Pharmaceutical composition comprising autotaxin inhibitor as active ingredient for preventing or treating calcification-related disease

Abstract

The present invention relates to a pharmaceutical composition comprising an autotaxin inhibitor as an active ingredient for preventing or treating calcification-related diseases. Specifically, the autotaxin inhibitor is useful for the prevention or treatment of calcification-related diseases such as vascular calcification, vascular stiffening, vascular inflammation, vascular fibrosis, vascular stenosis, valvular calcification, valvular inflammation, valvular fibrosis, aortic valve stenosis, and calcinosis cutis.

Description

Pharmaceutical composition for the prevention or treatment of calcification-related diseases containing an autotaxin inhibitor as an active ingredient

[0001] The present invention relates to a pharmaceutical composition for preventing or treating calcification-related diseases, comprising an autotaxin inhibitor as an active ingredient.

[0002] Autotaxin (ATX) is an enzyme responsible for the elevation of lysophosphatidic acid (LPA) in ascites and plasma. It is a secreted enzyme crucial for the conversion of lysopaatidylcholine (LPC) to the bioactive signaling molecule LPA. ATX is also known as ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D. ATX plays a role in pathological conditions including fibrosis, arthritis, neurodegeneration, neuropathic pain, and cancer.

[0003] LPA is a bioactive lipid that influences the migration, proliferation, and survival of various cell types. Plasma LPA levels are closely correlated with ATX activity, suggesting that ATX is a significant source of extracellular LPA. LPA binds to specific G-protein receptors (LPARs) and promotes intracellular signaling, including fibrosis, migration, and differentiation.

[0004] ATX or LPA are known to be involved in various diseases, such as fibrosis, inflammation, and calcification. Increased expression levels of ATX have been reported in calcified aortic valve tissue, and LPA has been shown to promote aortic valve mineralization. Furthermore, LPA is known to promote atherosclerosis and disease progression. Studies have demonstrated that ATX-induced LPA increases NFkB activation, leading to the expression of the inflammatory cytokine IL-6 and the bone-forming gene BMP2, which in turn induce aortic calcification.

[0005] However, no effective substance has yet been developed to treat or prevent calcification-related diseases through inhibition of ATX.

[0006] The present invention provides a pharmaceutical composition for preventing or treating calcification-related diseases, which comprises as an active ingredient a compound represented by the following chemical formula 1 as an autotaxin inhibitor, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0007] [Chemical Formula 1]

[0008]

[0009] In the above chemical formula 1,

[0010] X and Y are each independently CR' or N, except when both are N;

[0011] R' is hydrogen, C1-C10 alkyl or C6-C12 aryl;

[0012] R is indanyl, C6-C12arC1-C10alkyl or C6-C12arC3-C10cycloalkenyl;

[0013] The aralkyl and arcycloalkenyl of the above R may be further substituted with one or more substituents selected from halogen, C1-C10 alkoxy and halo C1-C10 alkoxy;

[0014] A is C2-C12 heteroaryl, carboxyl C1-C10 alkyl, C6-C12 aryl, C6-C12 arC1-C10 alkyl, C2-C12 heterocycloalkyl or NR1R2;

[0015] The heteroaryl, aryl, aralkyl and heterocycloalkyl of the above A may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0016] R1 and R2 are each independently hydrogen or carboxylC1-C10alkyl, or R1 and R2 may be connected to each other to form a saturated or unsaturated monocyclic, polycyclic or spiro ring;

[0017] The formed ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur, and may contain a C=C, C=N or N=N double bond, and CH2 in the formed ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0018] L is a single bond, -(CR3R4) a C(=O)-, -C(=O)-(CR3R4) a -, -C(=O)-(CR5R6) b -NH-(CR7R8) c -, -NH-(CR7R8) c -C(=O)-(CR5R6) b -, -C(=NR9)-(CR3R4)a-, C2-C12 heteroarylene, -(CR3R4) a -C2-C12 heterocycloalkylene-, -C2-C12 heterocycloalkenylene-(CR3R4) a -, -C2-C12 heterocycloalkylene-(CR3R4) a -(NH) d -, or and;

[0019] R3 to R8 are each independently hydrogen or C1-C10 alkyl;

[0020] R9 is hydroxy, C1-C10 alkoxy or mono- or di-C1-C10 alkylamino;

[0021] Y is NR 10 , O or S;

[0022] R 10are each independently hydrogen or C1-C10 alkyl;

[0023] a is an integer from 1 to 5;

[0024] b and c are each independently an integer from 0 to 5;

[0025] d is an integer of 0 or 1;

[0026] Q is carbonyl, C2-C12 heterocycloalkylene or C2-C12 heteroarylene;

[0027] The heteroarylene of the above Q is C1-C10 alkyl, haloC1-C10 alkyl, hydroxyC1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, NR 11 R 12 , -O(CH2) e R 13 , -(CH2) f R 14 and -C(=O)R 15 may be further substituted with one or more substituents selected from , wherein said alkyl, cycloalkyl, aryl and heteroaryl are NR 11 R 12 or may be further substituted with carboxyl;

[0028] R 11 and R 12 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C10 cycloalkyl;

[0029] e and f are each independently an integer from 0 to 5;

[0030] R 13 is hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heterocycloalkyl or carboxyl, and the aryl and heterocycloalkyl of R13 may be further substituted with one or more substituents selected from C1-C10 alkyl, haloC1-C10 alkyl and carboxyl;

[0031] R 14 and R 15are each independently C2-C12 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from halogen, C1-C10 alkyl, haloC1-C10 alkyl and C6-C12 aryl;

[0032] The above heteroaryl, heteroarylene, heterocycloalkylene, heterocycloalkenylene and heterocycloalkyl contain one or more heteroatoms selected from nitrogen, oxygen and sulfur.

[0033] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0034] The present invention provides a pharmaceutical composition for preventing or treating calcification-related diseases, comprising a compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0035] [Chemical Formula 1]

[0036]

[0037] In the above chemical formula 1,

[0038] X and Y are each independently CR' or N, except when both are N;

[0039] R' is hydrogen, C1-C10 alkyl or C6-C12 aryl;

[0040] R is indanyl, C6-C12arC1-C10alkyl or C6-C12arC3-C10cycloalkenyl;

[0041] The aralkyl and arcycloalkenyl of the above R may be further substituted with one or more substituents selected from halogen, C1-C10 alkoxy and halo C1-C10 alkoxy;

[0042] A is C2-C12 heteroaryl, carboxyl C1-C10 alkyl, C6-C12 aryl, C6-C12 arC1-C10 alkyl, C2-C12 heterocycloalkyl or NR1R2;

[0043] The heteroaryl, aryl, aralkyl and heterocycloalkyl of the above A may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0044] R1 and R2 are each independently hydrogen or carboxylC1-C10alkyl, or R1 and R2 may be connected to each other to form a saturated or unsaturated monocyclic, polycyclic or spiro ring;

[0045] The formed ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur, and may contain a C=C, C=N or N=N double bond, and CH2 in the formed ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0046] L is a single bond, -(CR3R4) a C(=O)-, -C(=O)-(CR3R4) a -, -C(=O)-(CR5R6) b -NH-(CR7R8) c -, -NH-(CR7R8) c -C(=O)-(CR5R6) b-, -C(=NR9)-(CR3R4)a-, C2-C12 heteroarylene, -(CR3R4) a -C2-C12 heterocycloalkylene-, -C2-C12 heterocycloalkenylene-(CR3R4) a -, -C2-C12 heterocycloalkylene-(CR3R4) a -(NH) d -, or and;

[0047] R3 to R8 are each independently hydrogen or C1-C10 alkyl;

[0048] R9 is hydroxy, C1-C10 alkoxy or mono- or di-C1-C10 alkylamino;

[0049] Y is NR 10 , O or S;

[0050] R 10 are each independently hydrogen or C1-C10 alkyl;

[0051] a is an integer from 1 to 5;

[0052] b and c are each independently an integer from 0 to 5;

[0053] d is an integer of 0 or 1;

[0054] Q is carbonyl, C2-C12 heterocycloalkylene or C2-C12 heteroarylene;

[0055] The heteroarylene of the above Q is C1-C10 alkyl, haloC1-C10 alkyl, hydroxyC1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, NR 11 R 12 , -O(CH2) e R 13 , -(CH2) f R 14 and -C(=O)R 15 may be further substituted with one or more substituents selected from , wherein said alkyl, cycloalkyl, aryl and heteroaryl are NR 11 R12 or may be further substituted with carboxyl;

[0056] R 11 and R 12 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C10 cycloalkyl;

[0057] e and f are each independently an integer from 0 to 5;

[0058] R 13 is hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heterocycloalkyl or carboxyl, and the aryl and heterocycloalkyl of R13 may be further substituted with one or more substituents selected from C1-C10 alkyl, haloC1-C10 alkyl and carboxyl;

[0059] R 14 and R 15 are each independently C2-C12 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from halogen, C1-C10 alkyl, haloC1-C10 alkyl and C6-C12 aryl;

[0060] The above heteroaryl, heteroarylene, heterocycloalkylene, heterocycloalkenylene and heterocycloalkyl contain one or more heteroatoms selected from nitrogen, oxygen and sulfur.

[0061] The above A can be selected from the following structures:

[0062]

[0063] (Above R c is C1-C7 alkyl or amino;

[0064] p is an integer from 0 to 5;

[0065] q and r are each independently an integer from 1 to 5;

[0066] m is an integer of 0, 1, or 2.)

[0067] The above L may be a single bond or selected from the following structures:

[0068]

[0069] (Above R d and R e are each independently hydrogen or C1-C7 alkyl;

[0070] R f is hydroxy, C1-C7alkoxy or mono- or di-C1-C7alkylamino;

[0071] Y is NR 10 , O or S;

[0072] R 10 are each independently hydrogen or C1-C7 alkyl;

[0073] s is an integer from 0 to 3;

[0074] t is an integer from 1 to 3.)

[0075] The above Q can be selected from the following structures:

[0076]

[0077] (Above R g is hydrogen or C1-C7 alkyl;

[0078] R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxyC1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, -O(CH2) e R 13 , -(CH2) f R 14 or -C(=O)R 15 and the above R h Alkyl, cycloalkyl, aryl and heteroaryl of NR11 R 12 or may be further substituted with carboxyl;

[0079] R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C7 cycloalkyl;

[0080] R 13 is C6-C12 aryl, C3-C9 heterocycloalkyl or carboxyl, and R 13 Aryl and heterocycloalkyl of may be further substituted with one or more substituents selected from C1-C7 alkyl, haloC1-C7 alkyl and carboxyl;

[0081] R 14 and R 15 are each independently C3-C9 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl of is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and the R 14 and R 15 The heterocycloalkyl may be further substituted with one or more substituents selected from halogen, C1-C7 alkyl, haloC1-C7 alkyl and C6-C12 aryl;

[0082] R i is hydrogen, C1-C7 alkyl or haloC1-C7 alkyl;

[0083] R j is hydrogen, C1-C7 alkyl, haloC1-C7 alkyl, C3-C7 cycloalkyl or C6-C12 aryl;

[0084] e is an integer from 0 to 3;

[0085] f is an integer from 0 to 3.)

[0086] The compound represented by the above chemical formula 1 can be selected from the following structures:

[0087]

[0088]

[0089]

[0090] A compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can act as an autotaxin inhibitor.

[0091] A compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can reduce the expression of an osteogenesis-related gene selected from the group consisting of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), Sp7 transcription factor (SP7), and bone γ-carboxyglutamic acid-containing protein (BGLAP).

[0092] A compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can reduce the expression of a fibrosis-related gene selected from the group consisting of fibronectin 1, integrin β, alpha smooth muscle actin (α-SMA), and collagen type I alpha 1 chain (Col1a1).

[0093] The above calcification-related disease may include at least one selected from the group consisting of vascular calcification, vascular stiffening, vascular inflammation, vascular fibrosis, vascular stenosis, valvular calcification, valvular inflammation, valvular fibrosis, aortic valve stenosis, and calcinosis cutis.

[0094] The present invention relates to a pharmaceutical composition for preventing or treating calcification-related diseases, characterized in that it comprises an autotaxin inhibitor as an active ingredient. Specifically, the autotaxin inhibitor is useful for preventing or treating calcification-related diseases such as vascular calcification, vascular stiffening, vascular inflammation, vascular fibrosis, vascular stenosis, valvular calcification, valvular inflammation, valvular fibrosis, aortic stenosis, and calcinosis cutis.

[0095] Figure 1 shows that compound 18 attenuates osteogenic differentiation of aortic valve interstitial cells (ALP staining, n=3).

[0096] Figure 2 shows that compound 18 attenuates osteogenic differentiation of aortic valve interstitial cells (alizarin red staining, n=3).

[0097] Figure 3(a) shows that compound 18 reduces the transcript expression of genes related to bone formation in vitro (n=3).

[0098] Figure 3(b) shows the effect of GLPG1690 on the transcript expression of genes related to osteogenesis in vitro (n=3).

[0099] Figure 4(a) shows that compound 18 reduces transcript expression of fibrosis-related genes in vitro (n=3).

[0100] Figure 4(b) compares the effects of compound 18 and BMS986278 (LPA1 antagonist) and HZN825 (LPAR1 antagonist) on transcript expression of in vitro fibrosis-related genes (n=3).

[0101] Figure 5 shows the attenuation of calcified lesion formation in animal experiments by compound 18.

[0102] Figure 6 shows the effect of compound 18 on the aortic valve in a rabbit model of calcific aortic valve disease at baseline and after 12 weeks of treatment, as determined by echocardiographic evaluation.

[0103] Figure 7 shows the effect of compound 18 on the aortic valve in a rabbit model of calcific aortic valve disease after 12 weeks of treatment, as determined by echocardiographic evaluation.

[0104] Hereinafter, the present invention will be described in more detail. Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this invention pertains. In the following description, descriptions of well-known functions and configurations that may unnecessarily obscure the gist of the present invention will be omitted.

[0105]

[0106] The present invention provides a pharmaceutical composition for preventing or treating calcification-related diseases, comprising a compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0107] [Chemical Formula 1]

[0108]

[0109] In the above chemical formula 1,

[0110] X and Y are each independently CR' or N, except when both are N;

[0111] R' is hydrogen, C1-C10 alkyl or C6-C12 aryl;

[0112] R is indanyl, C6-C12arC1-C10alkyl or C6-C12arC3-C10cycloalkenyl;

[0113] The aralkyl and arcycloalkenyl of the above R may be further substituted with one or more substituents selected from halogen, C1-C10 alkoxy and halo C1-C10 alkoxy;

[0114] A is C2-C12 heteroaryl, carboxyl C1-C10 alkyl, C6-C12 aryl, C6-C12 arC1-C10 alkyl, C2-C12 heterocycloalkyl or NR1R2;

[0115] The heteroaryl, aryl, aralkyl and heterocycloalkyl of the above A may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0116] R1 and R2 are each independently hydrogen or carboxylC1-C10alkyl, or R1 and R2 may be connected to each other to form a saturated or unsaturated monocyclic, polycyclic or spiro ring;

[0117] The formed ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur, and may contain a C=C, C=N or N=N double bond, and CH2 in the formed ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino;

[0118] L is a single bond, -(CR3R4) a C(=O)-, -C(=O)-(CR3R4) a -, -C(=O)-(CR5R6) b -NH-(CR7R8) c -, -NH-(CR7R8) c -C(=O)-(CR5R6) b -, -C(=NR9)-(CR3R4)a-, C2-C12 heteroarylene, -(CR3R4) a -C2-C12 heterocycloalkylene-, -C2-C12 heterocycloalkenylene-(CR3R4) a -, -C2-C12 heterocycloalkylene-(CR3R4) a -(NH) d -, or and;

[0119] R3 to R8 are each independently hydrogen or C1-C10 alkyl;

[0120] R9 is hydroxy, C1-C10 alkoxy or mono- or di-C1-C10 alkylamino;

[0121] Y is NR 10 , O or S;

[0122] R 10 are each independently hydrogen or C1-C10 alkyl;

[0123] a is an integer from 1 to 5;

[0124] b and c are each independently an integer from 0 to 5;

[0125] d is an integer of 0 or 1;

[0126] Q is carbonyl, C2-C12 heterocycloalkylene or C2-C12 heteroarylene;

[0127] The heteroarylene of the above Q is C1-C10 alkyl, haloC1-C10 alkyl, hydroxyC1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, NR 11 R 12 , -O(CH2) e R 13 , -(CH2) f R 14 and -C(=O)R 15 may be further substituted with one or more substituents selected from , wherein said alkyl, cycloalkyl, aryl and heteroaryl are NR 11 R 12 or may be further substituted with carboxyl;

[0128] R 11 and R 12 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C10 cycloalkyl;

[0129] e and f are each independently an integer from 0 to 5;

[0130] R 13 is hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heterocycloalkyl or carboxyl, and the aryl and heterocycloalkyl of R13 may be further substituted with one or more substituents selected from C1-C10 alkyl, haloC1-C10 alkyl and carboxyl;

[0131] R 14 and R 15 are each independently C2-C12 heterocycloalkyl, and the R 14 and R 15The heterocycloalkyl is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from halogen, C1-C10 alkyl, haloC1-C10 alkyl and C6-C12 aryl;

[0132] The above heteroaryl, heteroarylene, heterocycloalkylene, heterocycloalkenylene and heterocycloalkyl contain one or more heteroatoms selected from nitrogen, oxygen and sulfur.

[0133]

[0134] The term "alkyl" of the present invention refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed solely of carbon and hydrogen atoms, which may have 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

[0135] The term "aryl" of the present invention refers to an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and includes a single or fused ring system, each ring suitably containing 4 to 7, preferably 5 or 6, ring atoms, and even includes a form in which multiple aryls are connected by single bonds. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

[0136] The term "heteroaryl" of the present invention refers to an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeletal atoms, and the remaining aromatic ring skeletal atoms are carbon, and is a 5 to 6-membered monocyclic heteroaryl and a polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, the heteroaryl in the present invention also includes a form in which one or more heteroaryls are connected by a single bond. Examples of the heteroaryl group include, but are not limited to, pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisoxazole, thiophene, benzothiophene, furan, benzofuran, etc.

[0137] The term "halo" or "halogen" of the present invention refers to a halogen group element, including, for example, fluoro, chloro, bromo, and iodo.

[0138] The term "cycloalkyl" of the present invention refers to a monovalent saturated carbocyclic radical composed of one or more rings, which may have 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0139] The term "alkoxy" of the present invention refers to an -O-alkyl radical, which may have 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. Here, "alkyl" is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

[0140] The term "heterocycloalkyl" of the present invention refers to a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, wherein the non-aromatic heterocycle includes all forms of a saturated or unsaturated single ring, fused ring or spiro ring, and may be bonded via a heteroatom or a carbon atom. Examples of such heterocycloalkyl radicals may include monovalent radicals of non-aromatic heterocycles such as aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazaspiro[4.4]nonane, 2-azaspiro[4.4]nonane, etc.

[0141] The term "heterocycloalkenyl" of the present invention refers to a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S and necessarily containing at least one double bond, including all unsaturated single ring, fused ring or spiro ring forms, and may be bonded via a heteroatom or a carbon atom.

[0142] The term "cycloalkenyl" of the present invention refers to a monovalent unsaturated carbocyclic radical composed of one or more rings, which may have 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Specific examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0143] The terms “arylene” and “heteroarylene” of the present invention mean divalent radicals of an aromatic ring and a heteroaromatic ring.

[0144] The terms "heterocycloalkylene" and "heterocycloalkenylene" of the present invention mean divalent radicals of a saturated heterocycle and an unsaturated heterocycle.

[0145]

[0146] In a compound according to one embodiment of the present invention, the ring formed by connecting R1 and R2 may be in the form of a saturated or unsaturated monocyclic, polycyclic or spiro ring, and may preferably be a ring selected from the following structures:

[0147]

[0148] (Above R a is hydrogen, hydroxy, carboxyl, carbamoyl, C1-C10 alkylsulfonylamino, aminosulfonylamino (-NHSO2NH2) or amino;

[0149] R b is hydrogen, carboxyl or aminosulfonyl;

[0150] m is an integer of 0, 1, or 2.)

[0151]

[0152] In a compound according to one embodiment of the present invention, A may be selected from the following structures:

[0153]

[0154] (Above R c is C1-C7 alkyl or amino;

[0155] p is an integer from 0 to 5;

[0156] q and r are each independently an integer from 1 to 5;

[0157] m is an integer of 0, 1, or 2.)

[0158] In a specific embodiment of the present invention, A may be selected from the following structures:

[0159]

[0160]

[0161] In a compound according to one embodiment of the present invention, L may be a single bond or selected from the following structures:

[0162]

[0163] (Above R d and R e are each independently hydrogen or C1-C7 alkyl;

[0164] R f is hydroxy, C1-C7alkoxy or mono- or di-C1-C7alkylamino;

[0165] Y is NR 10 , O or S;

[0166] R 10 are each independently hydrogen or C1-C7 alkyl;

[0167] s is an integer from 0 to 3;

[0168] t is an integer from 1 to 3.)

[0169] In a specific embodiment of the present invention, L may be selected from the following structures:

[0170]

[0171]

[0172] In a compound according to one embodiment of the present invention, Q may be selected from the following structures:

[0173]

[0174] (Above R g is hydrogen or C1-C7 alkyl;

[0175] R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxyC1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, -O(CH2) e R 13 , -(CH2) f R 14 or -C(=O)R 15 and the above R h Alkyl, cycloalkyl, aryl and heteroaryl of NR 11 R 12or may be further substituted with carboxyl;

[0176] R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C7 cycloalkyl;

[0177] R 13 is C6-C12 aryl, C3-C9 heterocycloalkyl or carboxyl, and R 13 Aryl and heterocycloalkyl of may be further substituted with one or more substituents selected from C1-C7 alkyl, haloC1-C7 alkyl and carboxyl;

[0178] R 14 and R 15 are each independently C3-C9 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl of is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and the R 14 and R 15 The heterocycloalkyl may be further substituted with one or more substituents selected from halogen, C1-C7 alkyl, haloC1-C7 alkyl and C6-C12 aryl;

[0179] R i is hydrogen, C1-C7 alkyl or haloC1-C7 alkyl;

[0180] R j is hydrogen, C1-C7 alkyl, haloC1-C7 alkyl, C3-C7 cycloalkyl or C6-C12 aryl;

[0181] e is an integer from 0 to 3;

[0182] f is an integer from 0 to 3.)

[0183] In a specific embodiment of the present invention, Q may be selected from the following structures:

[0184]

[0185]

[0186] Additionally, in a specific embodiment of the present invention, R may be indanyl.

[0187]

[0188] Specifically, in the compound according to one embodiment of the present invention, the compound represented by the chemical formula 1 may be selected from the following structures, but is not limited thereto:

[0189]

[0190]

[0191]

[0192]

[0193] The compound represented by Chemical Formula 1 according to the present invention can be prepared and used in the form of a prodrug, a hydrate, a solvate, and a pharmaceutically acceptable salt to promote absorption in the body or increase solubility, and therefore the prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. In addition, the compound represented by Chemical Formula 1 has a chiral carbon, and thus its stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0194]

[0195] The term "pharmaceutically acceptable salt" of the present invention refers to a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The terms "hydrate", "solvate", "isomer", and "prodrug" of the present invention also have the same meaning as above. The pharmaceutical salt includes an acid addition salt formed by an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of formula 1 according to the present invention may also be converted into its salt by a conventional method.

[0196] The term "hydrate" of the present invention means a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0197] The term "solvate" of the present invention refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0198] The term "isomer" in the present invention refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers having an asymmetric carbon center, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included in the scope of the present invention.

[0199] The term "prodrug" in the present invention refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, prodrugs may be bio-hydrolyzable esters of compounds according to the present invention and pharmaceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) linked to an acid group that is metabolized to reveal the active site of the peptide.

[0200] Other terms may be interpreted as having the meaning commonly understood in the field to which the present invention belongs.

[0201] Various forms of the above prodrugs are known in the art, for example: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic press, 1985)]; b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991)]; c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992)]; d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988)]; and e) reference can be made to literature such as [N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)];

[0202] These prodrugs are mainly used in cases where solubility or absorption is relatively low, and when converted to a prodrug, not only does solubility and absorption increase, but ADME (absorption, distribution, metabolism, excretion) and PK profiles also improve.

[0203]

[0204] As mentioned above, the compound represented by Chemical Formula 1 according to the present invention, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can act as an autotaxin inhibitor, and ultimately provides a pharmaceutical composition for preventing or treating calcification-related diseases. If necessary, the pharmaceutical composition for preventing or treating calcification-related diseases further comprises a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof.

[0205] To this end, the inventors of the present invention have confirmed through specific experiments the effect of weakening the osteogenic metastasis of aortic valve interstitial cells and the effect of reducing the expression of osteogenic and fibrosis-related genes using the compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof. Accordingly, the compound can be usefully used for the prevention or treatment of calcification-related diseases.

[0206] Specifically, the compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can reduce the expression of an osteogenesis-related gene selected from the group consisting of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), Sp7 transcription factor (SP7), and bone γ-carboxyglutamic acid-containing protein (BGLAP). In addition, the compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof can reduce the expression of a fibrosis-related gene selected from the group consisting of fibronectin 1, integrin β, alpha smooth muscle actin (α-SMA), and collagen type I alpha 1 chain (Col1a1).

[0207] In addition, the present inventors have disclosed a compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as a target for eNOS. - / - As the effect of inhibiting calcific lesion formation in mice and attenuating calcific aortic valve stenosis in a rabbit model of CAVD was confirmed through specific experiments, it can be usefully used for the prevention or treatment of calcific-related diseases.

[0208]

[0209] The term "calcification-related disease" of the present invention broadly includes diseases occurring in blood vessels or valves, and may include, for example, all diseases occurring due to deposition of minerals such as calcium in blood vessels or valves, and includes, but is not limited to, one or more selected from the group consisting of vascular calcification, vascular stiffening, vascular inflammation, vascular fibrosis, vascular stenosis, valvular calcification, valvular inflammation, valvular fibrosis, aortic valve stenosis, and calcinosis cutis.

[0210] Specifically, the term "vascular calcification" of the present invention refers to the pathological deposition of minerals in the vascular system, which is often observed in patients with CDK or diabetes. Elevated calcium and / or phosphate levels may be a result of metabolic dysregulation due to diabetes, dyslipidemia, oxidative stress, uremia, and hyperphosphatemia, which lead to the formation of osteoblast-like cells, the formation of calcified deposits in the blood vessel walls, and their stiffness. In addition, the term "vascular stiffening" of the present invention refers to the hardening of the arterial wall due to calcification. Vascular stiffening consists of a decrease in the elasticity of the blood vessels, which increases the pulse pressure. In addition, the term "vascular inflammation" of the present invention refers to inflammation in the blood vessels due to calcification, and the term "vascular fibrosis" of the present invention refers to a condition in which blood vessels are damaged and scarred due to calcification. Additionally, the term "vascular stenosis" of the present invention refers to a symptom that occurs when blood vessels become narrow due to calcification, reducing the amount of blood flow through the blood vessels.

[0211] Meanwhile, the term "valve calcification" of the present invention, particularly aortic valve calcification, refers to the active regulation disorder of normal homeostatic processes and hemodynamic changes, such as calcification of the valve, particularly the aortic valve and mitral valve, and concurrently with ECM degradation, fibrosis, lipid accumulation, and neo-angiogenesis of the valve tissue. In addition, the term "valvular inflammation" of the present invention refers to inflammation of the valve due to calcification, and the term "valvular fibrosis" of the present invention refers to a state in which the valve is damaged and scarred due to calcification. In addition, the term "aortic valve stenosis" of the present invention refers to a disease in which the diameter of the aortic valve narrows, preventing sufficient blood flow from the left ventricle to the aorta. Aortic valve stenosis is caused by inflammation, leaflet fibrosis, thickening, and calcification due to endothelial damage caused by mechanical stress, and lipid infiltration. Aortic valve calcification is accompanied by aortic sclerosis. No drug has yet been identified that fundamentally improves aortic valve stenosis, and current treatment relies on prosthetic valve replacement, which involves removing the damaged valve and inserting an artificial one.

[0212]

[0213] Meanwhile, the term "calcinosis cutis" of the present invention refers to the deposition of calcium phosphate deposits on the skin, particularly on the extremities. When the dissolution point of calcium and phosphate is exceeded, precipitation of calcium salts and amorphous hydroxyapatite occurs.

[0214]

[0215] The term "pharmaceutical composition" of the present invention refers to a mixture of a compound of the present invention and other chemical components, such as a diluent or carrier. The pharmaceutical composition facilitates administration of the compound into a living organism. Various techniques for administering the compound exist, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may also be obtained by reacting acid compounds, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0216] The term "therapeutically effective amount" of the present invention means an amount of an active ingredient that is effective in alleviating or reducing to some extent one or more symptoms of a disorder being treated, or in delaying the onset of clinical markers or symptoms of a disease requiring prevention, when the amount of the compound administered is effective. Accordingly, a pharmacologically effective amount means an amount that has the effect of (1) reversing the rate of progression of a disease, (2) inhibiting to some extent further progression of the disease, and / or (3) alleviating to some extent (preferably, eliminating) one or more symptoms associated with the disease. A pharmacologically effective amount can be empirically determined by testing the compound in known in vivo and in vitro model systems for the disease requiring treatment.

[0217] The term "carrier" in the present invention is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of a living organism.

[0218] The term "diluent" in the present invention is defined as a compound that not only stabilizes the biologically active form of the target compound, but is also diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate-buffered saline, as it mimics the salt content of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound.

[0219] The compounds used herein may be administered to human patients on their own, or as pharmaceutical compositions mixed with other active ingredients, such as in combination therapy, or with suitable carriers or excipients. Techniques for the formulation and administration of compounds in this application are described in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18 th edition, 1990.

[0220] The pharmaceutical composition of the present invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, confectionery-making, powdering, emulsifying, encapsulating, trapping, or lyophilizing processes.

[0221] Accordingly, the pharmaceutical compositions for use according to the present invention may be prepared by conventional methods using one or more pharmacologically acceptable carriers comprising excipients or auxiliaries that facilitate processing of the active compound into a pharmaceutically usable formulation. Suitable formulations will depend on the chosen route of administration. Any of the known techniques, carriers, and excipients may be suitably used, and as understood in the art, for example, in Remingston's Pharmaceutical Sciences, as described above. In the present invention, the compound of formula 1 may be formulated as an injectable preparation, an oral preparation, etc., depending on the intended purpose.

[0222] For injection, the components of the present invention can be formulated as a liquid solution, preferably in a pharmacologically compatible buffer such as Hank's solution, Ringer's solution, or saline buffer. For administration via mucosal membranes, a non-penetrating agent suitable for the intended barrier is used in the formulation. Such non-penetrating agents are generally known in the art.

[0223] For oral administration, the compounds can be readily formulated by combining the active compounds with pharmacologically acceptable carriers known in the art. These carriers enable the compounds of the present invention to be formulated as tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions, etc. Preferably, capsules, tablets, pills, powders, and granules are possible, with capsules and tablets being particularly useful. Tablets and pills are preferably formulated as enteric coatings. A medicament for oral use can be prepared by mixing one or more compounds of the present invention with one or more excipients, optionally grinding the mixture, and, if necessary, processing the mixture of granules after permeating with suitable adjuvants to obtain a tablet or sugar core. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Cellulosic materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If necessary, carriers such as disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or its salts such as sodium alginate, lubricants such as magnesium stearate, and binders may be added.

[0224] Pharmaceutical preparations suitable for oral administration may include soft, sealed capsules made of gelatin and a plasticizer such as glycol or sorbitol, as well as push-lock capsules made of gelatin. Push-lock capsules may contain the active ingredients in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in a suitable solvent such as fatty acids, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be included. All preparations intended for oral administration must be in a strength suitable for such administration.

[0225] The compounds may be formulated for parenteral administration by injection, for example, as a bolus injection or continuous infusion. Injectable formulations may be presented in unit dose form, for example, as ampoules or multi-dose containers with an added preservative. The compositions may take the form of suspensions, solutions, or emulsions in oily or liquid vehicles, and may contain formulation ingredients such as suspending agents, stabilizers, and / or dispersing agents.

[0226] Additionally, it may be in the form of a dry powder that is dissolved in sterile water before use, for example, to remove the pyrogen.

[0227] The compounds may also be formulated as rectal administration compositions, such as suppositories or retention enemas, containing conventional suppository bases, such as cocoa butter or other glycerides.

[0228] Pharmaceutical compositions suitable for use in the present invention include compositions containing active ingredients in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prolong the survival of a subject being treated, or to prevent, alleviate, or relieve symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0229] When formulated in unit dosage form, the compound of formula 1 as an active ingredient is preferably contained in a unit dosage of about 0.1 to 1,000 mg. The dosage of the compound of formula 1 is prescribed by a physician according to factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dosage required for adult treatment can be administered once to three times a day depending on the frequency and intensity of administration, and a single dosage is usually in the range of about 1 to 1,000 mg. When administered intramuscularly or intravenously to adults, it can be divided into single doses and administered once to three times a day, and a single dosage of about 1 to 1,000 mg will usually be sufficient, but a higher daily dosage may be desirable for some patients.

[0230] The pharmaceutical composition of the present invention, as an autotaxin inhibitor, has been confirmed to have an effect of inhibiting osteogenic differentiation in human aortic valve interstitial cells, an effect of inhibiting fibro-calcification-related cytokines, and an effect of inhibiting osteogenic differentiation in human aortic valve interstitial cells. In addition, the effect of inhibiting calcification in an animal model of calcification has been confirmed, and thus, the composition can be usefully utilized for the prevention or treatment of calcification-related diseases. The term "inhibition" or "suppression" in the present invention means significantly reducing the in vivo expression amount or biological activity of a target substance.

[0231]

[0232] Alternatively, the present invention provides a use for a pharmaceutical composition for preventing or treating calcification-related diseases, which comprises a compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0233] Alternatively, the present invention provides a method for preventing or treating a calcification-related disease, comprising administering to a subject a compound represented by the above chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof. In this case, the term "subject" refers to a subject in need of treatment for a disease, and more specifically, refers to a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow.

[0234]

[0235] Hereinafter, the present invention will be described in more detail through preferred embodiments. However, these are presented as examples of the present invention and are not intended to limit the scope of the present invention in any way. The scope of the present invention will be defined solely by the claims set forth below.

[0236]

[0237] [Manufacturing example]

[0238] Manufacturing Example 1-1: Preparation of 5-bromo-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (5-bromo-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine) (compound im-1a)

[0239]

[0240] 5-Bromo-2-chloropyrimidine (2.0 g, 10.3 mmol), 2-aminoindane (1.6 mL, 12.4 mmol), and N,N-diisopropylethylamine (4.5 mL, 25.8 mmol) were dissolved in ethanol (10 mL) and stirred at 90 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered, washed with ethanol (20 mL), and dried to obtain the title compound im-1a (2.2 g, 72%) as a beige solid.

[0241] MS m / z: 290 [M+1] +

[0242] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.40 (s, 2H), 7.81 (d, 1H), 7.22-7.13 (m, 4H), 4.56-4.51 (m, 1H), 3.23 (dd, 2H), 3.86 (s, 3H), 2.88 (dd, 2H)

[0243]

[0244] Manufacturing Example 1-2: Preparation of 5-bromo-N-(2,3-dihydro-1H-inden-2-yl)pyridine-2-amine (5-bromo-N-(2,3-dihydro-1H-inden-2-yl)pyridine-2-amine) (compound im-1b)

[0245]

[0246] 5-Bromo-2-fluoropyridine (1.3 g, 7.5 mmol), 2-aminoindane (1.0 g, 7.5 mmol), and potassium carbonate (1.3 g, 9.0 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 140 °C for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, 20 mL of distilled water was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from methylene chloride and n-hexane to obtain the title compound im-1b (0.8 g, 38%) as a brown solid.

[0247] MS m / z:. 289 [M+1] +

[0248]

[0249] Manufacturing Example 2-1: Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxylic acid (2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxylic acid) (compound im-2a)

[0250]

[0251] (Step 1) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxylic acid ethyl ester (ethyl 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxylate) (compound im-2a-a)

[0252] Intermediate im-1a (5.0 g, 17.2 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and N,N-dimethylformamide (3 mL), and palladium(II) acetate (386 mg, 1.72 mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.43 g, 2.58 mmol), and triethylamine (7.2 mL, 0.052 mol) were sequentially added. The mixture was stirred at 75 °C for 16 h in a CO atmosphere of 1 atm. After completion of the reaction, the mixture was cooled to room temperature, distilled water (100 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2:8 → 5:5) to obtain the title compound im-2a-a (4.1 g, 84%) as a yellow solid.

[0253] MS m / z: 284 [M+1] +

[0254] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 8.80 (d, 2H), 8.46 (d, 1H), 7.23-7.14 (m, 4H), 4.70 (q, 1H), 4.27 (q, 2H), 3.28 (dd, 2H), 2.92 (dd, 2H), 1.29 (t, 3H)

[0255] (Step 2) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxylic acid (compound im-2a)

[0256] Compound im-2a-a (2.5 g, 8.6 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and distilled water (10 mL), lithium hydroxide (1.8 g, 0.043 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 2N aqueous hydrochloric acid solution was added to adjust the pH to 2 or lower, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to quantitatively obtain the title compound im-2a (2.2 g) as a white solid.

[0257] MS m / z: 256 [M+1] +

[0258] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.77 (d, 2H), 8.36 (d, 1H), 7.23-7.14 (m, 4H), 4.73-4.67 (m, 1H), 3.27 (dd, 2H), 2.92 (dd, 2H)

[0259]

[0260] Manufacturing Example 2-2: Preparation of 6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridine-3-carboxylic acid (6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridine-3-carboxylic acid) (compound im-2b)

[0261]

[0262] The title compound im-2b was obtained as a brown solid by the same method as in Preparation Example 2-1, except that the corresponding compound im-1b was used instead of compound im-1a.

[0263] MS m / z:. 255 [M+1] +

[0264] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.71 (m, 1H), 8.01 (m, 1H), 7.25-7.19 (m, 4H), 6.44-6.42 (m, 1H), 4.69 (m, 1H), 3.44-3.39 (m, 2H), 2.93-2.88 (m, 2H),

[0265]

[0266] Manufacturing Example 3: Preparation of 1-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}ethan-1-one (1-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}ethan-1-one) (compound im-3)

[0267]

[0268] Compound im-1a (0.2 g, 0.68 mmol) and bis(triphenylphosphine)dichloropalladium(II) (30 mg, 0.043 mmol) were dissolved in tetrahydrofuran (2 mL), the mixture was filled with nitrogen, and tributyl(ethoxyvinyl)tin (0.25 mL, 0.74 mmol) was added. The mixture was stirred at 75°C for 16 hours. A 2N aqueous potassium fluoride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dispersed in methanol (10 mL), and a 2N aqueous hydrochloric acid solution (5 mL) was added. The mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by column chromatography (ethyl acetate: n-hexane = 1:9 → 3:7) to obtain the title compound im-3 (0.11 g, 63%) as a white solid.

[0269] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.87 (s, 1H), 8.60 (s, 1H), 7.27-7.16 (m, 4H), 6.85 (m, 1H), 4.90 (m, 1H), 3.40 (dd, 2H), 2.90 (m, 2H), 2.44 (s, 3H)

[0270]

[0271] Manufacturing Example 4: Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-amine (N-(2,3-dihydro-1H-inden-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-amine) (compound im-4)

[0272]

[0273] Compound im-1a (4.5 g, 0.015 mol), bis(pinacolato)diboron (5.1 g, 0.020 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.27 g, 1.55 mmol), and potassium acetate (4.6 g, 0.046 mol) were dissolved in 1,4-dioxane (36 mL) and stirred at 100 °C for 18 hours under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, insoluble matter was removed using Celite, filtered, distilled water (100 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 15:85) to obtain the title compound im-4 (3.7 g, 71%) as a white solid.

[0274] MS m / z:. 338 [M+1] +

[0275] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.58 (s, 2H), 7.24-7.16 (m, 4H), 5.50 (d, 1H), 4.90-4.82 (m, 1H), 3.42-3.37 (m, 2H), 2.90-2.85 (m, 2H), 1.33 (s, 12H).

[0276]

[0277] Manufacturing Example 5: Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(piperazin-1-yl)pyrimidin-2-amine hydrochloride (compound im-5)

[0278]

[0279] (Step 1) Preparation of 4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazine-1-carboxylic acid tert-butyl ester (tert-butyl 4-{2-[(2,3-dihydro-1H-inden- 2-yl)amino]pyrimidin-5-yl}piperazine-1-carboxylate) (compound im-5-a)

[0280] Compound im-1a (0.9 g, 3.1 mmol), 1-tert-butoxycarbonyl piperazine (1.3 g, 6.9 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.22 g, 0.461 mmol), palladium(II) acetate (0.070 g, 0.31 mmol), and sodium tert-butoxide (0.92 g, 9.6 mmol) were dissolved in toluene (18 mL), filled with nitrogen, and stirred at 110 °C for 48 hours. After completion of the reaction, the mixture was cooled to room temperature, insoluble matter was removed by filtration using Celite, and the filtrate was extracted with ethyl acetate and distilled water. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 → 1:1) to obtain the title compound im-5-a (0.60 g, 49%) as a yellow solid.

[0281] MS m / z:. 396 [M+1] + .

[0282] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.08 (s, 2H), 7.22-7.17 (m, 4H), 5.24 (s, 1H), 4.73 (m, 1H), 3.58 (br, 4H), 3.40-3.36 (m, 2H), 2.94 (br, 4H), 2.88-2.84 (m, 2H), 1.48 (s, 9H)

[0283] (Step 2) Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(piperazin-1-yl)pyrimidin-2-amine hydrochloride (compound im-5)

[0284] Compound im-5-a (0.60 g, 1.51 mmol) was dissolved in methylene chloride (2 mL), and 4N dioxane hydrogen chloride solution (1 mL) was added at room temperature, followed by stirring for 1.5 hours. The solvent was removed by concentration under reduced pressure, and the title compound im-5 as a yellow solid was quantitatively obtained (0.44 g).

[0285] MS m / z:. 296 [M+1] + .

[0286] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.95 (s, 2H), 7.21-7.13 (m, 4H), 4.56 (m, 1H), 3.57 (br, 4H), 3.25 (m, 2H), 3.22 (br, 4H) 2.87 (m, 2H)

[0287]

[0288] Manufacturing Example 6: Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(piperidin-4-yl)pyrimidin-2-amine hydrochloride (compound im-6)

[0289]

[0290] (Step 1) Preparation of 4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (tert-butyl 4-{2- [(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate) (compound im-6-a)

[0291] Compound im-1a (0.93 g, 3.19 mmol) and N-tert-butoxycarbonyl-1,2,3,5-tetrahydropyridine-4-boric acid pinacol ester (0.99 g, 3.19 mmol) were dissolved in a mixed solvent of 1,4-dioxane (6 mL) / distilled water (2 mL), then sodium carbonate (1.0 g, 9.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) were added, nitrogen was supplied, and the mixture was stirred at 80 °C for 7 hours. After cooling to room temperature, insoluble matters were filtered off using Celite, and the filtrate was extracted with ethyl acetate and distilled water. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3:7) to obtain the title compound im-6-a (0.83 g, 98%) as a yellow solid.

[0292] MS m / z: 393 [M+1] + .

[0293] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.32 (s, 2H), 7.26-7.19 (m, 4H), 5.91 (s, 1H), 5.37 (d, 1H), 4.81-4.79 (m, 1H), 4.06 (s, 2H), 3.63 (s, 2H), 3.43-3.37 (m, 2H), 2.91-2.87 (m ,2H), 2.44 (s, 2H), 1.49 (s, 9H)

[0294] (Step 2) Preparation of 4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidine-1-carboxylic acid tert-butyl ester (tert-butyl 4-{2-[(2,3-dihydro-1H-inden- 2-yl)amino]pyrimidin-5-yl}piperidine-1-carboxylate) (compound im-6-b)

[0295] Compound im-6-a (0.30 g, 0.76 mmol) was dissolved in methanol (5 mL), Pd / C (10 wt%, 0.2 g) was added, and the mixture was stirred under hydrogen pressure (1 atm) for 15 hours. After completion of the reaction, the catalyst was removed using Celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3:7 → 5:5) to obtain the title compound im-6-b (0.17 g, 57%) as a yellow solid.

[0296] MS m / z: 395 [M+1] + .

[0297] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.14 (s, 2H), 7.23-7.17 (m, 4H), 5.33 (d, 1H), 4.79- 4.77 (m, 1H), 4.24 (s, 2H), 3.39 (dd, 2H), 2.90-2.79 (m,4H), 2.49 (t, 1H), 1.80 (d, 2H), 1.58 (d, 2H), 1.48 (s, 9H).

[0298] (Step 3) Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(piperidin-4-yl)pyrimidin-2-amine hydrochloride) (compound im-6)

[0299] Compound im-6-b (0.17 g, 0.43 mmol) was dissolved in methylene chloride (1 mL), 4N dioxane hydrogen chloride solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the title compound im-6 was quantitatively obtained (0.14 g) as a yellow solid.

[0300] MS m / z:. 295 [M+1] + .

[0301] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.81-8.63 (m, 2H), 8.27 (s, 2H), 7.77 (s, 1H), 7.14-7.23 (m, 4H), 4.63-4.60 (m, H), 3.22-3.37 (m, 4H), 2.77-3.01 (m, 4H), 2.68-2.74 (m, 1H), 1.99 (d, 2H), 1.73-1.83 (m, 2H)

[0302]

[0303] Manufacturing Example 7: Preparation of 1H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-c]pyridine hydrochloride (compound im-7)

[0304]

[0305] (Step 1) Preparation of 1H-[1,2,3]triazolo[4,5-c]pyridine (compound im-7-a)

[0306] 3,4-Diaminopyridine (2.0 g, 0.048 mol) was dissolved in 2N hydrochloric acid aqueous solution (25 mL), cooled to 0°C, and sodium nitrite (1.9 g, 0.027 mol) dissolved in distilled water (3 mL) was slowly added, and stirred for 1 hour. The resulting solid was filtered and washed with distilled water to obtain the title compound im-7-a (1.96 g, 89%) as a yellow solid.

[0307] MS m / z: 121 [M+1] + .

[0308] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 9.47 (s, 1H), 8.49 (d, 1H), 7.89 (d, 1H)

[0309] (Step 2) Preparation of 1H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-c]pyridine hydrochloride (compound im-7)

[0310] Compound im-7-a (1.0 g, 8.3 mmol) was dissolved in methanol (60 mL), and Pd / C (10 wt%, 2.0 g) and concentrated hydrochloric acid (1 mL) were added. The mixture was reacted under hydrogen pressure (75 psi) for 7 hours. The catalyst in the reaction mixture was removed by filtration using Celite, and the filtrate was concentrated and dried under reduced pressure to quantitatively obtain the title compound im-7 (1.38 g) as a yellow solid.

[0311] MS m / z: 125 [M+1] + .

[0312] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 9.54 (s, 2H), 4.34 (s, 2H), 2.98 (t, 2H)

[0313]

[0314] [Example]

[0315] Example 1: Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]-N-(3-oxo-3-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propyl)pyrimidine-5-carboxamide (2-[(2,3-dihydro-1H-inden-2-yl)amino]-N-(3-oxo-3-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propyl)pyrimidine-5-carboxamide) (Compound 1)

[0316]

[0317] (Step 1) Preparation of 3-(2-[(2,3-dihydro-1H-inden-2-yl) amino]pyrimidine-5-carboxamido)-propionic acid ethyl ester (ethyl 3-(2-[(2,3-dihydro-1H-inden-2-yl) amino]pyrimidine-5-carboxamido)-propanoate) (Compound 1-a)

[0318] Intermediate im-2a (0.10 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 3-aminopropionic acid ethyl ester hydrochloride (54 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.37 mmol) were sequentially added. The mixture was cooled to 0 °C, and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (0.30 g, 0.58 mmol) was slowly added. The mixture was stirred at room temperature under nitrogen for 15 hours. After completion of the reaction, 50 mL of distilled water was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 8:2 → ethyl acetate) to obtain the title compound 1-a (82 mg, 65%) as a white solid.

[0319] MS m / z:. 355 [M+1] + .

[0320] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.65 (br, 2H), 7.24-7.18 (m, 4H), 6.66 (br, 1H), 5.77 (d, 1H), 4.87-4.85 (m, 1H), 4.17 (q, 2H), 3.70 (q, 2H), 3.40 (dd, 2H), 2.89 (dd, 2H), 2.63 (t, 2H), 1.28 (t, 3H)

[0321] (Step 2) Preparation of 3-({2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxamido)propanoic acid (3-({2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carboxamido)propanoic acid) (Compound 1-b)

[0322] Compound 1-a (82 mg, 0.23 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and distilled water (1 mL), lithium hydroxide (48 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, 2N aqueous hydrochloric acid solution was added to adjust the pH to 2 or lower, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1-b (70 mg, 93%) as a white solid.

[0323] MS m / z:. 327 [M+1] + .

[0324] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.72 (br, 2H), 8.42 (s, 1H), 8.13 (s, 1H), 7.22-7.13 (m, 4H), 4.66 (q, 1H) 3.48-3.40 (m, 2H), 3.25 (dd, 2H), 2.89 (dd, 2H),

[0325] (Step 3) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]-N-(3-oxo-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propyl)pyrimidine-5-carboxamide (2-[(2,3-dihydro-1H-inden-2-yl)amino]-N-(3-oxo-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propyl)pyrimidine-5-carboxamide) (Compound 1)

[0326] Compound 1-b (70 mg, 0.21 mmol), compound im-7 (27 mg, 0.17 mmol), N,N-diisopropylethylamine (0.14 mL, 0.78 mmol), N,N-dimethylaminopyridine (5 mg, 0.04 mmol) were dissolved in 2 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (61 mg, 0.32 mmol) was slowly added at 0 °C, followed by stirring at room temperature under nitrogen for 15 hours. After completion of the reaction, distilled water (50 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride=5:95→7:93) to obtain the title compound 1 (4 mg, 5%) as a white solid.

[0327] MS m / z:. 433 [M+1] + .

[0328] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.69 (br, 2H), 8.40-8.36 (m, 1H) 8.11-8.09 (m, 1 H), 7.21-7.14 (m, 4H), 4.67-4.65 (m, 3 H), 3.79-3.76 (m, 2H), 3.46-3.34 (m, 2H), 2.28-3.22 (m, 2H), 2.90 (dd, 2H), 2.80 (s, 2H), 2.74-2.68 (m, 2H),

[0329]

[0330] Example 2: Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-(1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-3-{1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one) (Compound 2)

[0331]

[0332] (Step 1) Preparation of 3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propionic acid tert-butyl ester (tert-butyl 3-{1,4,6,7-tetrahydro-5H- [1,2,3]triazolo[4,5-c]pyridin-5-yl} propanoate) (compound 2-a)

[0333] Compound im-7 (0.1 g, 0.62 mmol) was dissolved in methylene chloride (1 mL), and after filling with nitrogen, tert-butyl acrylate (0.1 mL, 0.68 mmol) and triethylamine (0.2 mL, 1.6 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 6 hours. After cooling the reaction mixture to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol:methylene chloride = 3:97) to obtain the title compound 2-a (99 mg, 67%) as a colorless liquid.

[0334] MS m / z:. 253 [M+1] + .

[0335] 1 H NMR (CDCl3, 400MHz), δ (ppm): 3.89 (s, 2H), 3.41 (s, 2H), 3.01 (t, 2H), 2.91-2.88 (m, 2H), 1.49 (s, 9H)

[0336] (Step 2) Preparation of 3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propanoic acid hydrochloride (Compound 2-b)

[0337] Compound 2-a (99 mg, 0.42 mmol) was dissolved in methylene chloride (1 mL), and 4N dioxane hydrogen chloride solution (1 mL) was slowly added at 0 °C and stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to quantitatively obtain the title compound 2-b (90 mg) as a white solid.

[0338] MS m / z:. 197 [M+1] + .

[0339] (Step 3) Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one) (Compound 2)

[0340] Compound 2-b (49 mg, 0.21 mmol) and compound im-5 (60 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (0.13 g, 0.24 mmol) were sequentially added at 0 °C, and the mixture was stirred at room temperature under nitrogen for 3 hours. After completion of the reaction, distilled water (30 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 2 (27 mg, 36%) as an ivory solid.

[0341] MS m / z:. 474 [M+1] + .

[0342] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.07 (s, 2H), 7.24-7.18 (m, 4H), 5.16 (m, 1H), 4.74 (m, 1H), 3.84-3.62 (m, 6H), 3.42-3.34 (m, 2H), 3.04-2.82 (m, 12H), 2.82-2.62 (m, 2H)

[0343]

[0344] Example 3: Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin- 1-yl)-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one) (Compound 3)

[0345]

[0346] The title compound 3 was obtained by reacting in the same manner as in Example 2, except that the corresponding compound im-6 was used instead of compound im-5.

[0347] MS m / z:. 473 [M+1] + .

[0348] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.20 (s, 2H), 7.29 (d, 1H), 7.29-7.13 (m, 4H), 5.76 (s, 1H), 4.58-4.52 (m, 2H), 4.06-4.03 (m, 1H), 3.60 (s, 2H), 3.25-3.04 (m, 3H), 2.89-2.56 (m, 12 H), 1.75-1.39 (m, 4H)

[0349]

[0350] Example 4: Preparation of 4-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-oxopropyl]piperazine-1-sulfonamide (4-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-oxopropyl]piperazine-1-sulfonamide) (Compound 4)

[0351]

[0352] (Step 1) Preparation of 3-[4-(N-(tert-butoxycarbonyl)sulfamoyl)piperazin-1-yl]propionic acid ethyl ester (ethyl 3-[4-(N-(tert-butoxycarbonyl)sulfamoyl)piperazin-1-yl]propanoate) (compound 4-a)

[0353] Chlorosulfonyl isocyanate (0.11 mL, 1.30 mmol) and tert-butanol (0.12 mL, 1.30 mmol) were sequentially added to methylene chloride (2 mL) cooled to 0 °C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. After the reaction mixture was cooled to 0 °C again, 3-(piperazin-1-yl)propionic acid ethyl ester (240 mg, 1.082 mmol) and triethylamine (0.75 mL, 5.41 mmol) dissolved in methylene chloride (3 mL) were sequentially and slowly added while stirring, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, a 2 N hydrochloric acid aqueous solution (20 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 5:5 → methanol: methylene chloride = 1:9) to obtain the title compound 4-a (174 mg, 44%) as a yellow solid.

[0354] MS m / z:. 366 [M+1] + .

[0355] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 4.72-4.09 (m, 2H), 3.43 (s, 4H), 2.79-2.52 (m, 8H), 1.49 (s, 9H), 1.28-1.24 (m, 3H)

[0356] (Step 2) Preparation of 3-[4-(N-(tert-butoxycarbonyl)sulfamoyl)piperazin-1-yl]propanoic acid (Compound 4-b)

[0357] Compound 4-a (174 mg, 0.476 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and distilled water (1 mL), lithium hydroxide (110 mg, 2.63 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:9→2:8) to obtain the title compound 4-b (95 mg, 59%) as a white solid.

[0358] MS m / z:. 338 [M+1] + .

[0359] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 3.17-3.14 (m, 4H), 2.57 (t, 2H), 2.43 (s, 4H), 2.37 (t, 2H)

[0360] (Step 3) Preparation of 3-(4-sulfamoylpiperazin-1-yl)propanoic acid hydrochloride (compound 4-c)

[0361] Compound 4-b (95 mg, 0.28 mmol) was dissolved in methylene chloride (1 mL), 4N dioxane hydrogen chloride solution (1 mL) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to quantitatively obtain the title compound 4-c (72 mg) as a white solid.

[0362] MS m / z:. 238 [M+1] + .

[0363] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 7.11 (s, 2H), 3.65-3.12 (m, 10 H), 2.80 (t, 2H)

[0364] (Step 4) Preparation of 4-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-oxopropyl]piperazine-1-sulfonamide (4-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-3-oxopropyl]piperazine-1-sulfonamide) (Compound 4)

[0365] The title compound 4 was obtained by reacting in a similar manner to step 3 of Example 2, except that the corresponding compound 4-c was used instead of compound 2-b of Example 2.

[0366] MS m / z:. 515 [M+1] + .

[0367] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.15 (s, 2H), 7.21-7.12 (m, 4H), 7.05 (d, 1H), 6.79 (s, 2H), 4.54-4.52 (m, 1H), 3.59-3.58 (m, 4H), 3.22 (dd, 2H), 2.97-2.82 (m, 12H), 2.58-2.53 (m, 4H)

[0368]

[0369] Example 5: Preparation of 6-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-3-oxopropyl]benzo[d]oxazol-2(3H)-one (6-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-3-oxopropyl]benzo[d] oxazol-2(3H)-one) (Compound 5)

[0370]

[0371] (Step 1) Preparation of (E)-3-(3-hydroxy-4-nitrophenyl)acrylate ethyl ester (ethyl (E)-3-(3-hydroxy-4-nitrophenyl)acrylate) (compound 5-a)

[0372] 3-Hydroxy-4-nitrobenzaldehyde (0.50 g, 2.99 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethyl phosphonoacetate (1.32 mL, 6.59 mmol) and sodium ethoxide (0.45 g, 6.59 mmol) were sequentially added while stirring, and the mixture was stirred at room temperature for 14 hours. 2N aqueous hydrochloric acid solution (8 mL) was added to the reaction mixture to terminate the reaction, and the resulting solid was filtered, washed with distilled water and n-hexane, and dried under reduced pressure to obtain the title compound 5-a (0.52 g, 74%) as a yellow solid.

[0373] MS m / z:. 238 [M+1] + .

[0374] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 10.61 (s, 1H), 8.14-8.12 (d, 1H), 7.63-7.59 (d, 1H), 7.15-7.13 (d, 1H), 6.56-6.52 (d, 1H), 4.29 (m, 2H), 1.35 (t, 3H)

[0375] (Step 2) Preparation of 3-(4-amino-3-hydroxyphenyl)propionic acid ethyl ester (ethyl 3-(4-amino-3-hydroxyphenyl)propanoate) (compound 5-b)

[0376] Compound 5-a (0.77 g, 3.25 mmol) was dissolved in methanol (50 mL), Pd / C (10 wt%, 1.4 g) was added, and the mixture was stirred under hydrogen pressure (1 atm) for 15 hours. After completion of the reaction, the catalyst was removed using Celite, and the filtrate was concentrated under reduced pressure to remove the solvent, obtaining the title compound 5-b (0.62 g, 91%) as a gray solid.

[0377] MS m / z:. 210 [M+1] + .

[0378] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm):8.87 (br, 1H), 6.51-6.36 (m, 3H), 4.36 (br, 2H), 4.02 (m, 2H), 2.62 (t, 2H), 2.46 (t, 2H), 1.15 (t, 3H)

[0379] (Step 3) Preparation of 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propionic acid ethyl ester (ethyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propanoate) (compound 5-c)

[0380] Compound 5-b (0.70 g, 3.34 mmol) was dissolved in tetrahydrofuran (16 mL), and 1,1'-carbonyldiimidazole (0.91 g, 5.61 mmol) was added while stirring, and the mixture was refluxed for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 5-c (0.74 g, 94%) as a pink solid.

[0381] MS m / z:. 236 [M+1] + .

[0382] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 11.56 (br, 1H), 7.18 (s, 1H), 7.01-6.96 (m, 2H), 4.03 (m, 2H), 2.85 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H)

[0383] (Step 4) Preparation of 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propanoic acid (compound 5-d)

[0384] Compound 5-c (0.74 g, 3.14 mmol) was dissolved in tetrahydrofuran (16 mL), 1 N aqueous lithium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, 2 N aqueous hydrochloric acid solution was added to adjust the pH to 2 or lower, and the mixture was concentrated under reduced pressure to remove half of the solvent. The resulting solid was filtered. The filtrate was extracted with methylene chloride, and the organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 5-d (0.63 g, 97%) as a yellow solid.

[0385] MS m / z:. 208 [M+1] + .

[0386] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 12.88-11.02 (m, 2H), 7.18 (s, 1H), 7.12-6.94 (m, 2H), 2.82 (t, 2H), 2.58-2.50 (m, 2H),

[0387] (Step 5) Preparation of 6-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-3-oxopropyl]benzo[d]oxazol-2(3H)-one (6-[3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-3-oxopropyl]benzo[d]oxazol- 2(3H)-one) (Compound 5)

[0388] The title compound 5 was obtained by reacting in the same manner as step 3 of Example 2, except that the corresponding compound 5-d was used instead of 2-b of Example 2, and compound im-6 was used instead of compound im-5.

[0389] MS m / z:. 484 [M+1] + .

[0390] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 9.73 (br, 1H), 8.08 (s, 2H), 7.27 (s, 1H), 7.22-7.15 (m, 4H), 7.07 (s, 1H), 6.94 (d, 1H), 6.88 (d, 1H), 5.45 (d, 1H), 7.83-4.47 (m, 2H), 3.93 (d, 1H), 3.49 (s, 2H), 3.38 (dd, 2H), 3.12-2.94 (m, 3H), 2.87 (dd, 2H), 2.78-2.52 (m, 4H), 2.12-1.74 (m, 4H), 1.54-1.41 (m, 1H), 1.34-1.21 (m, 1H)

[0391]

[0392] Example 6: Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-2-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-2-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 6)

[0393]

[0394] (Step 1) Preparation of 2-chloro-1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)ethan-1-one (Compound 6-a)

[0395] Compound im-5 (80 mg, 0.22 mmol) was dissolved in methylene chloride (3 mL), and while stirring at 0 °C, triethylamine (0.1 mL) and chloroacetyl chloride (0.02 mL, 0.24 mmol) were sequentially added dropwise, and the mixture was stirred at 0 °C for 20 minutes. After completion of the reaction, 10 mL of methanol was added to dilute the mixture, and the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (ethyl acetate: n-hexane = 7:3) to obtain the title compound 6-a (74 mg, 91%) as a brown solid.

[0396] MS m / z:. 372 [M+1] + .

[0397] 1H NMR (CDCl3, 400MHz), δ (ppm): 8.09 (s, 2H), 7.24-7.14 (m, 4H), 5.22-5.19 (m, 1H), 4.74 (m, 1H), 4.11 (s, 2H), 3.82-3.65 (m, 4H), 3.42-3.34 (m, 2H), 3.08-2.98 (m, 4H), 2.90-2.82 (m, 2H).

[0398] (Step 2) Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-2-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)-2-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 6)

[0399] Compound 6-a (73 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), and while stirring, a solution of compound im-7 (70 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) in N,N-dimethylformamide (1 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, distilled water (20 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 6:94) to obtain the title compound 6 (36 mg, 40%) as a yellow solid.

[0400] MS m / z:. 460 [M+1] + .

[0401] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 11.39 (br, 1H), 8.07 (s, 2H), 7.24-7.17 (m, 4H), 5.20-5.16 (m, 2H), 4.74 (m, 1H), 3.82-3.74 (m, 6H), 3.50 (s, 2H), 3.37 (dd, 2H), 3.00-2.82 (m, 12H)

[0402]

[0403] Example 7: Preparation of 1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-2,2-dimethyl-3-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one (1-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}piperazin-1-yl)-2,2-dimethyl-3-{1,4,6,7-tetrahydro-5H- [1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one) (Compound 7)

[0404]

[0405] The title compound 7 was obtained as a yellow solid by the same reaction method as Example 6, except that 3-chloropivalic acid was used instead of chloroacetyl chloride.

[0406] MS m / z: .502 [M+1] + .

[0407] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 7.99 (s, 2H), 7.26-7.15 (m, 4H), 5.39-5.37 (d, 1H), 4.73 (m, 1H), 3.84-3.76 (m, 6H), 3.41-3.35 (dd, 2H), 2.98-2.78 (m, 12H), 1.36 (s, 6H)

[0408]

[0409] Example 8: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 8)

[0410]

[0411] (Step 1) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl} piperazin-1-yl)acetic acid tert-butyl ester (tert-butyl 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl} piperazin-1-yl)acetate) (Compound 8-a)

[0412] Compound im-5 (0.10 g, 0.27 mmol) was dissolved in methylene chloride (3 mL), and triethylamine (0.19 mL, 1.35 mmol) and tert-butyl bromoacetate (0.06 mL, 0.40 mmol) were sequentially added dropwise while stirring at 0°C, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, distilled water (20 mL) was added and extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4:6) to obtain the title compound 8-a (93 mg, 84%) as a beige solid.

[0413] MS m / z: .410 [M+1] + .

[0414] 1H NMR (CDCl3, 400MHz), δ (ppm): 8.08 (s, 2H), 7.24-7.15 (m, 4H), 5.11 (d, 1H), 4.72 (m, 1H), 3.38 (dd, 2H), 3.18 (s, 2H), 3.08 (t, 4H), 2.86 (dd, 2H), 2.75 (t, 4H), 1.48 (s, 9H)

[0415] (Step 2) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)acetic acid (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5- yl}piperazin-1-yl)acetic acid) (Compound 8-b)

[0416] Compound 8-a (93 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to quantitatively obtain the title compound 8-b (130 mg) as a yellow solid.

[0417] MS m / z:.354 [M+1] + .

[0418] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.18 (s, 2H), 7.20-7.11 (m, 4H), 4.84-3.92 (m, 7H), 3.59-3.29 (m, 4H), 3.21 (dd, 2H), 2.84 (dd, 2H)

[0419] (Step 3) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 8)

[0420] Compound 8-b (130 mg, 0.22 mmol) and compound im-7 (71 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (172 mg, 0.33 mmol) were sequentially added slowly at 0 °C, and the reaction mixture was stirred at room temperature under nitrogen for 15 hours. After completion of the reaction, distilled water (50 mL) was added and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 8 (12 mg, 12%) as a white solid.

[0421] MS m / z: .460 [M+1] + .

[0422] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.07 (d, 2H), 7.23-7.15 (m, 4H), 5.28-5.26 (m, 1H), 4.86 (d, 2H), 4.72 (m, 1H), 3.92 (dt, 2H), 3.41-3.34 (m, 4H), 3.08-3.02 (m, 2H), 3.00-2.82 (m, 6H), 2.74-2.62 (m, 4H)

[0423]

[0424] Example 9: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperidin- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 9)

[0425]

[0426] The title compound 9 was obtained by reacting in the same manner as in Example 8, except that the corresponding compound im-6 was used instead of compound im-5 of Example 8.

[0427] MS m / z:. 459 [M+1] + .

[0428] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.21 (d, 2H), 7.29-7.27 (m, 1H), 7.14-7.12 (m, 4H), 4.83-4.54 (m, 3H), 3.85-3.78 (m, 2H), 3.28-3.19 (m, 4H), 2.83-2.82 (m, 5H), 2.70-2.67 (m, 1H), 2.13-2.08 (m, 2H), 1.74-1.45 (m, 4H)

[0429]

[0430] Example 10: Preparation of 3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one (3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}propan-1-one) (Compound 10)

[0431]

[0432] The title compound 10 was obtained by reacting in the same manner as in Example 8, except that ethyl bromopropionate was used instead of tert-butyl bromoacetate in Example 8.

[0433] MS m / z:. [M+1] + .

[0434] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.07 (s, 2H), 7.22-7.15 (m, 4H), 5.19 (m, 1H), 4.80-4.71 (m, 3H), 3.95-3.77 (m, 2H), 3.41-3.35 (m, 2H), 3.06-3.02 (m, 4H), 2.89-2.83 (m, 6H), 2.73-2.71 (m, 6H)

[0435]

[0436] Example 11: Preparation of (S)-6-[5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)methyl]-2-oxooxazolidin-3-yl]benzo[d]oxazol-2(3H)-one ((S)-6-[5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl} piperazin-1-yl)methyl]-2-oxooxazolidin-3-yl]benzo[d]oxazol-2(3H)-one) (Compound 11)

[0437]

[0438] Compound im-5 (0.14 g, 0.38 mmol) and (R)-[2-oxo-3-(2-oxo-2,3-dihydrobenzo[d] oxazol-6-yl)oxazolidin-5-yl]methyl methanesulfonate (63 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (0.17 mL, 0.94 mmol) was added, and the mixture was stirred at 80 °C for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (20 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 7:93) to obtain the title compound 11 (5 mg, 5%) as a beige solid.

[0439] MS m / z:. 528 [M+1] + .

[0440] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 11.69 (s, 1H), 10.21 (s, 1H), 8.20 (s, 2H), 7.61 (s, 1H), 7.31-7.28 (m, ,1H), 7.22-7.12 (m, 4H), 5.24 (m, 1H), 4.54 (m, 1H), 4.24 (m, 1H), 3.83 (m, 2H), 3.78-3.48 (m, 4H), 3.25-3.20 (m, 3H), 3.16-2.91 (m, 4H), 2.86 (dd, 2H)

[0441]

[0442] Example 12: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide (Compound 12)

[0443]

[0444] (Step 1) Preparation of 6-aminobenzo[d]oxazol-2(3H)-one (compound 12-a)

[0445] 6-Nitro-2,3-dihydro-1,3-benzoxazol-2-one (3.4 g, 0.019 mol) was dissolved in methanol (20 mL), Pd / C (10 wt%, 0.63 g) was added, and the mixture was stirred at room temperature for 3 hours under hydrogen (1 atm). The catalyst was filtered off using Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the title compound 12-a (2.68 g, 95%) as a beige solid.

[0446] MS m / z:.151 [M+1] + .

[0447] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 10.98 (br, 1H), 6.69-6.67 (m, 1H), 6.44 (d, 1H), 6.30 (dd, 1H), 4.89 (br, 2H)

[0448] (Step 2) Preparation of 2-chloro-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide (Compound 12-b)

[0449] Compound 12-a (0.50 g, 3.33 mmol) was dissolved in methylene chloride (16 mL), and chloroacetyl chloride (0.3 mL, 3.7 mmol) diluted in methylene chloride (5 mL) was slowly added while stirring at 0 °C, and the mixture was refluxed and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was concentrated to 1 / 2 under reduced pressure, distilled water (15 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered, washed with methanol, and dried to obtain the title compound 12-b (0.27 g, 36%) as a brown solid.

[0450] MS m / z:.227 [M+1] + .

[0451] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 11.57 (br, 1H), 10.3 (s, 1H), 7.65 (d, 1H), 7.24 (dd, 1H), 7.05 (d, 1H), 4.24 (s, 2H)

[0452] (Step 3) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide (Compound 12)

[0453] The title compound 12 (32 mg, 62%) was obtained as a brown solid by the same method as Example 11, except that compound 12-b (40 mg, 0.16 mmol) was used instead of [2-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)oxazolidin-5-yl]methyl methanesulfonate.

[0454] MS m / z: .486 [M+1] + .

[0455] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 11.69 (br, 1H), 10.21 (br, 1H), 8.20 (s, 2H), 7.61 (d, 1H), 7.26-7.12 (m, 6H), 5.24 (br, 1H), 4.54 (m, 1H), 4.24 (m, 1H), 3.83 (t, 2H), 3.61 (m, 4H), 3.42-3.32 (m, 1H), 3.22 (dd, 2H), 3.04 (m, 4H), 2.86 (dd, 2H)

[0456]

[0457] Example 13: Preparation of 6-[2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)acetyl]benzo[d]oxazol-2(3H)-one (6-[2-(4-{2-[(2,3-dihydro-1H- inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)acetyl]benzo[d]oxazol-2(3H)-one) (Compound 13)

[0458]

[0459] [2-Oxo-3-(2-oxo-2,3-dihydro-1,3-benzooxazol-6-yl)-1,3-oxazolidin-5-yl]methyl methanesulfonate was replaced with 6-(2-chloroacetyl)-2,3-dihydro-1,3-benzooxazol-2-one (50 mg, 0.24 mmol) and the same reaction method as Example 11 was performed to obtain the title compound 13 (21 mg, 19%) as a yellow solid.

[0460] MS m / z: .471 [M+1] + .

[0461] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 12.07 (br, 1H), 8.12 (s, 2H), 7.90 (t, 1H), 7.21-7.11 (m, 5H), 6.96 (d, 1H), 4.52 (m, 1H), 3.87 (s, 2H), 3.22 (dd, 2H), 2.99 (m, 4H), 2.84 (dd, 2H), 2.66 (m, 4H)

[0462]

[0463] Example 14: Preparation of 6-[(1E)-2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-(hydroxyimino)ethyl]benzo[d]oxazol-2(3H)-one (6-[(1E)-2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-1-(hydroxyimino)ethyl]benzo[d]oxazol-2(3H)-one) (Compound 14)

[0464]

[0465] Compound 13 (15 mg, 0.032 mmol) was dissolved in a mixed solvent of methylene chloride (1 mL) and ethanol (4 mL), and hydroxylamine hydrochloride (18 mg, 0.22 mmol) and sodium acetate (44 mg, 0.63 mmol) were sequentially added. The mixture was stirred at 80 °C for 7 hours. After cooling to room temperature, the mixture was stirred for 14 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 14 (7 mg, 44%) as a yellow solid.

[0466] MS m / z: .486 [M+1] + .

[0467] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 11.39 (s, 1H), 8.09 (s, 2H), 7.62 (s, 1H), 7.58 (d, 1H), 7.11-7.20 (m, 4H), 7.06 (d, 1H), 6.93 (d, 1H), 4.50 (m, 1H), 3.68 (s, 2H), 3.20 (dd, 2H), 2.91 (m, 4H), 2.83(dd, 2H), 2.56 (m, 4H)

[0468]

[0469] Example 15: Preparation of 6-[(1E)-3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-(hydroxyimino)propyl]benzo[d]oxazol-2(3H)-one (6-[(1E)-3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl} piperazin-1-yl)-1-(hydroxyimino)propyl]benzo[d]oxazol-2(3H)-one) (Compound 15)

[0470]

[0471] (Step 1) Preparation of 6-(3-chloropropionyl)benzo[d]oxazol-2(3H)-one (6-(3-chloropropanoyl)benzo[d]oxazol-2(3H)-one) (Compound 15-a)

[0472] The title compound 15-a was synthesized according to the published method (WO 2008148449).

[0473] MS m / z:. 226 [M+1] + .

[0474] 1 H NMR (CDCl3, 400MHz), δ (ppm): 12.10 (s, 1H), 7.86-7.93 (m, 2H), 7.24 (d, 1H), 4.00 (t, 2H), 3.54 (t, 2H).

[0475] (Step 2) Preparation of 6-[(1E)-3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)-1-(hydroxyimino)propyl]benzo[d]oxazol-2(3H)-one (6-[(1E)-3-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)-1-(hydroxyimino)propyl]benzo[d]oxazol-2(3H)-one) (Compound 15)

[0476] Compound 15-a (81 mg, 0.36 mmol) was reacted in the same manner as in Examples 13 and 14 to obtain the title compound 15 (3 mg, 2%).

[0477] MS m / z:. 500 [M+1] + .

[0478]

[0479] Example 16: Preparation of 6-{5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)methyl]-4,5-dihydroisoxazol-3-yl}benzo[d]oxazol-2(3H)-one (6-{5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin- 1-yl)methyl]-4,5-dihydroisoxazol-3-yl}benzo[d]oxazol-2(3H)-one) (Compound 16)

[0480]

[0481] (Step 1) Preparation of (E)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde oxime (Compound 16-a)

[0482] The title compound 16-a was synthesized according to the published method (WO 2002050070).

[0483] MS m / z:179. [M+1] + .

[0484] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 11.79 (br, 1H), 11.34 (s, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 7.37 (d, 1H), 7.10 (d, 1H)

[0485] (Step 2) Preparation of 5-[4-allylpiperazin-1-yl]-N-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (5-[4-allylpiperazin-1-yl]-N-2,3-dihydro-1H-inden-2-yl)pyrimidin- 2-amine) (Compound 16-b)

[0486] Compound im-5 (0.15 g, 0.41 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (0.35 mL, 2.03 mmol) and allyl bromide (0.05 mL, 0.6 mmol) were slowly added. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, the mixture was cooled to room temperature, 20 mL of distilled water was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 7:93) to obtain the title compound 16-b (41 mg, 30%) as a dark brown solid.

[0487] MS m / z:336. [M+1] + .

[0488] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.09 (s, 2H), 7.22-7.15 (m, 4H), 5.88 (m, 1H), 5.27-5.10 (m, 3H), 4.73 (m, 1H), 3.38 (dd, 2H), 3.09-3.02 (m, 6H), 2.86 (dd, 2H), 2.68-2.59 (m, 4H)

[0489] (Step 3) Preparation of 6-{5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)methyl]-4,5-dihydroisoxazol-3-yl}benzo[d]oxazol-2(3H)-one (6-{5-[(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)methyl]-4,5-dihydroisoxazol-3-yl}benzo[d]oxazol-2(3H)-one) (Compound 16)

[0490] Compound 16-a (0.10 g, 0.56 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), N-chlorosuccinimide (0.083 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Compound 16-b (40 mg, 0.12 mmol) and sodium bicarbonate (50 mg, 0.60 mmol) were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 9 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 16 (17 mg, 28%) as a dark brown solid.

[0491] MS m / z:. 512 [M+1] + .

[0492] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 11.06 (br, 1H), 8.12 (s, 2H), 7.57 (s, 1H), 7.47 (d, 1H), 7.22-7.11 (m, 5H), 6.83 (d, 1H), 4.89 (m, 1H), 4.52 (m, 1H), 3.53-3.46 (m, 1H), 3.28-3.17 (m, 3H), 2.98 (m, 4H), 2.85 (dd, 2H), 2.70-2.54 (m, 6H)

[0493]

[0494] Example 17: Preparation of N-[2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1-yl)ethyl]-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (N-[2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)ethyl]-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide) (Compound 17)

[0495]

[0496] (Step 1) Preparation of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Compound 17-a)

[0497] 4-Amino-3-hydroxybenzoic acid (1 g, 6.5 mmol) and potassium carbonate (1.4 g, 10.5 mmol) were dissolved in distilled water (8 mL), and while stirring at 40 °C, methyl chloroformate (0.8 mL, 9.8 mmol) was slowly added dropwise, and then the temperature was raised to 80 °C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and a 2N hydrochloric acid aqueous solution was added so that the pH of the solution became 2 or lower, and the resulting solid was filtered, washed with cold water, and dried to obtain the title compound 17-a (0.66 mg, 57%) as a brown solid.

[0498] MS m / z: 179.13, [M+1] + : 180.13

[0499] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 7.63 (d, 1H), 7.53 (s, 1H), 6.93 (d, 1H)

[0500] (Step 2) Preparation of 5-[4-(2-aminoethyl)piperazin-1-yl]-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (Compound 17-b)

[0501] Compound im-5 (0.46 g, 1.4 mmol) and tert-butyl-N-(2-oxoethyl)-carbamate (0.2 g, 1.3 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (0.53 g, 2.5 mmol) was added and stirred at room temperature under a nitrogen atmosphere for 12 hours. Distilled water (50 mL) was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:9) to obtain a yellow solid, and then the synthetic method of Example 1-3 (step 6) was followed to obtain the title compound 17-b (0.1 g, 23%) as a light brown compound.

[0502] MS m / z:. 339 [M+1] + .

[0503] 1 H NMR (DO, 400 MHz), δ (ppm): 8.31 (s, 2H), 7.34-7.25 (m, 4H), 4.65 (m, 1H), 3.58-3.36 (m, 14H), 3.01-2.96 (m, 2H)

[0504] (Step 3) Preparation of N-[2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)ethyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (N-[2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}piperazin-1- yl)ethyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide] (Compound 17)

[0505] Compound 17-a (0.1 g, 0.6 mmol) was used instead of compound 2-b, and compound 17-b (0.11 g, 0.30 mmol) was used instead of compound im-5, and the reaction was carried out in the same manner as step 3 of Example 2, to obtain the title compound 17 (64 mg, 44%) as a yellow solid.

[0506] MS m / z:. 500 [M+1] + .)

[0507] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.38 (m, 1H), 8.12 (s, 2H), 7.72-7.68 (m, 2H), 7.19-7.12 (m, 4H), 6.95 (d, 1H), 4.55-4.49 (m, 1H), 3.41-3.38 (m, 2H), 3.24-3.18 (m, 2H), 2.98 (br, 4H), 2.87-2.82 (m, 2H), 2.57 (br, 4H), 2.54 (m, 2H)

[0508]

[0509] Example 18: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (Compound 18)

[0510]

[0511] (Step 1) Preparation of 3-hydrazinyl-3-oxopropionic acid ethyl ester (ethyl 3-hydrazineyl-3-oxopropanoate) (compound 18-a)

[0512] The title compound 18-a was synthesized according to a published method (European Journal of Medicinal Chemistry, 2008, 43(3), 584-594).

[0513] MS m / z:. 147 [M+1] + .

[0514] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.14 (br, 1H), 4.21 (m, 2H), 3.35 (s, 2H), 1.30 (t, 3H)

[0515] (Step 2) Preparation of 3-({2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carbonyl} hydrazineyl)-3-oxopropionic acid ethyl ester (ethyl 3-({2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carbonyl} hydrazineyl)-3-oxopropanoate) (Compound 18-b)

[0516] Compound im-2a (2.2 g, 8.7 mmol) was dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, and compound 18-a (1.9 g, 13.1 mmol), N,N-diisopropylethylamine (4.6 mL, 26.2 mmol), and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (6.8 g, 13.1 mmol) were sequentially added slowly, and stirred at room temperature for 14 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, distilled water (30 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Methylene chloride was added to the residue to form a solid, which was then filtered and dried to obtain the title compound 18-b (1.4 g, 43%) as a white solid.

[0517] MS m / z:.384 [M+1] + .

[0518] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 10.47 (s, 1H), 10.17 (s, 1H), 8.79 (d, 2H), 8.26 (d, 2H), 7.23-7.14 (m, 4H), 4.42 (q, 1H), 3.35 (s, 2H), 3.27 (dd, 1H), 2.91 (dd, 2H), 1.18 (t, 3H)

[0519] (Step 3) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetic acid ethyl ester (ethyl 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetate) (Compound 18-c)

[0520] Compound 18-b (0.17 g, 0.46 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0 °C, methyl N-(triethylammoniumsulfonyl)carbamate (0.16 g, 0.55 mmol) was added, and the mixture was stirred at 70 °C under a nitrogen atmosphere for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled water (80 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:ethyl acetate = 3:7) to obtain the title compound 18-c (0.12 g, 75%) as a yellow solid.

[0521] MS m / z:. 366[M+1] + .

[0522] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.94 (d, 2H), 7.25-7.19 (m, 4H), 5.80 (d, 1H), 4.90 (q, 1H), 4.02 (s, 1H), 3.44 (dd, 2H), 2.93 (dd, 2H), 1.28 (t, 3H)

[0523] (Step 4) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl) amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetic acid (Compound 18-d)

[0524] Compound 18-c (0.12 g, 0.35 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and distilled water (2 mL), lithium hydroxide (0.072 g, 1.72 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 2N aqueous hydrochloric acid solution was added to adjust the pH to 2 or lower, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 18-d (0.11 g, 95%) as a yellow solid.

[0525] MS m / z:. 338 [M+1] + .

[0526] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.87 (d, 2H), 8.45 (d, 2H), 7.24-7.14 (m, 4H), 4.71 (q, 1H), 4.12 (s, 1H), 3.29 (dd, 2H), 2.96 (dd, 2H)

[0527] (Step 5) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin- 5-yl}-1,3,4- oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin- 5-yl}ethan-1-one) (Compound 18)

[0528] Compound 18-d (0.19 g, 0.55 mmol) and compound im-7 (0.18 g, 1.09 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (0.33 mL, 1.9 mmol) and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (0.43 g, 0.82 mmol) were slowly added at 0 °C, and the reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 18 (0.065 g, 27%) as a white solid.

[0529] MS m / z:. 444 [M+1] + .

[0530] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.85-8.79 (m,2H), 8.43 (d, 1H), 7.24-7.14 (m, 4H), 4.81-4.68 (m, 3H), 4.44 (d, 2H), 4.10 (q, 1H), 3.85-3.83 (m, 2H), 2.24 (dd, 2H), 3.00-2.91 (m, 3H), 2.76-2.73 (m, 1H)

[0531]

[0532] Example 19: Preparation of 2-(5-{6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridin-3- yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin- 5-yl}ethan-1-one) (Compound 19)

[0533]

[0534] Compound im-2b was used instead of compound im-2a, and the reaction was carried out in the same manner as in Example 18 to obtain the title compound 19.

[0535] MS m / z:. 443 [M+1] + .

[0536] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.54 (d, 1H), 7.84-7.79 (m, 1H), 7.67 (d, 1H), 7.21-7.12 (m, 4H), 6.60 (d, 1H), 4.78 (s, 1H), 4.65 (s, 2H), 4.38-4.34 (m, 2H), 3.82-3.81 (m, 2H), 3.29-3.25 (m, 2H), 2.87-2.71 (m, 4H)

[0537]

[0538] Example 20: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadi- azol-2-yl)-1-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethan-1-one) (Compound 20)

[0539]

[0540] (Step 1) Preparation of 5,6,7,8-imidazol[1,2-a]pyrazine (Compound 20-a)

[0541] Intermediate 5H,6H,7H,8H-imidazo[1,2-a]pyrazine (compound 20-a) was synthesized according to the published methods (US2004 / 220189 A1 and US2008 / 153843 A1).

[0542] MS m / z:. 124 [M+1] + .

[0543] (Step 2) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)-1-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl}ethan-1-one) (Compound 20)

[0544] Compound 20 was obtained by reacting in the same manner as Example 18 using compound 20-a instead of compound im-7.

[0545] MS m / z:. 443 [M+1] + .

[0546] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.91 (d, 2H), 7.25-7.18 (m, 4H), 7.07 (d, 2H), 6.91 (d, 2H), 5.89-5.87 (m, 1H), 4.92-4.88 (m 3H), 4.17-4.07 (m, 4H), 3.42 (dd, 2H), 2.92 (dd, 2H)

[0547]

[0548] Example 21: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)-1-{3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 21)

[0549]

[0550] (Step 1) Preparation of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (Compound 21-a)

[0551] Intermediate 21-a was synthesized according to a publicly known method (Bioorgnaic & Medicinal Chemistry, 2008, 18(11), 3359-3363).

[0552] MS m / z:. 124 [M+1] + .

[0553] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 10.10 (br, 2H), 9.01 (s, 1H), 4.27 (s, 2H), 3.43-3.40 (m, 2H), 2.92 (s, 2H)

[0554] (Step 2) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)-1-{3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 21)

[0555] Compound 21 was obtained by reacting in the same manner as Example 18 using compound 21-a instead of compound im-7.

[0556] MS m / z:. 443 [M+1] + .

[0557] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.90 (d, 2H), 7.54 (d, 1H), 7.25-7.17 (m, 4H), 5.92 (t, 1H), 4.90-4.84 (m, 1H), 4.69-4.63 (m, 2H), 4.16 (d, 2H), 3.97-3.86 (m, 2H), 3.49 (s, 2H), 3.41 (dd, 2H), 2.92 (dd, 2H), 2.80-2.74 (m, 2H)

[0558]

[0559] Example 22: Preparation of 6-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (6-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)acetyl]-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one) (Compound 22)

[0560]

[0561] (Step 1) Preparation of 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (Compound 22-a)

[0562] Intermediate 22-a was synthesized according to the publicly known method (WO 2009121812).

[0563] MS m / z:. 151 [M+1] + .

[0564] (Step 2) Preparation of 6-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (6-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)acetyl]-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one) (Compound 22)

[0565] Compound 22 was obtained by reacting in the same manner as Example 18 using compound 22-a instead of compound im-7.

[0566] MS m / z:. 470 [M+1] + .

[0567] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 11.57 (s, 1H), 8.85-8.79 (m, 2H), 8.44-8.42 (m, 1H), 7.30-7.14 (m, 5H), 6.23-6.18 (m, 1H) 4.73-4.68 (m, 1H), 4.47-4.33 (m, 4H), 3.75-3.70 (m, 2H), 3.29-3.22 (m, 2H), 2.93 (dd, 2H), 2.71-2.60 (m, 1H), 2.50 (m, 1H)

[0568]

[0569] Example 23: Preparation of 5-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,3,4,5,6,7-hexahydro-2H-imidazo[4,5-c]pyridin-2-one (5-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]-1,3,4,5,6,7-hexahydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 23)

[0570]

[0571] (Step 1) Preparation of 3-Bromo-piperidin-4-one hydrobromide (Compound 23-a)

[0572] The title compound (23-a) was synthesized according to a published method (Journal of Medicinal Chemistry, 2010, 53(19), 7107-7118).

[0573] MS m / z:.179 [M+1] + .

[0574] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 9.23 (br, 2H), 5.06-5.03 (m, 1H), 4.00-3.95 (m, 1H), 3.71-3.49 (m, 3H), 2.84-2.76 (m, 2H)

[0575] (Step 2) Preparation of 3-bromobromo-4-oxopiperidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester ((9H-fluoren-9-yl)methyl 3-bromo-4-oxopiperidine-1-carboxylate) (Compound 23-b)

[0576] Compound 23-a (2.6 g, 0.010 mol) was dissolved in a mixed solvent of distilled water (3 mL) and 1,4-dioxane (2 0 mL). While stirring at 0 °C, sodium carbonate (3.2 g, 0.030 mol) and 9-fluorenylmethoxycarbonyl chloride (2.6 g, 0.010 mmol) were sequentially and slowly added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled water (30 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9) to obtain the title compound 23-b (2.7 g, 69%) as a white solid.

[0577] MS m / z: 401. [M+1] + .

[0578] 1 H NMR (CDCl3, 400MHz), δ (ppm): 7.78 (d, 2H), 7.59 (d, 2H), 7.42-7.30 (m, 4H), 4.79-4.54 (m, 2H), 4.26 (t, 1H), 3.96-3.52 (m, 4H), 2.96-2.74 (m, 1H), 2.39-2.18 (m, 1H)

[0579] (Step 3) Preparation of 2-oxo-1,2,3,4,6,7-hexahydro-5H-imidazo[4,5-c] pyridine-5-carboxylic acid (9H-fluoren-9-yl)methyl ester ((9H-fluoren-9-yl)methyl 2-oxo- 1,2,3,4,6,7-hexahydro-5H-imidazo[4,5-c] pyridine-5-carboxylate) (Compound 23-c)

[0580] Compound 23-b (0.60 g, 1.50 mmol) and urea (0.55 mg, 8.99 mmol) were dissolved in acetic acid (2.6 mL), cooled to 0°C, and 30% aqueous ammonia solution (0.64 mL) was added while stirring, and stirred at 100°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 23-c (0.22 g, 40%) as a yellow solid.

[0581] MS m / z:.362 [M+1] + .

[0582] 1 H NMR (CDCl3, 400MHz), δ (ppm): 9.86-9.64 (m, 2H), 7.78-7.64 (m, 2H), 7.54-7.24 (m, 6H), 4.51-4.36 (m, 2H), 4.30-4.12 (m, 3H), 3.72-3.56 (m, 2H), 2.42-2.30 (m, 2H)

[0583] (Step 4) Preparation of 1,3,4,5,6,7-hexahydro-2H-imidazo[4,5-c]pyridin-2-one (Compound 23-d)

[0584] Compound 23-c (0.22 g, 0.60 mmol) was dissolved in tetrahydrofuran (25 mL), piperidine (5 mL) was slowly added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and diethyl ether was added to the residue to produce a solid. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound 23-d (77 mg) as a beige solid.

[0585] MS m / z:. 140 [M+1] + .

[0586] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 9.43 (d, 2H), 3.42-3.33 (m, 2H), 2.83 (t, 2H), 2.17 (m, 2H)

[0587] (Step 5) Preparation of 5-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,3,4,5,6,7-hexahydro-2H-imidazo[4,5-c]pyridin-2-one (5-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]-1,3,4,5,6,7-hexahydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 23)

[0588] Compound 23 was obtained by reacting in the same manner as in Example 18 using compound 23-d instead of compound im-7.

[0589] MS m / z:. 459 [M+1] + .

[0590] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 9.78-9.61 (m, 2H), 8.89-8.76 (m, 2H), 8.42 (d, 2H), 7.26-7.12 (m, 4H), 4.71 (m, 1H), 4.38-4.32 (m, 2H), 4.24 (d, 2H), 3.76-3.71 (m, 2H), 3.27 (m, 2H), 2.94 (dd, 2H), 2.44-2.28 (m, 2H)

[0591]

[0592] Example 24: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1,3,4-oxadiazol-2-yl)-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one) (Compound 24)

[0593]

[0594] (Step 1) Preparation of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (Compound 24-a)

[0595] Intermediate 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (compound 24-a) was synthesized according to a publicly known method (Journal of Medicinal Chemistry, 2014, 57(9), 3687-3706).

[0596] MS m / z:. 125 [M+1] + .

[0597] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 7.86 (s, 1H), 4.02 (t, 2H), 3.90 (s, 2H), 3.11 (m, 2H), 2.82 (br, 1H)

[0598] (Step 2) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl}ethan-1-one) (Compound 24)

[0599] Compound 24 was obtained by reacting in the same manner as Example 18 using compound 24-a instead of compound im-7.

[0600] MS m / z:.444 [M+1] + .

[0601] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.88-8.81 (m, 2H), 7.95 (d, 1H), 7.28-7.20 (m, 4H), 5.84-5.79 (m, 1H), 4.98 (s, 2H), 4.91 (m, 1H), 4.39-4.29 (m, 2H), 4.24-4.14 (m, 4H), 3.44 (dd, 2H), 2.94 (dd, 2H)

[0602]

[0603] Example 25: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol- 2-yl)-1-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one) (Compound 25)

[0604]

[0605] (Step 1) Preparation of 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (Compound 25-a)

[0606] Compound 25-a was synthesized according to the published method (US 20070232600887).

[0607] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 9.39 (br, 2H), 7.57 (s, 1H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (t, 2H).

[0608] (Step 2) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)-1-{1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one) (Compound 25)

[0609] Compound 25 was obtained by reacting in the same manner as in Example 18 using compound 25-a instead of compound im-7.

[0610] MS m / z:. 443 [M+1] + .

[0611] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 12.54 (br, 1H), 8.86-8.78 (m, 2H), 8.42 (d, 2H), 7.24-7.14 (m, 4H), 4.70 (m, 1H), 4.64-4.46 (m, 2H), 4.36 (d, 2H), 3.82-3.74 (m, 2H), 3.29 (dd, 2H), 2.94 (dd, 2H), 2.84-2.62 (m, 2H)

[0612]

[0613] Example 26: Preparation of 1-{2-amino-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl}-2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)ethan-1-one (1-{2-amino-6,7-dihydrothiazolo[4,5-c]pyridin- 5(4H)-yl}- 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl) ethan-1-one) (Compound 26)

[0614]

[0615] (Step 1) Preparation of 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-amine dihydrobriomide (Compound 26-a)

[0616] Compound 23-b (0.7 g, 2.7 mmol) was dissolved in ethanol (7 mL), thiourea (0.21 g, 2.7 mmol) was added, and the mixture was refluxed and stirred for 9 hours. After completion of the reaction, the resulting solid was filtered and washed with ethanol. The filtrate was concentrated, and the resulting solid was filtered again. The solid was collected and dried to obtain the title compound 26-a (0.46 g, 53%) as a pink solid, which was used in the next reaction without any additional purification.

[0617] MS 155.9 (M+H)

[0618] (Step 2) Preparation of 1-{2-amino-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl}-2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)ethan-1-one (1-{2-amino-6,7-dihydrothiazolo[4,5-c]pyridin- 5(4H)-yl}-2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)ethan-1-one) (Compound 26)

[0619] Compound 26 was obtained by reacting in the same manner as Example 18 using compound 26-a instead of compound im-7.

[0620] MS m / z:. 475 [M+1] + .

[0621] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.86 (d, 2H), 8.41 (d, 1H), 7.23-7.14 (m, 4H), 6.85 (d, 2H), 4.74-4.69 (m, 1H), 4.57-4.31 (m, 4H), 3.79-3.76 (m, 2H), 3.31-3.26 (m, 2H), 2.97-2.91 (m, 3H), 2.62 (s, 1H)

[0622]

[0623] Example 27: 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1,3,4-oxadiazol-2-yl)-1-{1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl}ethan- 1-one) (Compound 27-1) and Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)-1-{1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl}ethan-1-one) (Compound 27-2)

[0624]

[0625] (Step 1) Preparation of tert-butyl 4-[(dimethylamino)methylidene]-3-oxopiperidine-1-carboxylic acid tert-butyl ester (tert-butyl 4-[(dimethylamino)methylidene]-3-oxopiperidine-1-carboxylate) (Compound 27-1-a) and 2-[(dimethylamino)methylidene]-3-oxopiperidine-1-carboxylic acid tert-butyl ester (tert-butyl 2-[(dimethylamino)methylidene]- 3-oxopiperidine-1-carboxylate) (Compound 27-2-a)

[0626] Tert-Butyl 3-oxopiperidine-1-carboxylate (1.0 g, 5.02 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (1 mL) and refluxed for 1 h. After completion of the reaction, the solvent was removed, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain a mixture of the title compounds (27-1-a and 27-2-a) (0.89 g, 70%).

[0627] MS m / z:.255 [M+1] + .

[0628] 1 H NMR (CDCl3, 400MHz), δ (ppm): 4.24-4.01 (m, 1H), 3.20-2.80 (m, 8H), 2.39-2.08 (m, 3H), 1.73 (m, 1H), 1.43 (s, 1H)

[0629] (Step 2) Preparation of 1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (tert-butyl 1,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridine-6-carboxylate) (Compound 27-1-b) and 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridine-4-carboxylic acid tert-butyl ester (tert-butyl 1,5,6,7-tetrahydro-4H-pyrazolo [4,3-b]pyridine-4-carboxylate) (Compound 27-2-b)

[0630] A mixture of compounds 27-1-a and 27-2-a (0.89 g, 3.50 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (0.35 g, 6.99 mmol) was added, and the mixture was refluxed for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and the solvent was removed to obtain a mixture of the title compounds (27-1-b and 27-2-b) (0.64 g, 81%), which was used in the next reaction without any separate purification process.

[0631] (Step 3) Preparation of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine hydrochloride (Compound 27-2-c) and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine hydrochloride (Compound 27-2-c)

[0632] A mixture of compounds 27-1-b and 27-2-b (0.64 g, 2.86 mmol) was dissolved in methylene chloride (5 mL), cooled to 0°C, 4 N dioxane hydrogen chloride solution (5 mL) was added, and the mixture was stirred for 15 hours. After completion of the reaction, the solvent was removed, and diethyl ether was added to the resulting residue to produce a solid. The resulting solid was filtered and washed with diethyl ether to quantitatively obtain a mixture of the title compounds (27-1-c and 27-2-c) (0.55 g).

[0633] MS m / z:. 124 [M+1] + .

[0634] (Step 4) 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1,3,4-oxadiazol- 2-yl)-1-{1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl}ethan- 1-one) (Compound 27-1) and Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)-1-{1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)-1-{1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl}ethan-1-one) (Compound 27-2)

[0635] A mixture of compounds 27-1-c and 27-2-c was used instead of intermediate im-7, and the reaction was carried out in the same manner as in Example 18 to obtain a mixture of the title compounds 27-1 and 27-2.

[0636] (Compound 27-1)

[0637] MS m / z: .443 [M+1] + .

[0638] 1H NMR (CDCl3, 400 MHz), δ (ppm): 8.98-8.76 (m, 2H), 7.38 (s, 1H), 7.28-7.18 (m, 4H), 5.84-5.81 (m, 1H), 5.30 (d, 1H), 4.89 (m, 1H), 4.79 (d, 2H), 4.16 (d, 2H), 3.86 (dt, 2H), 3.42 (dd, 2H), 2.92 (dd, 2H), 2.74 (dt, 2H)

[0639] (Compound 27-2)

[0640] MS m / z: .443 [M+1] + .

[0641] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.85 (d, 2H), 8.42 (m, 1H), 7.99 (m, 1H), 7.24-7.14 (m, 4H), 4.72 (m, 1H), 4.67 (s, 2H), 3.27 (dd, 2H), 2.94 (dd, 2H), 2.74-2.66 (m, 2H), 2.04-1.94 (m, 2H)

[0642]

[0643] Example 28: Preparation of N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}aminosulfonamide (N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}aminosulfonamide) (Compound 28)

[0644]

[0645] (Step 1) Preparation of N-(pyrrolidin-3-yl)aminosulfonamide hydrochloride (Compound 28-a)

[0646] Intermediate N-(pyrrolidin-3-yl)aminosulfonamide hydrochloride (compound 28-a) was synthesized according to the publicly known method (WO 2011160020).

[0647] MS m / z:. 166 [M+1] + .

[0648] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 9.30 (s, 2H), 6.99 (s, 1H), 6.77 (s, 1H), 3.92 (s, 2H), 3.33-3.04 (m, 4H), 2.17-1.89 (m, 2H)

[0649] (Step 2) Preparation of N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}aminosulfonamide (N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}aminosulfonamide) (Compound 28)

[0650] Compound 28 was obtained by reacting in the same manner as Example 18 using compound 28-a instead of compound im-7.

[0651] MS m / z:. 485 [M+1] + .

[0652] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.86 (s, 2H), 8.43 (d, 2H), 7.23-7.14 (m, 4H), 6.95 (dd, 1H), 6.70 (d, 2H), 4.74-4.69 (m, 1H), 4.19-4.12 (m, 2H), 3.94-3.43 (m, 4H), 3.33-3.26 (m, 2H), 2.97-2.91 (m, 2H), 2.16-1.87 (m, 2H)

[0653]

[0654] Example 29: Preparation of N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}methanesulfonamide (Compound 29)

[0655]

[0656] (Step 1) Preparation of N-(pyrrolidin-3-yl)methanesulfonamide (Compound 29-a)

[0657] Intermediate N-(pyrrolidin-3-yl)methanesulfonamide (compound 29-a) was synthesized according to the known method (US 20110183985).

[0658] MS m / z:. 166 [M+1] + .

[0659] (Step 2) Preparation of N-{1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]pyrrolidin-3-yl}methanesulfonamide (Compound 29)

[0660] Compound 29 was obtained by reacting in the same manner as in Example 18 using compound 29-a instead of compound im-7.

[0661] MS m / z:. 484 [M+1] +.

[0662] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm) 8.85 (d, 2H), 5.41 (d, 2H), 7.45 (dd, 1H), 7.23-7.14 (m, 4H), 4.74-4.69 (m, 1H), 4.15 (s, 2H), 4.00-3.38 (m, 4H), 3.31-3.26 (m, 2H), 2.99-2.92 (m, 5H), 2.21-1.80 (m, 2H)

[0663]

[0664] Example 30: Preparation of 1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid (1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid) (Compound 30)

[0665]

[0666] (Step 1) Preparation of 1-benzyl-4-(methoxycarbonyl)pyridin-1-ium (Compound 30-a)

[0667] Methyl isonicotinate (1.0 g, 7.3 mmol) was dissolved in methanol (10 mL), benzyl bromide (0.95 mL, 8.75 mmol) was added, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed. The residue was then added with n-hexane to produce a solid. The resulting solid was filtered and washed with n-hexane to quantitatively obtain the title compound 30-a (1.7 g) as a yellow solid.

[0668] MS m / z:. 229 [M+1] + .

[0669] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.39 (d, 2H), 8.54 (d, 2H), 7.56-7.45 (m, 5H), 3.98 (s, 3H)

[0670] (Step 2) Preparation of methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester (compound 30-b)

[0671] Compound 30-a (2.1 g, 9.2 mmol) was dissolved in ethanol (20 mL), cooled to 0 °C, sodium borohydride (0.38 g, 0.010 mol) and distilled water (4 mL) were added, and stirred at room temperature for 1 hour. After completion of the reaction, distilled water (20 mL) was added and extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title compound 30-b (1.84 g) as a yellow liquid, which was used in the next reaction without any separate purification process.

[0672] MS m / z:. 232 [M+1] + .

[0673] 1 H NMR (CDCl3, 400MHz), δ (ppm): 7.33-7.24 (m, 5H), 6.88-6.87 (m, 1H), 3.73 (s, )3H), 3.61 (s, 2H), 3.14-3.12 (m, 2H), 2.61 (t, 2H), 2.41-2.41 (m, 2H)

[0674] (Step 3) Preparation of 4-methyl 1-[2-(trimethylsilyl)ethyl] 3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 4-methyl 1-[2-(trimethylsilyl)ethyl] diester (Compound 30-c)

[0675] Compound 30-b (1.8 g, 7.9 mmol) was dissolved in methylene chloride (5 mL), cooled to 0°C, 2-(trimethylsilyl)ethyl chloroformate (2.8 g, 0.016 mol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9) to obtain the title compound 30-c (1.34 g, 59%) as a colorless liquid.

[0676] MS m / z:. 286 [M+1] + .

[0677] 1 H NMR (CDCl3, 400MHz), δ (ppm): 6.89 (s, 1H), 4.21 (t, 2H), 4.15-4.11 (m, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 2.41 (s, 2H), 1.02 (t, 2H), 0.05 (s, 9H)

[0678] (Step 4) Preparation of methyl 1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester (compound 30-d)

[0679] Compound 30-c (0.50 g, 1.75 mmol) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 30-d (0.22 g, 89%) as a brown liquid.

[0680] MS m / z:. 142 [M+1] + .

[0681] 1 H NMR (CDCl3, 400MHz), δ (ppm): 6.95 (s, 1H), 3.75 (s, 3H), 3.53 (s, 2H), 2.99 (t, 2H), 2.32 (s, 3H)

[0682] (Step 5) Preparation of 1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid (1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxa-diazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid) (Compound 30)

[0683] Compound 30 was obtained by reacting in the same manner as in Example 18 using compound 30-d instead of compound im-7.

[0684] MS m / z:. 447 [M+1] + .

[0685] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 8.86-8.63 (m, 2H), 8.43-8.42 (m, 1H), 7.23-7.14 (m, 4H), 7.00-6.69 (m, 1H), 4.74-4.62 (m, 1H), 4.40-4.28 (m, 2H), 4.24-4.09 (m, 1H), 3.70-3.59 (m, 2H), 3.23-3.22 (m, 3H), 2.97-2.87 (m, 3H), 2.38-2.18 (m, 1H)

[0686]

[0687] Example 31: Preparation of 1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxamide (1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (Compound 31)

[0688]

[0689] (Step 1) Preparation of 3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 1-tert-butyl 4-methyl diester (1-(tert-butyl) 4-methyl 3,6-dihydropyridine-1,4(2H)- dicarboxylate) (Compound 31-a)

[0690] Compound 30-d (0.33 g, 2.34 mmol) was dissolved in methylene chloride (15 mL), and di-tert-butyl dicarbonate (0.76 g, 3.49 mmol) and triethylamine (0.6 mL, 4.4 mmol) were sequentially added slowly, and the mixture was stirred at room temperature for 15 hours. 2N aqueous hydrochloric acid solution (2 mL) was added to the reaction mixture, stirred for 10 minutes, distilled water (20 mL) was further added, and the mixture was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9) to obtain the title compound 31-a (0.15 g, 27%) as a colorless liquid.

[0691] MS m / z:. 242 [M+1] + .

[0692] 1 H NMR (CDCl3, 400MHz), δ (ppm): 6.89 (br, 1H), 4.07 (m, 2H), 3.76 (s, 3H), 3.51 (m, 2H), 2.40 (m, 2H), 1.47 (s, 9H)

[0693] (Step 2) Preparation of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (Compound 31-b)

[0694] Compound 31-a (0.15 g, 0.63 mmol) was dissolved in tetrahydrofuran (3 mL), 1 N aqueous lithium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2 N aqueous hydrochloric acid solution was added to adjust the pH to 2 or lower, and the mixture was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 31-b (0.13 g, 92%) as a white solid.

[0695] MS m / z:. 228 [M+1] + .

[0696] 1 H NMR (CDCl3, 400MHz), δ (ppm): 7.02 (br, 12H), 4.11 (m, 2H), 3.53 (m, 2H), 2.40 (m, 2H), 1.48 (s, 9H)

[0697] (Step 3) Preparation of tert-butyl 4-carbamoyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (tert-butyl 4-carbamoyl-3,6-dihydropyridine-1(2H)- carboxylate) (Compound 31-c)

[0698] Compound 31-b (0.13 g, 0.59 mmol) and ammonium chloride (0.16 g, 2.93 mmol) were dissolved in N,N-dimethylformamide (7 mL), cooled to 0 °C, and then N,N-diisopropylethylamine (0.51 mL, 2.93 mmol) and benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (0.46 g, 0.89 mmol) were sequentially added dropwise thereto slowly and stirred at room temperature for 15 hours. After completion of the reaction, distilled water (50 mL) was added and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 5:95) to obtain the title compound 31-c quantitatively (0.14 g) as a white solid.

[0699] MS m / z:.227 [M+1] + .

[0700] 1 H NMR (CDCl3, 400MHz), δ (ppm): 6.62 (s, 1H), 6.21-5.54 (m 2H), 4.19 (m, 2H), 3.54 (m, 2H), 2.39 (m, 2H), 1.47 (s, 9H)

[0701] (Step 4) Preparation of 1,2,3,6-tetrahydropyridine-4-carboxamide (compound 31-d)

[0702] Compound 31-c (0.14 g, 0.59 mmol) was dissolved in methylene chloride (2 mL), and 4N dioxane dichloride solution (2 mL) was added at 0°C. The mixture was stirred at room temperature for 9 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and methylene chloride was added to the residue to produce a solid. The resulting solid was filtered and washed with methylene chloride to obtain the title compound 31-d (41 mg, 43%) as a white solid.

[0703] MS m / z:. 127 [M+1] + .

[0704] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 9.12 (m, 2H), 7.54 (br, 1H), 7.18 (br, 1H), 6.54 (s, 1H), 3.70 (m, 2H), 3.17 (m, 2H), 2.43 (m, 2H)

[0705] (Step 5) Preparation of 1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxamide (1-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4- oxadiazol-2-yl)acetyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (Compound 31)

[0706] Compound 31 was obtained by reacting in the same manner as Example 18 using compound 31-d instead of compound im-7.

[0707] MS m / z:. 446 [M+1] + .

[0708] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.83 (d, 2H), 8.42 (d, 1H), 7.43 (br, 1H), 7.26-7.12 (m, 4H), 7.08-7.02 (m, 1H), 6.58-6.52 (m, 1H), 4.71 (m, 1H), 4.38-4.04 (m, 4H), 3.64-3.54 (m, 2H), 3.32-3.24 (m, 2H), 2.94 (dd, 2H), 2.42-2.21 (m, 2H)

[0709]

[0710] Example 32: Preparation of 4-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetamido]benzoic acid (4-[2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)acetamido]benzoic acid) (Compound 32)

[0711]

[0712] The title compound 32 was obtained by reacting in the same manner as in Example 18 using tert-butyl 4-aminobenzoate instead of compound im-7.

[0713] MS m / z:. 457 [M+1] + .

[0714] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 10.72 (s, 1H), 8.85 (d, 2H), 8.43 (d, 1H), 7.92-7.90 (m, 4H), 7.24-7.14 (m, 4H), 4.74-4.68 (m, 1H), 3.27-3.25 (m, 2H), 2.97-2.91 (m, 2H)

[0715]

[0716] Example 33: Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1,2,4-oxadiazol-5-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin- 5-yl}ethan-1-one) (Compound 33)

[0717]

[0718] (Step 1) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carbonitrile (2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carbonitrile) (Compound 33-a)

[0719] Compound im-1a (2.5 g, 8.6 mmol) and copper(I) cyanide (1.0 g, 11.2 mmol) were dissolved in N,N-dimethylformamide (41 mL) and stirred at 180°C for 18 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (50 mL) and washed twice with 10% aqueous sodium cyanide solution (50 mL). The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 15:85) to obtain the title compound 33-a (1.48 g, 73%) as a white solid.

[0720] MS m / z:. 237 [M+1] + .

[0721] 1H NMR (CDCl3, 400MHz), δ (ppm): 8.556 (s, 1H), 8.249 (s, 1H), 7.252-7.134 (m, 4H), 6.189 (d, 1H), 4.900-4.796 (m, 1H), 3.432-3.375 (m, 2H), 2.920-2.852 (m, 2H)

[0722] (Step 2) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]-N-hydroxypyrimidine-5-carboximidamide (2-[(2,3-dihydro-1H-inden-2-yl)amino]- N-hydroxypyrimidine- 5-carboximidamide) (Compound 33-b)

[0723] Compound 33-a (0.30 g, 1.27 mmol), hydroxylamine hydrochloride (0.21 g, 3.02 mmol), and potassium carbonate (0.36 g, 2.59 mmol) were dissolved in a mixed solvent of methanol (9 mL) and distilled water (1 mL), and the mixture was refluxed and stirred at 100 °C for 2 hours. Distilled water (50 mL) was added to the reaction mixture, and the resulting solid was filtered, washed with distilled water, and dried to obtain the title compound 33-b (0.2 g, 59%) as a white solid.

[0724] MS m / z:. 270 [M+1] + .

[0725] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.76 (m, 2H), 8.53 (s, 2H), 7.72 (d, 1H), 7.13-7.22 (m, 4H), 5.82 (br, 1H), 4.58-4.70 (m, 1H), 3.22-3.29 (m, 2H), 2.86-2.93 (m, 2H)

[0726] (Step 3) Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)acetic acid ethyl ester (ethyl 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,4- oxadiazol-5-yl)acetate) (Compound 33-c)

[0727] Compound 33-b (0.37 g, 1.37 mmol) was dissolved in toluene (18 mL), cooled to 0 °C, sodium hydride (41 mg, 1.70 mmol) was added, and stirred at room temperature for 30 minutes. The mixture was cooled again to 0 °C, ethyl malonyl chloride (0.21 mL, 1.64 mmol) was added, and stirred at 80 °C for 9 hours. After completion of the reaction, insoluble matters were removed using Celite, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:1) to obtain the title compound 33-c (0.29 mg, 58%) as a yellow solid.

[0728] MS m / z:. 366 [M+1] + .

[0729] 1 H NMR (CDCl3, 400 MHz), δ (ppm): δ 8.92 (m, 2H), 7.18-7.25 (m, 4H), 5.83 (d, 1H), 4.87-4.93 (m, 1H), 4.27 (q, 2H), 3.43 (dd, 2H), 2.92 (dd, 2H), 1.31 (t, 3H)

[0730] (Step 4) Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)acetic acid (2-(3-{2-[(2,3-dihydro-1H-inden-2- yl)amino]pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)acetic acid) (Compound 33-d)

[0731] Compound 33-c (0.29 g, 0.79 mmol) was used instead of compound 18-c, and the reaction was carried out in the same manner as step 4 of Example 18 to obtain the title compound 33-d (0.19 g, 73%).

[0732] MS m / z:. [M+1] + .

[0733] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.869 (d, 2H), 8.312 (d, 1H), 7.142-7.240 (m, 4H), 4.678-4.732 (m, 1H), 4.226 (s, 2H), 3.167-3.295 (m, 2H), 2.910-2.966 (dd, 2H)

[0734] (Step 5) Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}-1,2,4-oxadiazol-5-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo [4,5-c]pyridin-5-yl}ethan-1-one) (Compound 33)

[0735] Compound 33 was obtained by reacting in the same manner as step 5 of Example 18 using compound 33-d instead of compound 18-d.

[0736] MS m / z:.444 [M+1] + .

[0737] 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.81-8.86 (m, 2H), 8.30 (d, 1H), 7.24-7.14 (m, 4H), 4.80-4.51 (m, 5H), 3.85-3.83 (m, 2H), 3.31-3.25 (m, 2H), 2.97-2.67 (m, 4H)

[0738]

[0739] Example 34: Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)-1-{1,4,6,7-tetrahydro-5H- [1,2,3]triazolo[4,5-c]pyridin-5-yl} ethan-1-one) (Compound 34)

[0740]

[0741] (Step 1) Preparation of 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (ethyl 3-ethoxy-3-iminopropanoate hydrochloride) (compound 34-a)

[0742] The title compound 34-a was prepared according to the published method (Synthesis, 2016, 48(17), 2851-2862).

[0743] MS m / z:160 [M+1] + .

[0744] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): δ 4.13-4.09 (m, 4H), 3.45 (s, 2H), 1.20-1.18 (m, 6 H)

[0745] (Step 2) Preparation of 2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidine-5-carbohydrazide (Compound 34-b)

[0746] Compound im-2a (6.0 g, 0.02 mol) was dissolved in ethanol (50 mL), hydrazine hydrate (10 mL, 0.21 mol) was added, and the mixture was stirred at 80°C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, the resulting solid was filtered, washed with ethanol, and dried to obtain the title compound 34-b (5.3 g, 83%) as a white solid.

[0747] MS m / z: .270[M+1] + .

[0748] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 9.58 (s, 1H), 8.71 (d, 2H), 8.08 (d, 2H), 7.23-7.13 (m, 4H), 4.69-4.63 (m, 1H) 4.41 (s, 2H), 3.26 (dd, 2H), 2.9 (dd, 2H)

[0749] (Step 3) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)acetic acid ethyl ester (ethyl 2-(5-{2-[(2,3-dihydro-1H- inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)acetate) (Compound 34-c)

[0750] Compound 34-a (0.88 g, 4.53 mmol) and compound 34-b (0.61 g, 2.26 mmol) were dissolved in ethanol (10 mL), triethylamine (0.95 mL, 6.80 mmol) was added, and the mixture was stirred at 90 °C for 24 hours under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, distilled water (20 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 6:4 → 7:3) to obtain the title compound 34-c (0.27 g, 33%) as a yellow solid.

[0751] MS m / z:365 [M+1] + .

[0752] 1 H NMR (CDCl3, 400 MHz), δ (ppm): 8.93 (s, 2H), 7.26-7.16 (m, 4H), 5.77 (d, 1H), 4.90-4.85 (m, 1H), 4.30-4.21 (m, 2H), 3.99 (s, 2H), 3.42 (dd, 2H), 2.91 (dd, 2H), 1.42-1.35 (m, 3H)

[0753] (Step 4) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)acetic acid (Compound 34-d)

[0754] The title compound 34-d (52 mg, 77%) was obtained by reacting in the same manner as step 4 of Example 18 using compound 34-c (73 mg, 0.20 mmol) instead of compound 18-c.

[0755] MS m / z:337 [M+1] + .

[0756] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.82 (s, 2H), 7.96 (s, 1H), 7.23-7.15 (m, 4H), 4.69-4.67 (m, 1H), 3.79 (s, 2H), 3.29-3.25 (m, 2H), 2.92 (dd, 2H)

[0757] (Step 5) Preparation of 2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(5-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-4H-1,2,4-triazol-3-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin- 5-yl}ethan-1-one) (Compound 34)

[0758] Compound 34-d (52 mg, 0.154 mmol) was used instead of compound 18-d, and the reaction was carried out in the same manner as step 5 of Example 18 to obtain the title compound 34 (10 mg, 15%) as a yellow solid.

[0759] MS m / z:443 [M+1] + .

[0760] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.80 (d, 2H), 8.08-7.82 (m, 1H), 7.22-7.15 (m, 4H), 4.84-4.68 (m, 3H), 4.13-3.83 (m, 4H), 3.31-3.24 (m, 2H), 2.95-2.73(m, 4H)

[0761]

[0762] Example 35: Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan- 1-one) (Compound 35)

[0763]

[0764] (Step 1) Preparation of 1-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-3-(dimethylamino)prop-2-en-1-one (1-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}-3-(dimethylamino) prop-2-en-1-one) (Compound 35-a)

[0765] Compound im-3 (0.10 g, 0.39 mmol) was dissolved in toluene (3 mL), N,N-dimethylformamide dimethylacetal (0.06 mL, 0.45 mmol) was added, and the mixture was stirred at 120°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled water (20 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 35-a (0.11 g, 92%).

[0766] MS m / z:. 309 [M+1] + .

[0767] 1H NMR (CDCl3, 400MHz), δ (ppm): 8.84 (br, 2H), 7.81 (d, 1H), 7.25-7.17 (m, 4H), 5.64 (d, 1H), 5.55 (d, 1H), 4.90-4.86 (m, 1H), 4.27 (q, 2H), 3.41 (dd, 2H), 3.16 (br, 3H), 2.92 (br, 3H), 2.90 (dd, 2H)

[0768] (Step 2) Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(1H-pyrazol-3-yl)pyrimidin-2-amine (Compound 35-b)

[0769] Compound 35-a (0.11 g, 0.36 mmol) was dissolved in ethanol (15 mL), hydrazine hydrate (0.19 g, 3.71 mmol) was added, and the mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 35-b (97 mg, 98%) as a red solid.

[0770] MS m / z:. 309 [M+1] + .

[0771] 1 H NMR (CDCl3, 400 MHz), δ (ppm): δ 8.73 (br, 2H), 7.63 (d, 1H), 7.25-7.17 (m, 4H), 6.54 (d, 1H), 5.50 (d, 1H), 4.90-4.84 (m, 1H), 3.43 (dd, 2H), 2.91 (dd, 2H)

[0772] (Step 3) Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)acetic acid (2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}-1H-pyrazol-1-yl)acetic acid) (Compound 35-c)

[0773] Compound 35-b (97 mg, 0.35 mmol) was dissolved in acetone (12 mL), and potassium carbonate (0.2 g, 1.4 mmol) and tert-butyl bromoacetate (0.06 mL, 0.64 mmol) were added, and the mixture was refluxed for 13 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (30 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methylene chloride (2 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed, and diethyl ether was added to the resulting residue to produce a solid. The resulting solid was filtered and washed with diethyl ether to obtain the title compound 35-c (94 mg, 80%) as a beige solid.

[0774] MS m / z:.336 [M+1] + .

[0775] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.70 (s, 2H), 7.77 (d, 1H), 7.74-7.61 (m, 1H), 7.25-7.12 (m, 4H), 6.69-6.68 (d, 1H), 4.98 (s, 2H), 4.65 (m, 1H), 3.27 (dd, 2H), 2.91 (dd, 2H)

[0776] (Step 4) Preparation of 2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5- yl}ethan-1-one) (Compound 35)

[0777] Compound 35 was obtained by reacting in the same manner as step 5 of Example 18 using compound 35-c instead of compound 18-d.

[0778] MS m / z:. 442 [M+1] + .

[0779] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.64 (d, 2H), 7.56 (dd, 1H), 7.21 (m,, 4H), 6.51 (dd, 1H), 5.69 (dd, 1H), 5.13 (d, 1H), 4.87-4.83 (m, 3H), 3.93 (dt, 2H), 3.43-3.38 (m, 2H), 2.93-2.83 (m, 4H)

[0780]

[0781] Example 36: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5- yl}ethan-1-one) (Compound 36)

[0782]

[0783] (Step 1) Preparation of 2-[4-(4,4,5,5-tetramethyltetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetic acid tert-butyl ester (tert-Butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate) (Compound 36-a)

[0784] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.6 mmol) and cesium carbonate (1.3 g, 3.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), tert-butyl bromoacetate (0.6 mL, 3.9 mmol) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain the title compound 36-a (1.1 g, 63%) as a yellow solid.

[0785] MS m / z:. 309 [M+1] + .

[0786] 1 H NMR (CDCl3, 400MHz), δ (ppm): 7.82 (s, 1H), 7.75 (s, 1H), 4.82 (s, 2H), 1.47 (s, 9H), 1.31 (s, 12H)

[0787] (Step 2) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)acetic acid (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin- 5-yl}-1H-pyrazol-1-yl)acetic acid) (Compound 36-b)

[0788] Compound 36-a (0.2 g, 0.7 mmol), compound im-1a (0.2 g, 0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol), and potassium carbonate (0.2 g, 1.2 mmol) were dissolved in a mixed solvent of acetonitrile and distilled water (4:1, 10 mL), filled with nitrogen, and stirred at 110 °C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (20 mL) was added, and extracted with distilled water. A saturated sodium bicarbonate solution was added to the aqueous layer, and extraction was performed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methylene chloride (2 mL), trifluoroacetic acid (1.5 mL), and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed, and diethyl ether was added to the resulting residue to produce a solid. The resulting solid was filtered and washed with diethyl ether to obtain the title compound 36-b (110 mg, 55%) as a pale yellow solid.

[0789] MS m / z:. 336 [M+1] + .

[0790] (Step 3) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H- pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 36)

[0791] Compound 36-b (97 mg, 0.3 mmol) was used instead of compound 18-d, and the reaction was carried out in the same manner as step 5 of Example 18 to obtain the title compound 36 (44 mg, 34%) as a white solid.

[0792] MS m / z:. 442 [M+1] + .

[0793] 1H NMR (CD3OD, 400 MHz,) δ (ppm) 8.632 (s, 2H), 8.028 (d, 1H), 7.870 (d, 1H), 7.232-7.147 (m, 4H), 5.334-5.297 (m, 2H), 4.825-4.739 (m, 3H), 3.946-3.916 (m, 2H), 3.397-3.341 (m, 2H), 2.993-2.835 (m, 4H)

[0794]

[0795] Example 37: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-pyrazol-1-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide) (Compound 37)

[0796]

[0797] Compound 12-a (54 mg, 0.40 mmol) prepared in Example 12 (step 1) was used instead of compound im-7, and compound 36-b (60 mg, 0.20 mmol) prepared in Example 36 (step 2) was used instead of compound 18-d, and the reaction was carried out in the same manner as step 5 of Example 18 to obtain the title compound 37 (6 mg, 7%) as a white product.

[0798] MS m / z:. 468 [M+1] + .

[0799] 1 H NMR (400MHz, DMSO-d6), δ (ppm): 10.349 (s, 1H), 8.540 (s, 2H), 8.099 (s, 1H), 7.840 (s, 1H), 7,588 (s, 1H), 7.435 (d, 1H), 7.183-7.091 (m, 5H), 6.981 (d, 1H), 4.972 (s, 2H), 4.613-4.560 (m, 1H), 3.249-3.191 (m, 2H), 2.891-2.834 (m, 2H)

[0800]

[0801] Example 38: Preparation of 2-(4-{6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridin-3-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{6-[(2,3-dihydro-1H-inden-2-yl)amino]pyridin-3-yl}-1H- pyrazol- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 38)

[0802]

[0803] Compound 1-d was used instead of compound 1-a, and the reaction was carried out in the same manner as steps 2 and 3 of Example 36 to obtain the white title compound 38 (33 mg, 27%).

[0804] MS m / z: 441 [M+1] + .

[0805] 1 H NMR (400 MHz, CD₃OD) δ (ppm) 8.116-8.033 (m, 3H), 7.891 (d, 1H), 7.286-7.179 (m, 4H), 7.068 (d, 1H), 5.348-5.307 (m, 2H), 4.793 (s, 2H), 4.575-4.518 (m, 1H), 3.976-3.917 (m, 2H), 3.496-3.438 (m, 2H), 3.039-2.987 (m, 2H), 2.977-2.832 (m, 2H)

[0806]

[0807] Example 39: Preparation of 2-(4-{5-[(2,3-dihydro-1H-inden-2-yl)amino]pyrazin-2-yl}-1H-pyrazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{5-[(2,3-dihydro-1H-inden-2-yl)amino]pyrazin-2-yl}-1H-pyrazol- 1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 39)

[0808]

[0809] Compound 1-e was used instead of compound 1-a, and the reaction was carried out in the same manner as steps 2 and 3 of Example 36 to obtain the title compound 39 (25 mg, 12%) as a white product.

[0810] MS m / z: 442 [M+1] + .

[0811] 1 H NMR (400 MHz, CD3OD) δ (ppm) 8.273 (s, 1H), 8.042-8.013 (d, 1H), 7.927-7.914 (d, 1H), 7.866 (s, 1H), 7.230-7.125 (m, 4H), 5.328-5.291 (m, 2H), 4.833-4.796 (m, 2H), 4.690-4.657 (m, 1H), 3.974-3.910 (m, 2H), 3.391-3.333 (m, 2H), 2.956-2.848 (m, 4H)

[0812]

[0813] Example 40: Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-imidazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H- imidazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one) (Compound 40)

[0814]

[0815] (Step 1) Preparation of 4-iodo-1-(triphenylmethyl)-1H-imidazole (4-iodo-1-(triphenylmethyl)-1H-imidazole) (Compound 40-a)

[0816] 4-Iodo-1H-imidazole (3.0 g, 0.015 mol) and triphenylmethyl chloride (6.0 g, 0.021 mol) were dissolved in anhydrous N,N-dimethylformamide (50 mL), cooled to 0 °C, triethylamine (7.2 mL, 0.052 mol) was slowly added, and stirred at room temperature for 14 h. The reaction mixture was concentrated, distilled water (100 mL) was added, and stirred at room temperature for 20 min. The solid was filtered, and the filtrate was washed with distilled water and diethyl ether to obtain the title compound 40-a (4.4 g, 66%) as a white solid.

[0817] MS m / z:. 437 [M+1] + .

[0818] 1 H NMR (CDCl3, 400MHz), δ (ppm): 7.34-7.36 (m, 9H), 7.32 (s, 1H), 7.10-7.12 (m, 6H), 6.91 (s, 1H)

[0819] (Step 2) Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-[1-(triphenylmethyl)-1H-imidazol-4-yl] pyrimidin-2-amine (Compound 40-b)

[0820] Compound im-4 (0.69 g, 2.03 mmol), compound 40-a (0.68 g, 1.56 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol), and 2N sodium carbonate aqueous solution (2.5 mL) were dissolved in 1,4-dioxane (10 mL), nitrogen was filled, and the mixture was stirred at 100 °C for 9 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3:7) to obtain the title compound 40-b (0.65 g, 80%) as a red solid.

[0821] MS m / z:. 520 [M+1] + .

[0822] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.61 (br, 2H), 8.41 (s, 1H), 7.50 (s, 1H), 7.29-7.37 (m, 11H), 7.15-7.24 (m, 8H), 7.00 (s, 1H), 5.40 (d, 1H), 4.79-4.83 (m, 1H), 3.39 (dd, 2H), 2.86 (dd, 2H)

[0823] (Step 3) Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(1H-imidazol-4-yl)pyrimidin-2-amine (Compound 40-c)

[0824] Compound 40-b (0.68 g, 1.31 mmol) was dissolved in methylene chloride (20 mL), trifluoroacetic acid (3 mL) and anisole (0.5 mL) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, a 2N hydrochloric acid aqueous solution was added until the pH was 2 or lower, washed with methylene chloride, and the aqueous layer was added a 2N sodium hydroxide solution until the pH was 10 or higher, and extracted again with methylene chloride and ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:9) to obtain the title compound 40-c (0.27 g, 73%) as a dark brown solid.

[0825] MS m / z:. 278 [M+1] + .

[0826] 1 H NMR (CDCl3, 400MHz), δ (ppm): 8.68 (s, 2H), 7.73 (s, 1H), 7.16-7.25 (m, 4H), 7.19 (s, 1H), 5.47 (d, 1H), 4.83-4.85 (m, 1H), 3.41 (dd, 2H), 2.90 (dd, 2H)

[0827] (Step 4) Preparation of 2-(4-{2[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-imidazol-1-yl)acetic acid (2-(4-{2[(2,3-dihydro-1H-inden-2-yl)amino] pyrimidin-5-yl}-1H-imidazol-1-yl)acetic acid) (Compound 40-d)

[0828] Compound 40-c (0.22 g, 0.79 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), and sodium hydride (29 mg, 1.2 mmol) was added while stirring at 0 °C, stirred for 30 minutes, cooled again to 0 °C, tert-butyl bromoacetate (0.13 mL, 0.87 mmol) was added, and stirred at 80 °C for 9 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water (50 mL) was added, and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methylene chloride (2 mL), trifluoroacetic acid (1.5 mL) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed, and diethyl ether was added to the residue to produce a solid. The resulting solid was filtered and washed with diethyl ether to obtain the title compound 40-d (0.16 g, 60% yield in 2 steps) as a beige solid.

[0829] MS m / z:. 336 [M+1] + .

[0830] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 8.67 (s, 2H), 7.55 (s, 1H), 7.16-7.25 (m, 4H), 7.13 (s, 1H), 5.68 (d, 1H), 4.81-4.85 (m, 1H), 3.41 (dd, 2H), 2.89 (dd, 2H)

[0831] (Step 5) Preparation of 2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}-1H-imidazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl}ethan-1-one (2-(4-{2-[(2,3-dihydro-1H-inden-2-yl)amino]pyrimidin-5-yl}- 1H-imidazol-1-yl)-1-{1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5- yl}ethan-1-one) (Compound 40)

[0832] Compound 40-d (50 mg, 0.14 mmol) was used instead of compound 18-d, and the reaction was carried out in the same manner as step 5 of Example 18 to obtain the title compound 40 (17 mg, 28%) as a pink solid.

[0833] MS m / z:. 442[M+1] + .

[0834] 1 H NMR (DMSO-d6, 400MHz), δ (ppm): 8.64 (s, 2H), 7.61 (d, 1H), 7.46-7.42 (m, 2H), 7.22-7.14 (m, 4H), 5.20 (d, 2H), 4.76-4.60 (m, 3H), 3.83-3.82 (m, 2H), 3.26 (dd, 2H), 2.93-2.67 (m, 4H)

[0835]

[0836] The structures of compounds 1 to 40 prepared in Examples 1 to 40 are described in Table 1 below.

[0837]

[0838] [Table 1]

[0839]

[0840]

[0841]

[0842]

[0843] [Experimental Example]

[0844] Human-derived sample experiments

[0845] Human aortic valve tissues were obtained from recipient hearts of patients with calcific aortic valve disease (CAVD) who underwent aortic valve replacement (AVR) and non-CAVD controls. Each sample was used to prepare valvular interstitial cells (VICs). The Institutional Review Board (IRB) of Asan Medical Center, Seoul, approved the study protocol for the collection of human samples (Reference No. 2013-0442), and all patients provided written informed consent.

[0846]

[0847] cell culture

[0848] VICs were prepared and maintained from the aortic valve leaflets and aorta, respectively. VICs were isolated from human aortic valve leaflets by enzymatic separation and were maintained in 10% fetal bovine serum (Thermo Scientific), penicillin (100 U ml -1 , Life Technologies) and streptomycin sulfate (Life Technologies). Cells at passages 2 to 10 were used in experiments to induce calcification of VIC.

[0849]

[0850] osteogenic differentiation

[0851] To induce osteogenic differentiation of patient-derived VICs, 0.25 mM L-ascorbic acid, 10 mM β-glycerophosphate, and 10 nM dexamethasone were added to complete medium (DMEM, Thermo Scientific). The osteogenic medium was replaced every 3 days, and culture was performed for up to 3 weeks.

[0852]

[0853] Alkaline phosphatase (ALP) and alizarin red (AR) staining

[0854] Osteogenic transdifferentiation and calcification were induced by ALP and AR staining. ALP staining was performed using an alkaline phosphatase kit (Sigma) according to the manufacturer's instructions. For AR staining, cells were washed three times with PBS, fixed in 4% formaldehyde for 30 minutes, washed three times with PBS, and exposed to 2% AR dye (Aqueous, Sigma) for 10 minutes.

[0855]

[0856] Calcium analysis

[0857] Calcium concentration in 0.1 M HCl extracts from cultured cells was quantified colorimetrically by the o-cresolphthalein method.

[0858]

[0859] Alkaline phosphatase (ALP) activity assay

[0860] ALP activity was determined. One week after osteogenic stimulation, ALP activity was determined in VSMC or hVIC.

[0861]

[0862] quantitative real-time polymerase chain reaction (qPCR)

[0863] Total RNA extraction and qPCR were performed. Briefly, total RNA was isolated using the RNeasy kit (Qiagen) according to the manufacturer's instructions. cDNA was synthesized using the RevertAid First-strand cDNA Synthesis Kit (Thermo Scientific, EU), and PCR was performed in a BIO-RAD T100TM thermocycler. qPCR analysis was performed in optical 96-well plates using the Power SYBR Green 1-Step Kit and the ABI 7000 Real-Time PCR System (Applied Biosystems) according to the manufacturer's instructions. Gene expression was compared with the expression of GAPDH, which served as an internal control.

[0864]

[0865] animal testing

[0866] All animal procedures were performed in accordance with protocols approved by the Ulsan National University Institutional Committee for the Care and Use of Laboratory Animals (2018-12-074). The present inventors obtained endothelial nitric oxide synthase-deficient (eNOS) mice on a C57BL / 6 background from the Jackson Laboratory (Bar Harbor, ME, USA). - / - ) mice were purchased and used as an animal model of CAVD. These mice were maintained on a 12-hour light / dark cycle and randomly assigned to compound 18 treatment group (n = 6) and untreated group (n = 6) at 8 weeks of age. Compound 18 was orally administered once daily at 10, 30, and 90 mg / kg / day for 24 weeks. The untreated group was orally administered vehicle (saline).

[0867]

[0868] In vivo fluorescence imaging

[0869] Osteogenic activity was detected by tail vein injection of a bisphosphonate-binding imaging agent (Osteosense680, VisEn Medical Inc., Bedford, MA, USA) or saline (control) 24 hours before imaging in experimental animals. Osteosense680 binds to calcified sites, particularly hydroxyapatite, and acts as an imaging agent to detect osteoblast function and in vivo calcification. After euthanasia, calcification deposits were imaged using an OptixMX3 (Advanced Research Technologies Inc., Saint-Laurent, QC, Canada).

[0870]

[0871] cardiac ultrasound examination

[0872] Echocardiography was performed in anesthetized CAVD rabbits using intramuscular administration of ketamine (30 mg / kg) and xylazine (6 mg / kg). Transvalvular gradient and aortic valve area were determined. Briefly, aortic valve area was determined using the standard continuity equation. The diameter of the left ventricular outflow tract was determined in the parasternal long-axis view. Stroke volume was measured proximal to the aortic valve using pulsed Doppler in the apical five-chamber view. Additionally, continuous-wave Doppler acquisition was used to measure the integral of transvalvular flow used in the continuity equation for calculating aortic valve area, and peak and mean transaortic pressure gradients were recorded.

[0873]

[0874] Statistical analysis

[0875] All quantitative experiments were performed at least three times. Results are expressed as mean ± SEM or mean ± SD. In vitro data were normally distributed with similar differences between groups. Because the number of animals in each group was small and some distributions were not normal in the animal studies, continuous variables were compared between groups using nonparametric analysis of variance. Statistical significance was assessed using a two-tailed Student's t test or nonparametric Kruskal-Wallis, Mann-Whitney, or Wilcoxon signed-rank test. Tukey's correction was performed to adjust for multiple versus single comparisons. A p value of <0.05 was considered statistically significant.

[0876]

[0877] Experimental Example 1: Effect of reducing osteogenic differentiation of aortic valve interstitial cells in vitro

[0878] We isolated VICs from human aortic valve tissue, induced their osteogenic differentiation using osteogenic media, and investigated the effect of compound 18 on osteogenic differentiation of these cells. Treatment with compound 18 significantly attenuated ALP staining levels after 1 week, consistent with a decrease in ALP activity (Fig. 1). In contrast, GLPG1690 did not attenuate ALP staining levels, but ALP activity was slightly reduced at a concentration of 10 μM GLPG1690 (Fig. 1).

[0879] Furthermore, treatment of these cells with compound 18 significantly reduced matrix mineralization (approximately 50%), as evidenced by alizarin red staining, at concentrations as low as 0.1 μM compared to the untreated group, and further reduced alizarin red staining at doses of 1 and 10 μM compound 18 (Fig. 2). Notably, the reduction in alizarin red staining was associated with a parallel decrease in calcium concentration in VICs (Fig. 2). Taken together, these results indicated that compound 18 could significantly attenuate calcium deposition in hVICs.

[0880]

[0881] Experimental Example 2: Effect of reducing the expression of genes related to osteogenesis and fibrosis.

[0882] Given that increased transcription factors are associated with osteogenic differentiation of hVICs when grown in osteogenic media, we next investigated whether the attenuation of osteogenic conversion of VICs by compound 18 was accompanied by a decrease in the expression of osteogenic-related genes. To this end, we assessed the transcript levels of these genes using qPCR and osteogenic differentiation assays. Treatment of VICs with compound 18 at a dose of 1 μM decreased the mRNA expression of alkaline phosphatase (ALP), an enzyme critically required for biomineralization, and this decrease persisted at a concentration of 10 μM compound 18 (Figure 3). Transcript expression levels of other bone markers, including runt-related transcription factor 2 (RUNX2), the Sp7 transcription factor (also known as osterix), and bone γ-carboxyglutamic acid-containing protein (BGLAP, also known as osteocalcin), were also dramatically reduced by compound 18 (Figure 3(a)). Unlike compound 18, GLPG1690 did not affect the mRNA expression of ALP and BGLAP in these cells, but reduced the mRNA levels of RUNX2 and SP7 at a concentration of 10 μM GLPG1690 (Fig. 3(b)).

[0883] Previous clinical observations have suggested that fibrosis is a common complication of aortic valve stenosis. To assess the effect of compound 18 on the transcript expression of fibrosis-related genes, we examined the mRNA expression of these genes in VICs following exposure to compound 18 and found lower mRNA levels for Fibronectin 1, Integrin β, alpha smooth muscle actin (α-SMA), and collagen type I alpha 1 chain (Col1a1) as determined by qPCR (Fig. 4(a)), confirming the inhibitory induction effect of compound 18 on fibrosis.

[0884] In addition, the present inventors treated 5 ng / ml of TGF-b in DHLF cells from patients with pulmonary fibrosis with various concentrations of compound 18, BMS986278 (LPA1 antagonist), or HZN825 (LPAR1 antagonist) for 24 hours, harvested the cells, extracted RNA, and converted to cDNA to measure the expression of fibronectin 1, alpha-smooth muscle actin (α-SMA), and collagen type I alpha 1 chain (Col1a1). As a result, it was confirmed that compound 18 suppressed the expression of fibrosis-related genes in a concentration-dependent manner and had a superior fibrosis inhibitory effect compared to inhibitors of the same series, BMS986278 (LPA1 antagonist) or HZN825 (LPAR1 antagonist) (Fig. 4(b)).

[0885]

[0886] Experimental Example 3: Effect of inhibiting calcific lesion formation in eNOS- / - mice

[0887] The present inventors have investigated the molecular imaging of in vitro calcification after injection of a fluorescent bisphosphonate-binding molecule preparation (Osteosense680) in an animal model of CAVD, eNOS. - / -The efficacy of compound 18 to prevent calcific lesion formation in mice was evaluated. Fluorescence reflectance imaging showed that administration of compound 18 at a dose of 10 mg / kg / day significantly reduced eNOS compared to vehicle-treated control animals. - / - Compound 18 potentially reduced in vivo calcification in mice, with further reductions observed at doses of 30 and 90 mg / kg / day (Fig. 5). These results indicate that compound 18 inhibits calcification in an animal model of CAVD in mice.

[0888]

[0889] Experimental Example 4: Effect of attenuating calcific aortic stenosis in a rabbit model of CAVD.

[0890] We used a rabbit model of CAVD, in which a combined diet of high cholesterol and vitamin D (VitD) supplementation is well known to induce aortic valve stenosis and calcium deposition in rabbits. A key finding of this analysis was that integrated transvalvular flow measured using continuous wave Doppler showed a significant increase in peak aortic velocity and mean aortic pressure gradient in the HFD + VitD group at week 9, whereas the compound 18 treatment group showed no significant changes in these Doppler parameters in the first set of experiments (Figure 6). The HFD + VitD rabbit group showed a significant increase in aortic valve area when measured with a standard continuous diet, whereas compound 18 treatment reversed the increase to a level similar to that seen in the control rabbits in the first set of experiments (Figure 6). These results demonstrated the beneficial effect of compound 18 through attenuation of HFD + VitD-induced aortic valve stenosis in vivo.

[0891] In a second set of experiments, similar results were obtained after 12 weeks of treatment with compound 18 (Fig. 7).

[0892]

[0893] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing or treating calcification-related diseases, comprising a compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] [Chemical Formula 1] In the above chemical formula 1, X and Y are each independently CR' or N, except when both are N; R' is hydrogen, C1-C10 alkyl or C6-C12 aryl; R is indanyl, C6-C12arC1-C10alkyl or C6-C12arC3-C10cycloalkenyl; The aralkyl and arcycloalkenyl of the above R may be further substituted with one or more substituents selected from halogen, C1-C10 alkoxy and halo C1-C10 alkoxy; A is C2-C12 heteroaryl, carboxyl C1-C10 alkyl, C6-C12 aryl, C6-C12 arC1-C10 alkyl, C2-C12 heterocycloalkyl or NR1R2; The heteroaryl, aryl, aralkyl and heterocycloalkyl of the above A may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino; R1 and R2 are each independently hydrogen or carboxylC1-C10alkyl, or R1 and R2 may be connected to each other to form a saturated or unsaturated monocyclic, polycyclic or spiro ring; The formed ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur, and may contain a C=C, C=N or N=N double bond, and CH2 in the formed ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from hydroxy, carboxyl, carbamoyl, aminosulfonyl, C1-C10 alkylsulfonylamino, C6-C12 arylsulfonylamino, aminosulfonylamino (-NHSO2NH2) and amino; L is a single bond, -(CR3R4) a C(=O)-, -C(=O)-(CR3R4) a -, -C(=O)-(CR5R6) b -NH-(CR7R8) c -, -NH-(CR7R8) c -C(=O)-(CR5R6) b -, -C(=NR9)-(CR3R4)a-, C2-C12 heteroarylene, -(CR3R4) a -C2-C12 heterocycloalkylene-, -C2-C12 heterocycloalkenylene-(CR3R4) a -, -C2-C12 heterocycloalkylene-(CR3R4) a -(NH) d -, or and; R3 to R8 are each independently hydrogen or C1-C10 alkyl; R9 is hydroxy, C1-C10 alkoxy or mono- or di-C1-C10 alkylamino; Y is NR 10 , O or S; R 10 are each independently hydrogen or C1-C10 alkyl; a is an integer from 1 to 5; b and c are each independently an integer from 0 to 5; d is an integer of 0 or 1; Q is carbonyl, C2-C12 heterocycloalkylene or C2-C12 heteroarylene; The heteroarylene of the above Q is C1-C10 alkyl, haloC1-C10 alkyl, hydroxyC1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, NR 11 R 12 , -O(CH2) e R 13 , -(CH2) f R 14 and -C(=O)R 15 may be further substituted with one or more substituents selected from , wherein said alkyl, cycloalkyl, aryl and heteroaryl are NR 11 R 12 or may be further substituted with carboxyl; R 11 and R 12 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C10 cycloalkyl; e and f are each independently an integer from 0 to 5; R 13 is hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heterocycloalkyl or carboxyl, and the aryl and heterocycloalkyl of R13 may be further substituted with one or more substituents selected from C1-C10 alkyl, haloC1-C10 alkyl and carboxyl; R 14 and R 15 are each independently C2-C12 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and may be further substituted with one or more substituents selected from halogen, C1-C10 alkyl, haloC1-C10 alkyl and C6-C12 aryl; The above heteroaryl, heteroarylene, heterocycloalkylene, heterocycloalkenylene and heterocycloalkyl contain one or more heteroatoms selected from nitrogen, oxygen and sulfur.

2. In paragraph 1, A pharmaceutical composition for the prevention or treatment of calcification-related diseases, characterized in that the above A is selected from the following structures: (Above R c is C1-C7 alkyl or amino; p is an integer from 0 to 5; q and r are each independently an integer from 1 to 5; m is an integer of 0, 1, or 2.) 3. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, wherein L is a single bond or is selected from the following structures: (Above R d and R e are each independently hydrogen or C1-C7 alkyl; R f is hydroxy, C1-C7alkoxy or mono- or di-C1-C7alkylamino; Y is NR 10 , O or S; R 10 are each independently hydrogen or C1-C7 alkyl; s is an integer from 0 to 3; t is an integer from 1 to 3.) 4. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, wherein the above Q is selected from the following structures: (Above R g is hydrogen or C1-C7 alkyl; R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxyC1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, -O(CH2) e R 13 , -(CH2) f R 14 or -C(=O)R 15 and the above R h Alkyl, cycloalkyl, aryl and heteroaryl of NR 11 R 12 or may be further substituted with carboxyl; R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, C2-C12 heteroaryl or C3-C7 cycloalkyl; R 13 is C6-C12 aryl, C3-C9 heterocycloalkyl or carboxyl, and R 13 Aryl and heterocycloalkyl of may be further substituted with one or more substituents selected from C1-C7 alkyl, haloC1-C7 alkyl and carboxyl; R 14 and R 15 are each independently C3-C9 heterocycloalkyl, and the R 14 and R 15 The heterocycloalkyl of is a saturated or unsaturated single ring, fused ring or spiro ring, or CH2 in the ring may be substituted with C(=O), and the R 14 and R 15 The heterocycloalkyl may be further substituted with one or more substituents selected from halogen, C1-C7 alkyl, haloC1-C7 alkyl and C6-C12 aryl; R i is hydrogen, C1-C7 alkyl or haloC1-C7 alkyl; R j is hydrogen, C1-C7 alkyl, haloC1-C7 alkyl, C3-C7 cycloalkyl or C6-C12 aryl; e is an integer from 0 to 3; f is an integer from 0 to 3.) 5. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, characterized in that the compound represented by the above chemical formula 1 is selected from the following structures:

6. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, characterized in that the compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof acts as an autotaxin inhibitor.

7. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, characterized in that the compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof reduces the expression of an osteogenesis-related gene selected from the group consisting of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), Sp7 transcription factor (SP7), and bone γ-carboxyglutamic acid-containing protein (BGLAP).

8. In paragraph 1, A pharmaceutical composition for preventing or treating calcification-related diseases, characterized in that the compound represented by the following chemical formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof reduces the expression of a fibrosis-related gene selected from the group consisting of fibronectin 1, integrin β, alpha smooth muscle actin (α-SMA), and collagen type I alpha 1 chain (Col1a1).

9. In paragraph 1, A pharmaceutical composition for preventing or treating a calcification-related disease, characterized in that the calcification-related disease comprises at least one selected from the group consisting of vascular calcification, vascular stiffening, vascular inflammation, vascular fibrosis, vascular stenosis, valvular calcification, valvular inflammation, valvular fibrosis, aortic valve stenosis, and calcinosis cutis.

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