification. Title compound, 0.322 g, 99.9%, pale yellow oil).

[0444] [Step 2] Synthesis of N-(3-fluorophenyl)piperidine-4-carboxamide hydrochloride TIFF2024515739000344.tif25102 A solution of tert-butyl 4-((3-fluorophenyl)carbamoyl)piperidine-1-carboxylate (0.322 g, 0.999 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.258 g, 99.8%, pale yellow oil).

[0445] [Step 3] Synthesis of tert-butyl (S)-2-(4-((3-fluorophenyl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000345.tif30122A solution of N-(3-fluorophenyl)piperidine-4-carboxamide hydrochloride (0.258 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, 0.889 mL, 1.496 mmol), and N,N-diisopropylethylamine (0.521 mL, 2.992 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as it was without further purification (title compound, 0.410 g, 98.0%, pale yellow oil).

[0446] [Step 4] Synthesis of (S)-N-(3-fluorophenyl)-1-prolylpiperidine-4-carboxamide hydrochloride TIFF2024515739000346.tif30126 A solution of tert-butyl (S)-2-(4-((3-fluorophenyl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate (0.419 g, 0.999 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.350 g, 98.5%, pale yellow oil).

[0447] [Step 5] Synthesis of 1-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-prolyl)-N-(3-fluorophenyl)piperidine-4-carboxamide TIFF2024515739000347.tif23157A solution of (S)-N-(3-fluorophenyl)-1-prolylpiperidine-4-carboxamide hydrochloride (0.356 g, 1.000 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, 1.000 mmol), and sodium bicarbonate (0.252 g, 3.001 mmol) in cyclopentyl methyl ether (CPME, 5 mL) was stirred at 50 °C for 18 h, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of ammonium chloride was poured into the concentrate. The organic layer was extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 5%) to obtain the title compound (0.109 g, 21.0%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ10.46-10.07(m,1H),8.27(d,J=95.0Hz,1H),7.89-7.81(m,1H),7.67(dd,J=40 .6,11.7Hz,1H),7.33(d,J=8.0Hz,2H),7.05(dd,J=9.5,3.4Hz,1H),6.95-6.83(m,1H),6.68(td,J=3.4 ,1.8Hz,1H),5.12-4.92(m,1H),4.44-4.28(m,1H),4.21-4.01(m,1H),3.71-3.56(m,2H),3.30-3.12(m ,1H),2.82-2.58(m,2H),2.39-2.13(m,1H),1.98-1.77(m,5H),1.68-1.39(m,2H).LRMS(ES)m / z521.5(M + +1).

[0448] Examples 131, 132 and 133 Example compounds 131, 132 and 133 were each synthesized in a manner substantially similar to that of Example compound 130, except that the compound in the table below was used as a starting material instead of 3-fluoroaniline. [Table 45]

[0449] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 46]

[0450] TIFF2024515739000350.tif106156

[0451] Example 331: Synthesis of compound 331, (2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)pyrazolidin-1-yl)(4-(2,2,2-trifluoroethyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl 4-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidine-1-carboxylate TIFF2024515739000351.tif191101-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (3.000 g, 13.084 mmol), oxalyl dichloride (1.122 mL, 13.084 mmol), and N,N-dimethylformamide (0.050 mL, 0.654 mmol) were dissolved in dichloromethane (30 mL) at room temperature and stirred at the same temperature for 1 hour. To this solution, 4-(trifluoromethyl)piperidine (1.236 g, 8.074 mmol) and triethylamine (1.688 mL, 12.110 mmol) were added to a solution of dichloromethane (5 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and water was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the material used as is without further purification (title compound, 1.500 g, 102.0%, white solid).

[0452] [Step 2] Synthesis of tert-butyl 4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate TIFF2024515739000352.tif19101 tert-Butyl 4-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidine-1-carboxylate (1.500 g, 4.116 mmol) prepared in step 1, boron trifluoride (45.00% solution in Et2O, 0.457 mL, 20.581 mmol), and sodium borohydride (0.311 g, 8.232 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, removed moisture with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was used as is without further purification (title compound, 0.500 g, 34.7%, white solid).

[0453] [Step 3] Synthesis of 1-(piperidin-4-ylmethyl)-4-(trifluoromethyl)piperidine TIFF2024515739000353.tif14112 A solution of tert-butyl 4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (0.500 g, 1.427 mmol) prepared in step 2 and hydrochloric acid (4.00 M solution in dioxane, 1.784 mL, 7.134 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.300 g, 84.0%, white solid).

[0454] [Step 4] Synthesis of tert-butyl (S)-2-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000354.tif24134A solution of 1-(piperidin-4-ylmethyl)-4-(trifluoromethyl)piperidine (0.300 g, 1.199 mmol) prepared in step 3, (tert-butoxycarbonyl)-L-proline (0.516 g, 2.397 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.911 g, 2.397 mmol), and N,N-diisopropylethylamine (1.044 mL, 5.993 mmol) in dichloromethane (30 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated by removing the solvent under reduced pressure, and an aqueous solution of N-sodium bicarbonate was poured into the concentrate, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The obtained material was used as it was without further purification (title compound, 0.500 g, 93.2%, brown oil).

[0455] [Step 5] Synthesis of (S)-1-prolyl-4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine TIFF2024515739000355.tif24131 A solution of tert-butyl (S)-2-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate (0.300 g, 0.670 mmol) prepared in step 4 and hydrochloric acid (4.00 M solution in dioxane, 1.676 mL, 6.703 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed of the solvent under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.200 g, 85.9%, brown oil).

[0456] [Step 6] 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-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone TIFF2024515739000356.tif19142 A solution of (S)-1-prolyl-4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidine (0.300 g, 0.863 mmol) prepared in step 5, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.060 g, 0.216 mmol), and sodium bicarbonate (0.218 g, 2.590 mmol) in acetonitrile (20 mL) at room temperature was stirred at 70 °C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / dichloromethane = 10%) to obtain the title compound (0.005 g, 1.1%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.56-8.03(m,2H),7.87(d,J=1.7Hz,1H),7.09-6.95(m,1H),6.68(s,1H),5.01(m,1H),4.41-3.87(m,2H), 3.73-3.44(m,4H),3.24-2.85(m,6H),2.38-2.02(m,4H),2.01-1.57(m,8H),1.48(s,1H),1.10-0.75(m,2H);LRMS(ES)m / z548.6(M + +1).

[0457] Example 402: Synthesis of Compound 402 Example compound 402 was synthesized in a manner substantially similar to that of Example compound 331, except that (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was used instead of (tert-butoxycarbonyl)-L-proline.

[0458] Example 406: Synthesis of Compound 406 Example compound 406 was synthesized in a manner substantially similar to that of Example compound 331, except that 3-fluoroazetidine was used instead of 4-(trifluoromethyl)piperidine.

[0459] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 47]

[0460] Example 186: Synthesis of compound 186, (S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-2-cyclohexyl-1-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)ethan-1-one [Step 1] Synthesis of tert-butyl 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate TIFF2024515739000358.tif1489tert-Butyl 4-oxopiperidine-1-carboxylate (0.500 g, 2.509 mmol), 3,3-difluoroazetidine (0.325 g, 2.509 mmol), sodium triacetoxyborohydride (0.798 g, 3.764 mmol), and triethylamine (0.350 mL, 2.509 mmol) in dichloromethane (10 mL) were stirred at room temperature for 18 hours. The reaction mixture was poured into aqueous sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.653 g, 94.2%, clear oil).

[0461] [Step 2] Synthesis of 4-(3,3-difluoroazetidin-1-yl)piperidine hydrochloride TIFF2024515739000359.tif2095A solution of tert-butyl 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate (0.653 g, 2.363 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.363 mL, 9.452 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.502 g, 99.9%, white solid).

[0462] [Step 3] Synthesis of tert-butyl (S)-(1-cyclohexyl-2-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2-oxoethyl)carbamate TIFF2024515739000360.tif30119A solution of 4-(3,3-difluoroazetidin-1-yl)piperidine hydrochloride (0.258 g, 1.213 mmol) prepared in step 2, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (0.312 g, 1.213 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 1.082 mL, 1.820 mmol), and N,N-diisopropylethylamine (0.634 mL, 3.639 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into an aqueous solution of N-sodium bicarbonate, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as is without further purification (title compound, 0.415g, 82.3%, clear oil).

[0463] [Step 4] Synthesis of (S)-2-amino-2-cyclohexyl-1-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)ethan-1-one hydrochloride TIFF2024515739000361.tif30100 A solution of tert-butyl (S)-(1-cyclohexyl-2-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2-oxoethyl)carbamate (0.415 g, 0.999 mmol) prepared in step 3 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.999 mL, 3.995 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.351 g, 99.9%, pale yellow solid).

[0464] [Step 5] Synthesis of (S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-2-cyclohexyl-1-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)ethan-1-one TIFF2024515739000362.tif30154 A solution of (S)-2-amino-2-cyclohexyl-1-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)ethan-1-one hydrochloride (0.351 g, 0.998 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, 0.998 mmol), and sodium bicarbonate (0.251 g, 2.993 mmol) in acetonitrile (5 mL) at room temperature was stirred at 70° C. for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was subjected to reduced pressure to remove the solvent. The concentrate was then purified and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0% to 10%), and the obtained substance was again purified and concentrated by chromatography (SiO2 plate, 20 × 20 × 1 mm; dichloromethane / methanol) to give the title compound (0.041 g, 7.9%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ9.71(s,1H),8.47(dd,J=23.4,9.4Hz,1H),7.57( dd,J=3.1,1.7Hz,1H),7.23-7.07(m,1H),6.54(dt,J=3.8,2.0Hz,1H),6.28(s,1 H),5.23-5.05(m,1H),4.41-4.05(m,2H),3.66-3.44(m,5H),3.22-3.09(m,1H) ,2.51-2.35(m,1H),1.96-1.52(m,9H),1.21-0.89(m,6H).LRMS(ES)m / z516.6(M + +1).

[0465] Example 390: Synthesis of Compound 390 Example compound 390 was synthesized in a manner substantially similar to that of Example compound 186, except that (tert-butoxycarbonyl)-L-proline was used instead of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid.

[0466] Example 391: Synthesis of Compound 391 Example compound 391 was synthesized in a manner substantially similar to that of Example compound 390, except that 4,4-difluoropiperidine was used instead of 3,3-difluoroazetidine.

[0467] Example 400: Synthesis of Compound 400 Example compound 400 was synthesized by substantially the same method as that for example compound 390, except that 2-(furan-2-yl)-7-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine was used instead of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

[0468] Example 405: Synthesis of Compound 405 Example compound 405 was synthesized in a manner substantially similar to that of Example compound 390, except that 1-(2-methoxyethyl)piperazine was used instead of 3,3-difluoroazetidine, and tert-butyl 3-oxoazetidine-1-carboxylate was used instead of tert-butyl 4-oxopiperidine-1-carboxylate.

[0469] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 48]

[0470] TIFF2024515739000364.tif160156

[0471] Example 25: Synthesis of Compound 25, (S)-2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one [Step 1] Synthesis of benzyl 4-((tert-butoxycarbonyl)-L-alanyl)piperazine-1-carboxylate TIFF2024515739000365.tif24149A solution of benzylpiperazine-1-carboxylate (1.000 g, 4.540 mmol), (tert-butoxycarbonyl)-L-alanine (0.859 g, 4.540 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 2.611 g, 13.620 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 1.840 g, 13.620 mmol), and N,N-diisopropylethylamine (3.954 mL, 22.699 mmol) in dichloromethane (30 mL) was stirred at room temperature for 18 hours. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 10%) to give the title compound (1.200 g, 67.5%) as a colorless oil.

[0472] [Step 2] Synthesis of tert-butyl (S)-(1-oxo-1-(piperazin-1-yl)propan-2-yl)carbamate JPEG2024515739000366.jpg30129 Benzyl 4-((tert-butoxycarbonyl)-L-alanyl)piperazine-1-carboxylate (1.200 g, 3.065 mmol) prepared in step 1 was dissolved in methanol (20 mL) and stirred at room temperature, then Pd / C (0.100 mg) was added slowly at the same temperature, and the mixture was stirred for 18 hours at the same temperature with a hydrogen balloon. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was removed of the solvent under reduced pressure, and the obtained material was used as is without further purification (title compound, 0.746 g, 94.6%, colorless oil).

[0473] [Step 3] Synthesis of tert-butyl (S)-(1-oxo-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-2-yl)carbamate JPEG2024515739000367.jpg20150 tert-Butyl (S)-(1-oxo-1-(piperazin-1-yl)propan-2-yl)carbamate (0.080 g, 0.311 mmol) prepared in step 2, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.072 g, 0.311 mmol), and potassium carbonate (0.086 g, 0.622 mmol) were dissolved in acetonitrile (2 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was removed from the solvent under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.065 g, 61.6%, light brown oil).

[0474] [Step 4] Synthesis of (S)-2-amino-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one JPEG2024515739000368.jpg24137A solution of tert-butyl (S)-(1-oxo-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-2-yl)carbamate (0.065 g, 0.192 mmol) prepared in step 3 and trifluoroacetic acid (0.147 mL, 1.915 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.042 g, 91.7%, yellow oil).

[0475] [Step 5] 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-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one JPEG2024515739000369.jpg20153 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.042 g, 0.150 mmol) prepared in step 4, (S)-2-amino-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one (0.036 g, 0.150 mmol), and triethylamine (0.042 mL, 0.300 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and the solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.010 g, 15.3%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.40(s,1H),8.02(d,J=8.6Hz,1H),7.61(s,1H),7 .21(s,1H),6.59(s,1H),5.39-5.31(m,1H),4.05-3.97(m,1H),3.93-3.85(m,1H) ),3.74-3.67(m,1H),3.59-3.50(m,1H),3.15-2.98(m,2H),2.93-2.81(m,2H),2 .78-2.74(m,1H),2.70-2.62(m,1H),1.44(d,J=6.8Hz,3H).LRMS(ES)m / z440.4(M + +1).

[0476] Example 4: Synthesis of Compound 4 Example compound 4 was synthesized in a manner substantially similar to that for example compound 25, except that (tert-butoxycarbonyl)-L-phenylalanine was used instead of (tert-butoxycarbonyl)-L-alanine. 1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.69(d,J=9.2Hz,1H),7.62(s,1H),7.32-7.07 (m,5H),6.59(s,1H),6.32(s,1H),5.63(q,J=8.4Hz,1H),3.81-3.71(m,1H),3.68-3.60(m ,1H),3.57-3.48(m,2H),3.09(d,J=7.7Hz,2H),2.91(q,J=9.0,8.5Hz,2H),2.70-2.64(m, 1H),2.64-2.54(m,1H),2.41(t,J=9.3Hz,1H),2.04(t,J=9.6Hz,1H);LRMS(ES)m / z516.3(M + +1). Example 64: Synthesis of Compound 64, (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)(2,4-difluorophenyl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate A solution of (tert-butoxycarbonyl)-L-proline (10.763 g, 50.000 mmol), piperazine (12.920 g, 150.000 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 19.170 g, 100.000 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 7.432 g, 55.000 mmol), and N,N-diisopropylethylamine (26.127 mL, 150.000 mmol) in dichloromethane (200 mL) at room temperature was stirred at the same temperature for 18 h. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80 g cartridge; methanol / dichloromethane = 0% to 15%) to obtain the title compound (6.718 g, 47.4%) as a white solid.

[0477] [Step 2] Synthesis of tert-butyl (S)-2-(4-(2,4-difluorobenzoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000371.tif24135A solution of tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.283 g, 1.000 mmol) prepared in step 1 and 2,4-difluorobenzoyl chloride (0.124 mL, 1.000 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the material obtained was used as is without further purification (title compound, 0.420 g, 99.2%, pale yellow oil).

[0478] [Step 3] Synthesis of (S)-(2,4-difluorophenyl)(4-prolylpiperazin-1-yl)methanone hydrochloride TIFF2024515739000372.tif25119A solution of tert-butyl (S)-2-(4-(2,4-difluorobenzoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.420 g, 0.992 mmol) prepared in step 2 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.992 mL, 3.967 mmol) in dichloromethane (3 mL) was stirred at room temperature for 3 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.356 g, 99.8%, white solid).

[0479] [Step 4] Synthesis of (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)(2,4-difluorophenyl)methanone TIFF2024515739000373.tif20159A solution of (S)-(2,4-difluorophenyl)(4-prolylpiperazin-1-yl)methanone hydrochloride (0.356 g, 0.989 mmol) prepared in step 3, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.277 g, 0.989 mmol), and triethylamine (0.414 mL, 2.968 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.227 g, 43.7%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.75-8.05(m,2H),7.97-7.80(m,1H),7.74-7.48(m,1H),7.47-7.33(m,1H),7.34-7.14(m,1H),7.13-7. 00(m,1H),6.74-6.61(m,1H),5.11-4.88(m,1H),4.03-3.38(m,10H),2.38-2.13(m,1H),2.03-1.77(m,3H);LRMS(ES)m / z524.5(M + +1).

[0480] Example 5: Synthesis of Compound 5 Example compound 5 was synthesized in a manner substantially similar to that of Example compound 64, except that (tert-butoxycarbonyl)-L-phenylalanine was used instead of (tert-butoxycarbonyl)-L-proline, and isobutyryl chloride was used instead of 2,4-difluorobenzoyl chloride.

[0481] Examples 46 and 63 Example compounds 46 and 63 were synthesized by substantially the same method as that for synthesizing Example compound 64, except that benzoyl chloride and 3-hydroxybenzoyl chloride, respectively, were used instead of 2,4-difluorobenzoyl chloride.

[0482] Example 99: Synthesis of Compound 99 Example compound 99 was synthesized in a manner substantially similar to that of Example compound 64, except that (tert-butoxycarbonyl)-D-proline was used instead of (tert-butoxycarbonyl)-L-proline, and morpholine-4-carbonyl chloride was used instead of 2,4-difluorobenzoyl chloride.

[0483] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 49]

[0484] TIFF2024515739000375.tif77158

[0485] Example 71: Synthesis of compound 71, (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-(isopropylsulfonyl)piperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(4-(isopropylsulfonyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000376.tif25122 tert-Butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.283 g, 1.000 mmol) prepared in step 1 of Example 64, propane-2-sulfonyl chloride (0.226 mL, 2.000 mmol), and potassium carbonate (0.415 g, 3.000 mmol) were dissolved in acetonitrile (8 mL) at room temperature and stirred at 50° C. for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.770 g, 98.8%, pale yellow oil).

[0486] [Step 2] Synthesis of (S)-1-(isopropylsulfonyl)-4-prolylpiperazine hydrochloride TIFF2024515739000377.tif25107A solution of tert-butyl (S)-2-(4-(isopropylsulfonyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.770 g, 1.977 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.977 mL, 7.907 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 hours. The reaction mixture was removed under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.640 g, 99.4%, pale yellow oil).

[0487] [Step 3] 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-(isopropylsulfonyl)piperazin-1-yl)methanone TIFF2024515739000378.tif22159A solution of 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.400 g, 1.427 mmol) prepared in step 2, (S)-1-(isopropylsulfonyl)-4-prolylpiperazine hydrochloride (0.651 g, 1.998 mmol), and sodium bicarbonate (0.360 g, 4.282 mmol) in cyclopentyl methyl ether (CPME, 10 mL) was stirred at 70 °C for 18 h, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.068 g, 9.7%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.70-8.09(m,2H),7.90-7.84(m,1H),7.10-6.98(m,1H),6.75-6.63(m,1H),5.09-4.92(m,1H),3.97-3. 53(m,6H),3.53-3.38(m,3H),3.31-3.11(m,2H),2.32-2.16(m,1H),2.05-1.78(m,3H),1.36-1.18(m,6H);LRMS(ES)m / z490.6(M + +1).

[0488] Example 6: Synthesis of Compound 6 Example compound 6 was synthesized in a manner substantially similar to that of Example compound 71, except that benzenesulfonyl chloride was used instead of propane-2-sulfonyl chloride, and (tert-butoxycarbonyl)-L-phenylalanine was used instead of (tert-butoxycarbonyl)-L-proline.

[0489] Examples 68, 69, 70 and 72 Example compounds 68, 69, 70 and 72 were synthesized in substantially the same manner as the synthesis method of Example compound 71, except that the compound in the table below was used as a starting material instead of propane-2-sulfonyl chloride. [Table 50]

[0490] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 51]

[0491] TIFF2024515739000381.tif207156

[0492] TIFF2024515739000382.tif106156

[0493] Example 111: Synthesis of compound 111, (S)-(1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-2-yl)(4-butylpiperazin-1-yl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate TIFF2024515739000383.tif19129(S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (2.012 g, 10.000 mmol), piperazine (2.584 g, 30.000 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 8.918 mL, 15.000 mmol) were dissolved in dichloromethane (40 mL) at room temperature and stirred for 18 hours at the same temperature. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.508 g, 18.9%) as a colorless oil.

[0494] [Step 2] Synthesis of tert-butyl (S)-2-(4-butylpiperazine-1-carbonyl)azetidine-1-carboxylate TIFF2024515739000384.tif17136A solution of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate (0.150 g, 0.557 mmol) prepared in step 1, N,N-diisopropylethylamine (0.097 mL, 0.557 mmol), and 1-bromobutane (0.060 mL, 0.557 mmol) in acetonitrile (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.181 g, 99.9%, colorless oil).

[0495] [Step 3] Synthesis of (S)-azetidin-2-yl(4-butylpiperazin-1-yl)methanone hydrochloride TIFF2024515739000385.tif16114 tert-Butyl (S)-2-(4-butylpiperazine-1-carbonyl)azetidine-1-carboxylate (0.181 g, 0.556 mmol) prepared in step 2 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.556 mL, 2.225 mmol) in dichloromethane (3 mL) were stirred at 40° C. for 4 hours, and the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained material was used as is without further purification (title compound, 0.145 g, 99.6%, white solid).

[0496] [Step 4] Synthesis of (S)-(1-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-2-yl)(4-butylpiperazin-1-yl)methanone TIFF2024515739000386.tif18153A solution of (S)-azetidin-2-yl(4-butylpiperazin-1-yl)methanone hydrochloride (0.145 g, 0.554 mmol) prepared in step 3, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.155 g, 0.554 mmol), and sodium bicarbonate (0.140 g, 1.662 mmol) in cyclopentyl methyl ether (CPME, 4 mL) was stirred at 50 °C for 18 h, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.135 g, 57.5%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.78-8.01(m,2H),7.92-7.82(m,1H),7.12-6.99(m,1H),6.73-6.62(m,1H),5.20(dd,1H),4.10-3.89(m,2H),3.8 6-3.14(m,5H),2.74-2.55(m,1H),2.46-2.02(m,6H),1.50-1.35(m,2H),1.35-1.19(m,2H),0.88(t,J=7.3Hz,3H).;LRMS(ES)m / z426.6(M + +1).

[0497] Examples 17 and 18 Example compounds 17 and 18 were synthesized by substantially the same method as that for Example compound 111, except that tert-butyl (S)-(1-oxo-3-phenyl-1-(piperazin-1-yl)propan-2-yl)carbamate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate, and 1-(bromomethyl)-3-fluorobenzene and 1-(bromomethyl)-4-fluorobenzene were used instead of 1-bromobutane.

[0498] Examples 21, 22, 23 and 24 Example compounds 21, 22, 23 and 24 were synthesized in a manner substantially similar to that of Example compound 111, except that tert-butyl (S)-(1-oxo-1-(piperazin-1-yl)propan-2-yl)carbamate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate, and the compound in the table below was used instead of 1-bromobutane as a starting material. [Table 52]

[0499] Example 45: Synthesis of Compound 45 Example compound 45 was synthesized in a manner substantially similar to that of Example compound 18, except that tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate was used instead of tert-butyl (S)-(1-oxo-3-phenyl-1-(piperazin-1-yl)propan-2-yl)carbamate.

[0500] Example 47: Synthesis of Compound 47 Example compound 47 was synthesized in a manner substantially similar to that of Example compound 111, except that tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate.

[0501] Example 66: Synthesis of Compound 66 Example compound 66 was synthesized in a manner substantially similar to that of Example compound 111, except that tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate, and (1-bromoethyl)benzene was used instead of 1-bromobutane.

[0502] Example 101: Synthesis of Compound 101 Example compound 101 was synthesized in a manner substantially similar to that of Example compound 111, except that tert-butyl (R)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)azetidine-1-carboxylate.

[0503] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 53]

[0504] TIFF2024515739000389.tif160155

[0505] TIFF2024515739000390.tif165155

[0506] TIFF2024515739000391.tif165155

[0507] TIFF2024515739000392.tif149155

[0508] 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)piperazine-1-carboxamide [Step 1] tert-Butyl (S)-2-(4-(m-tolylcarbamoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000393.tif27142 tert-Butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-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) dissolved in diethyl ether (2 mL) at room temperature was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.198 g, 44.9%) as a white solid.

[0509] [Step 2] Synthesis of (S)-4-Prolyl-N-(m-tolyl)piperazine-1-carboxamide TIFF2024515739000394.tif25111 A mixture of tert-butyl (S)-2-(4-(m-tolylcarbamoyl)piperazine-1-carbonyl)pyrrolidine-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) was stirred at room temperature and stirred at the same temperature for 18 h. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, and the organic layer was extracted with dichloromethane, then filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The material obtained was used as is without further purification (title compound, 0.098 g, 65.2%, light brown oil).

[0510] [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)piperazine-1-carboxamide TIFF2024515739000395.tif231552-(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 2, (S)-4-prolyl-N-(m-tolyl)piperazine-1-carboxamide (0.056 g, 0.178 mmol), and triethylamine (0.050 mL, 0.357 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, the organic layer was extracted with dichloromethane, and the solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.017 g, 18.4%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.58-7.45(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=8.8Hz,4H),2.28-2.11(m,1H),2.08-1.85(m,2H);LRMS(ES)m / z517.2(M + +1).

[0511] Example 100: Synthesis of Compound 100 Example compound 100 was synthesized by a method substantially similar to the synthesis method of example compound 61, except that tert-butyl (R)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate, and isocyanate benzene was used instead of 1-isocyanato-3-methylbenzene.

[0512] Examples 62, 115, 116 and 117 Example compounds 62, 115, 116 and 117 were each synthesized in a manner substantially similar to that of Example compound 61, except that the compounds in the table below were used as starting materials instead of 1-isocyanate-3-methylbenzene. [Table 54]

[0513] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 55]

[0514] TIFF2024515739000398.tif144156

[0515] Example 82: Synthesis of compound 82, (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-(4-methylpiperazin-1-yl)phenyl)methanone [Step 1] Synthesis of tert-butyl (S)-2-(4-(3-(4-methylpiperazin-1-yl)benzoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate TIFF2024515739000399.tif20136 A solution of tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.150 g, 0.529 mmol) prepared in Step 1 of Example 64, 3-(4-methylpiperazin-1-yl)benzoic acid (0.117 g, 0.529 mmol), triethylamine (0.221 mL, 1.588 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in EtOAc, 0.945 mL, 1.588 mmol) in dichloromethane (2 mL) at room temperature was stirred for 3 hours at the same temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained material was used as is without further purification (title compound, 0.250 g, 97.3%, pale yellow oil).

[0516] [Step 2] Synthesis of (S)-(3-(4-methylpiperazin-1-yl)phenyl)(4-prolylpiperazin-1-yl)methanone hydrochloride TIFF2024515739000400.tif20122 tert-Butyl (S)-2-(4-(3-(4-methylpiperazin-1-yl)benzoyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.250 g, 0.515 mmol) prepared in step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.515 mL, 2.059 mmol) in dichloromethane (2 mL) were stirred at 40° C. for 2 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was subjected to removal of the solvent under reduced pressure, and the resulting material was used as is without further purification (title compound, 0.210 g, 96.7%, pale yellow solid).

[0517] [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)piperazin-1-yl)(3-(4-methylpiperazin-1-yl)phenyl)methanone JPEG2024515739000401.jpg17159The (S)-(3-(4-methylpiperazin-1-yl)phenyl)(4-prolylpiperazin-1-yl)methanone hydrochloride (0.210 g, 0.498 mmol) prepared in step 2, 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (0.126 g, 0.448 mmol), and sodium bicarbonate (0.125 g, 1.493 mmol) were dissolved in cyclopentyl methyl ether (CPME, 3 mL) at room temperature and stirred at 70 ° C for 18 hours, and the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.042 g, 14.5%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.60-8.09(m,2H),7.90-7.85(m,1H),7.36-7.23(m,1H),7.10-7.01(m,2H),6.99-6.89(m,1H),6.82(s,1H),6.73-6.65 (m,1H),5.00(s,1H),4.04-3.48(m,10H),3.26-2.93(m,6H),2.38-2.14(m,4H),2.03-1.77(m,3H),1.17(t,J=7.3Hz,2H);LRMS(ES)m / z586.6(M + +1).

[0518] Examples 83, 102, 103, 104, 105 and 106 Example compounds 83, 102, 103, 104, 105 and 106 were synthesized in substantially the same manner as in the synthesis of Example compound 82, except that the following starting material was used instead of tert-butyl (S)-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate in the synthesis of Example compound 82. [Table 56]

[0519] The analytical data of the compounds produced by the above-mentioned methods are as shown in the table below. [Table 57]

[0520] TIFF2024515739000404.tif191156

[0521] Example 53: Synthesis of compound 53, 4-(2-(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)ethyl)morpholine [Step 1] Synthesis of (7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-proline TIFF2024515739000405.tif20132A solution of L-proline (1.151 g, 10.000 mmol), 2-(furan-2-yl)-5-(methylsulfonyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine (2.803 g, 10.000 mmol), and triethylamine (2.788 mL, 20.000 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h at the same temperature. The material obtained was used as is without further purification (title compound, 3.151 g, 99.9%, light brown oil).

[0522] [Step 2] Synthesis of 4-(2-(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)ethyl)morpholine TIFF2024515739000406.tif20155 Step 1: (7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-L-proline (0.315 g, 1.000 mmol), 4-(2-(piperazin-1-yl)ethyl)morpholine hydrochloride (0.354 g, 1.500 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50.00% solution in A solution of DMF (1.908 mL, 3.000 mmol) and triethylamine (0.279 mL, 2.000 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into water, and the organic layer was extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0%~10%) to give the title compound (0.010 g, 2.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.61-8.00(m,2H),7.92-7.80(m,1H),7.11-6.98(m,1H),6.74-6.60(m,1H),5.09-4.90(m,1H) ,3.76-3.46(m,10H),2.79-2.63(m,1H),2.49-2.36(m,9H),2.35-2.13(m,3H),1.99-1.79(m,3H);LRMS(ES)m / z497.5(M + +1).

[0523] Example 54: Synthesis of Compound 54 Example compound 54 was synthesized in a manner substantially similar to that of Example compound 53, except that 1-cyclohexylpiperazine was used instead of 4-(2-(piperazin-1-yl)ethyl)morpholine hydrochloride. 1 H NMR(400MHz,DMSO-d6)δ8.64-8.01(m,2H),7.92-7.82(m,1H),7.11-6.98(m,1H),6.78-6.60(m,1H),5.08-4.91(m,1H),3.77-3.44(m,5H),3 .30-3.08(m,1H),2.84-2.64(m,1H),2.45-2.17(m,4H),2.04-1.66(m,7H),1.59(d,J=12.4Hz,1H),1.35-1.00(m,6H);LRMS(ES)m / z466.5(M + +1).

[0524] Measurement and Analysis Protocols for the Activity of the Compounds of the Invention Experimental Example 1. Evaluation of binding affinity to A2a receptor The binding affinity of the compounds according to the examples of the present invention to human adenosine A2a receptors was evaluated by SB drug discovery in the UK.

[0525] Radioligand binding assays were performed using [3H]-NECA (5'-N-[Adenine-2,8-3H]-Ethylcarboxamidoadenosine) and adenosine A2a membranes prepared from HEK-293 cells transfected with human adenosine A2a receptors. Membranes used in the assay were incubated with radioligand until equilibrium was reached. To separate radioligand-bound membranes, unbound radioligand was separated using a Packard filtermate Harverster and glass filter plates.

[0526] 20 μL of A2a membranes were mixed with 20 μL of [3H]-NECA (37 nM final concentration) and 10 μL of test compound or standard inhibitor dissolved in binding buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA pH 7.4) in a non-binding 96-well plate and incubated at room temperature for 1 h. Before filtration, the 96-well harvest filter plate was coated with 0.33% polyethyleneimine for 30 min and then washed with analysis buffer. The binding reaction was transferred to the filter plate and washed three times with washing buffer. The plate was then dried and the radioactivity was counted in a scintillation counter (Topcount NXT, Packard) after adding scintillant.

[0527] The IC binding affinity for human adenosine A2a receptor obtained by the above experimental method 50 (μM) are shown in the table below. [Table 58]

[0528] TIFF2024515739000408.tif227153

[0529] TIFF2024515739000409.tif228153

[0530] TIFF2024515739000410.tif228153

[0531] TIFF2024515739000411.tif234153

[0532] TIFF2024515739000412.tif168153

[0533] From the above results, it can be seen that the compounds according to the examples of the present invention have excellent binding affinity to human adenosine A2a receptors. Experimental example 2. Kinetic solubility test The solubility of the compound of the present invention was measured to evaluate its physical properties. The reagents and plates used in the experiment are as shown in the table below. TIFF2024515739000413.tif134154

[0534] Each compound according to the present invention was dissolved in dimethylsulfoxide to prepare solutions of various concentrations (500, 370, 250, 125, 62.5, 31.25, 15.62, 7.81, 3.90, 1.95 μM). 10 μL of each solution was taken and mixed with 190 μL of a prepared solution (buffer solution, artificial gastric fluid, or artificial intestinal fluid), and the amount of precipitation at each concentration was measured after 1 hour using a nephelometer (NEPHELOstar (BMG LABTECH)) to evaluate the solubility. The nephelometer is an instrument that measures solubility by nephelometry, and can measure the solubility of a compound by dissolving the compound in a desired solvent at various concentrations and then measuring the solubility based on the magnitude of scattered light by insoluble particles when a laser is transmitted through the solution. As a result, it was confirmed that the compound of the present invention exhibits excellent solubility under neutral conditions and in the gastric and intestinal fluid conditions in the digestive tract. Although the present invention has been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] W 1 is O or S; W 2 is N or CH; Z 1 is CH or N; Z 2 is C or N; Z 3 is N, O or S; Q is C-R 4 or N; R 1 is H or -CH 3 and R 2 is H, R 3 is H or -La-Ra, or R 2 and R 3 are linked to form a ring, wherein 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; W 3 is CH or N, W 4 is CH 2 Or O, but W 3 When is CH, W 4 is CH 2 (not being the case), phenyl or -phenylene-O-benzyl, and when Ra is C1-C5 alkyl or phenyl, at least one of the H in each of these may be substituted with -OH or C1-C5 alkoxy; R 2 and R 3 are linked to form a ring that is a 4- to 6-membered N-containing heterocycloalkyl (wherein at least one H of the N-containing heterocycloalkyl may be independently replaced by C1-C5 alkyl or OH), or a 6- to 8-membered N-containing spiroheterocycloalkyl; R 4 is H or C1-C5 alkyl; R 5 teeth, -NH-(CH 2 ) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing either O or N; (wherein n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , R f and R g Two selected from are connected to CH 2 or CH 2 -CH 2 may be formed; (wherein m and q are each independently an integer of 0 to 3, m and q cannot be 0 at the same time, R j is H or a halogen; (wherein r, s, t and u are each independently 1 or 2); The R 5 In L 1 is a single bond or C1-C3 alkylene; L 2 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)-; R h is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C5 alkylene)-phenyl, -phenylene-O-(C1-C5 alkyl), -phenylene-C(=O), -phenylene-piperazinyl, 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, Or -NR 6 R 7 and R 6 and R 7 are each independently C1-C5 alkyl or C1-C5 haloalkyl; R h One or more H may be independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH, or halogen.

2. In the above Chemical Formula 1, W 1 、W 2 、Z 1 、Z 2 、Z 3 、Q、R 1 、R 2 、R 3 、R 4 、 Each as defined in claim 1; W 1 If is O, then W 2 is CH; W 1 If S, then W 2 is N; R 5 teeth, -NH-(CH 2 ) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing O; (wherein n is 0 or 1, R c , R e , R f and R g are each independently H or C1-C5 alkyl; or (wherein m and q are each independently an integer of 0 to 3, m and q cannot be 0 at the same time, R j is H or a halogen; (wherein r, s, t and u are each independently 1 or 2); may be; The R 5 In the above, L 1 , L 2 and R h is as defined in claim 1, 2. A compound represented by the formula 1 according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

3. In the above Chemical Formula 1, W 1 、W 2 、Z 1 、Z 2 、Z 3 、 Each as defined in claim 1; Q is C-R 4 and R 1 and R 2 are each H; R 3 is H or -La-Ra, where 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; W 3 is CH or N, W 4 is CH 2 Or O, but W 3 When is CH, W 4 is CH 2 (not being the same as above), phenyl, or -phenylene-O-benzyl, and when Ra is C1-C5 alkyl or phenyl, at least one of the H in each of these may be substituted with -OH or C1-C5 alkoxy; R 4 is H or C1-C5 alkyl; R 5 teeth, (wherein n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , R f and R g Two selected from are connected to CH 2 or CH 2 -CH 2 may be formed; (wherein m and q each independently represent an integer from 0 to 3; R j is H or a halogen; (wherein r, s, t and u are each independently 1 or 2); may be; The R 5 In L 1 is a single bond or C1-C3 alkylene; L 2 is a single bond, -C(=O)- or -S(=O) 2 - and R h is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C3-C6 cycloalkyl, phenoxy, phenyl, a 5- or 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N and O, or a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and S; R h At least one H may be independently substituted with C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen; 2. A compound represented by the formula 1 according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

4. In the above Chemical Formula 1, W 1 、W 2 、Z 1 、Z 2 、Z 3 、R 1 、 Each as defined in claim 1; Q is C-R 4 or N; R 2 and R 3 are joined together to form a 4- to 6-membered N-containing heterocycloalkyl, where at least one or more H of said N-containing heterocycloalkyl are each independently optionally replaced with C1-C5 alkyl or OH, or a 6- to 8-membered N-containing spiroheterocycloalkyl; R 4 is H or C1-C5 alkyl; R 5 teeth, -NH-(CH 2 ) y -R b (wherein y is an integer from 1 to 3, and R b is a 5- or 6-membered heterocycloalkyl containing O; (wherein n is 0 or 1, R c , R d , R e , R f and R g are each independently H or C1-C5 alkyl, but R c , R d , R e , R f and R g Two selected from are connected to CH 2 or CH 2 -CH 2 may be formed; (wherein m and q are each independently an integer of 0 to 3, m and q cannot be 0 at the same time, R j is H or a halogen; (wherein r, s, t and u are each independently 1 or 2); The R 5 In L 1 is a single bond or C1-C3 alkylene; L 2 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)-; R h is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, halogen, C3-C6 cycloalkyl, phenoxy, phenyl, -(C1-C3 alkylene)-phenyl, -phenylene-O-(C1-C5 alkyl), -phenylene-C(=O)-, -phenylene-piperazinyl, 4- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, Or -NR 6 R 7 and R 6 and R 7 are each independently C1-C5 alkyl or C1-C5 haloalkyl; R h At least one H may be independently substituted with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, OH or halogen; 2. A compound represented by the formula 1 according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

5. Any compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof:

6. Any one selected from the group consisting of the following compounds: The compound of claim 5, its stereoisomer or a pharma- ceutically acceptable salt thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, its stereoisomer or a pharma- ceutically acceptable salt thereof as an active ingredient.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for the treatment or prevention of an adenosine A2a receptor-related disease.

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

10. The pharmaceutical composition of claim 9, wherein the cancer is one or more selected from lung cancer, gastric cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colon 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-related cancer.

11. 10. The pharmaceutical composition of claim 9, wherein the inflammatory disease is one or more 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 mellitus.

12. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an adenosine A2a receptor-associated disease.

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