Aminopyridine derivative, preparation method therefor, and pharmaceutical composition for preventing or treating diseases containing same as active ingredient

Abstract

The present invention relates to a compound of chemical formula 1 and a pharmaceutical composition comprising same. The compound according to the present invention, a stereoisomer thereof, an isotopic variant thereof, and a pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of dyslipidemia or diseases associated with an increase in PCSK9 activity.

Description

Aminopyridine derivatives, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of diseases containing the same as an active ingredient

[0001] The present invention relates to a novel compound having inhibitory ability against PCSK9 (Proprotein convertase subtilisin / kexin type 9), a method for preparing the same, and the use of the same for diseases related to PCSK9 activity.

[0002]

[0003] Dyslipidemia, particularly an increase in low-density lipoprotein (LDL) cholesterol (LDL-C) levels in the blood, is known to be a major cause of hyperlipidemia, which in turn is a risk factor for atherosclerotic cardiovascular diseases including severe arteriosclerosis, stroke, heart failure, myocardial infarction, and coronary heart disease (Prior Art 1 and 2).

[0004] Currently, treatments for reducing blood cholesterol levels are broadly divided into two types. The first is to directly reduce the amount of cholesterol produced in the liver, and the second is a method that ultimately reduces the concentration of blood LDL-C by increasing the expression of the low-density lipoprotein receptor (LDLR) to cause blood LDL cholesterol to enter cells, thereby allowing LDL-C to be metabolized in the liver and excreted.

[0005] Statins, which are representative drugs that inhibit cholesterol production in the liver, are prescribed as first-line drugs for patients with dyslipidemia, but they are known to often cause side effects such as muscle pain due to muscle toxicity and the development of diabetes due to increased blood sugar, and have limitations such as cholesterol levels not being controlled in some patients despite administration of the maximum dose (Prior Art 3).

[0006] Recently, as it has been known that PCSK9 expression is increased by statin drugs, monoclonal antibodies and siRNA therapeutics have been developed as a method to enhance the LDL-C reduction effect by increasing the expression of LDLR in hepatocytes through the combination or monotherapy of PCSK9 inhibitors (Prior Art 4 and 5).

[0007] Currently, PCSK9-blocking antibodies such as alirocumab and evolocumab, and the siRNA therapeutic inclisiran are prescribed as injectables, but for dyslipidemia and related cardiovascular diseases requiring long-term management, there is still a need for the development of potent small molecule inhibitors with high ease of administration.

[0008] Accordingly, the inventors completed the present invention by investigating a novel compound capable of acting as a PCSK9 inhibitor and demonstrating that it can prevent hypercholesterolemia and atherosclerotic cardiovascular disease associated with PCSK9 activity.

[0009]

[0010] [Prior Art Literature]

[0011] 1. Assmann, G.; Schulte, H. The Prospective Cardiovascular Munster (PROCAM) Study: Prevalence of Hyperlipidemia in Persons with Hypertension and / or Diabetes Mellitus and the Relationship to Coronary Heart Disease. Am. Heart J. 1988, 116 (6), 1713-1724.

[0012] 2. Drechsler, M.; Megens, R. T. A.; van Zandvoort, M.; Weber, C.; Soehnlein, O. Hyperlipidemia-Triggered Neutrophilia Promotes Early Atherosclerosis. Circulation 2010, 122 (18), 1837- 1845.

[0013] 3. Massimiliano R.; Nicola F.; Maciej B.; Cesare R S.; Alberto C. Side effects of statins: from pathophysiology and epidemiology to diagnostic and therapeutic implications, Cardiovascular Research, 2022, 118 (17), 3288-3304.

[0014] 4. Kwon, H.J.; · Lagace, T.A.; · McNutt, M.C. Molecular basis for LDL receptor recognition by PCSK9 Proc. Natl. Acad. Sci. U S A. 2008, 105, 1820-1825.

[0015] 5. Bao, X.; Liang, Y.; Chang, H. Targeting proprotein convertase subtilisin / kexin type 9 (PCSK9): from bench to bedside. Sig Transduct Target Ther. 2024, 9(13).

[0016]

[0017] The object of the present invention is to provide a novel compound of Formula 1 below, which can be usefully used to improve, treat, or prevent PCSK9 activity-related diseases, such as dyslipidemia, by controlling the activity of PCSK9, and a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof (hereinafter also simply referred to as “compound, etc.”).

[0018] In addition, the object of the present invention is to provide a pharmaceutical composition for the prevention, improvement, or treatment of PCSK9-related diseases comprising a compound of Formula 1, an isotope variant thereof, or a pharmaceutically acceptable salt as an active ingredient.

[0019] Another objective of the present invention is to provide a use of the said compound for the manufacture of a drug for the prevention, improvement, or treatment of PCSK9-related diseases.

[0020] Another objective of the present invention is to provide a method for preventing, improving, or treating PCSK9-related diseases by administering the said compound.

[0021] Another objective of the present invention is to provide a method for preparing a compound represented by the above chemical formula 1.

[0022] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0023]

[0024] The present disclosure is summarized as follows:

[0025] 1. A compound represented by the structure of Chemical Formula 1 below, its optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0026] [Chemical Formula 1]

[0027]

[0028] In the above formula

[0029] A is a tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring, wherein the tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S;

[0030] L is a 6-membered heteroarylene comprising 1 to 3 heteroatoms that are bonded or substituted or unsubstituted and selected from the group consisting of N, O, and S;

[0031] B is a 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring, wherein the 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S;

[0032] R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Each is independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos;

[0033] R2 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Aryl, 4- to 12-membered heteroaryl, halo, -NH-C(=O)-R 3, Each is independently selected from the group consisting of -C(=O)-NH-(CH2)p-OR3 or -C(=O)OR3, wherein p is an integer from 0 to 3, and R3 is hydrogen or C 1-6 It is alkyl;

[0034] n is an integer from 0 to 4;

[0035] m is an integer from 0 to 4.

[0036]

[0037] 2. In the above Paragraph 1,

[0038] The above A is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring comprises 1 to 3 selected from the group consisting of N, O, and S.

[0039] Compound, pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant.

[0040]

[0041] 3. In any one of the preceding paragraphs above,

[0042] A is a compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant selected from the group consisting of the following:

[0043] , , , ,

[0044] , , , ,

[0045] , , , ,

[0046]

[0047] 4. In any one of the preceding paragraphs above,

[0048] R1 is hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-4 Thioalkyl, C 3-4 Cycloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-4 Alkyl, quaternary to hexavalent heterocycloalkyl, C 6-10A compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant thereof, each independently selected from the group consisting of aryls, tetroaryls, and halos, wherein the tetrocycloalkyl or tetroaryls comprises 1 to 3 selected from the group consisting of N, O, and S.

[0049]

[0050] 5. In any one of the preceding paragraphs above,

[0051] L is bonded, or deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 A compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant thereof, which is a pyridineylene substituted or unsubstituted with a hydroxyalkyl group.

[0052]

[0053] 6. In any one of the preceding paragraphs above,

[0054] B is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring comprises 1 to 3 selected from the group consisting of N, O, and S.

[0055] Compound, pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant.

[0056]

[0057] 7. In any one of the preceding paragraphs above,

[0058] R2 is any one of the following: a compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant:

[0059]

[0060]

[0061]

[0062]

[0063] 8. In any one of the preceding paragraphs above,

[0064] B-(R2) m A compound, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotope variant selected from the group consisting of:

[0065]

[0066]

[0067] In the above formula,

[0068] R2 and m are as defined in Paragraph 1, and

[0069] V is selected from the group consisting of C, O, S, and N, and

[0070] If there are multiple R2s, each R2 may be the same or different from the others.

[0071]

[0072] 9. In any one of the preceding paragraphs above,

[0073] B-(R2) m A compound, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotope variant selected from the group consisting of:

[0074]

[0075] , , , ,

[0076] , , ,

[0077] , , , , , ,

[0078] , , , .

[0079] ,

[0080] , .

[0081]

[0082] 10. Compounds represented by the structure of Chemical Formula 1-1 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0083] [Chemical Formula 1-1]

[0084]

[0085] In the above formula,

[0086] The definitions of A, R1 and n are identical to the definitions in Paragraph 1;

[0087] V is C, O, S, or N, and represents a single or double bond, wherein if V is O and S, R4 does not exist;

[0088] The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, or

[0089] R4 and R5 or R5 and R6 together comprise a 4- to 7-membered heterocycle or C comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S. 4-8 Forms a cycloalkyl group, wherein the above 4 to 7-membered heterocycle or C 4-8 The cycloalkyl group of can be unsubstituted or substituted by 1 to 3 R7 groups, and

[0090] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and

[0091] R9 is hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl.

[0092]

[0093] 11. In any one of the preceding paragraphs above,

[0094] is any one selected from the group consisting of: a compound, its optical isomer, solvate, isotopic variant, or pharmaceutically acceptable salt:

[0095]

[0096]

[0097] In the above formula,

[0098] The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos,

[0099] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and

[0100] p is an integer from 0 to 4.

[0101]

[0102] 12. Compounds represented by the structures of Chemical Formula 1-2 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0103] [Chemical Formula 1-2]

[0104]

[0105]

[0106] In the above formula,

[0107] The definitions of A, R1 and n are identical to the definitions in Paragraph 1;

[0108] D is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of;

[0109] V is C, O, S, N and;

[0110] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0111] R9 is hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl; and

[0112] p is an integer from 0 to 4.

[0113]

[0114] 13. Compounds represented by the structures of Chemical Formulas 1-3 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0115] [Chemical Formula 1-3]

[0116]

[0117] In the above formula,

[0118] The definitions of A, R1 and n are identical to the definitions in Paragraph 1;

[0119] E is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of;

[0120] V is C, O, S, or N;

[0121] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0122] R9 is hydrogen, deuterium (hereinafter also referred to as “D”), halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl; and

[0123] p is an integer from 0 to 4.

[0124]

[0125] 14. Compounds represented by the structures of Chemical Formulas 1-4 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0126] [Chemical Formula 1-4]

[0127]

[0128] In the above formula,

[0129] The definitions of A, R1 and n are identical to the definitions in Paragraph 1;

[0130] V is C, O, S, or N;

[0131] R8 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0132] q is an integer from 0 to 4.

[0133]

[0134] 15. In any one of the preceding paragraphs above,

[0135] The compound represented by the above chemical formula 1 is a compound selected from the group consisting of the compounds of 1 to 120 below, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant:

[0136] Compound 1: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0137] Compound 2: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0138] Compound 3: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0139] Compound 4: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0140] Compound 5: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0141] Compound 6: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one;

[0142] Compound 7: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one;

[0143] Compound 8: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0144] Compound 9: 1-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one;

[0145] Compound 10: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0146] Compound 11: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0147] Compound 12: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0148] Compound 13: 2-[6-[[(1S,3S)-3-(5,7-dihydrothieno[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0149] Compound 14: 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0150] Compound 15: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid;

[0151] Compound 16: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-N-(2-hydroxyethyl)-1,3-benzothiazole-6-carboxamide;

[0152] Compound 17: 2-[6-[[(1S,3S)-3-[[5-(2-oxozetidine-1-yl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0153] Compound 18: 1-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one;

[0154] Compound 19: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0155] Compound 20: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one;

[0156] Compound 21: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-diethyl-1,2,4-triazole-3-one;

[0157] Compound 22: 2-[6-[,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0158] Compound 23: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[0159] Compound 24: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methyl-1-propan-2-ylpyrazole-3-one;

[0160] Compound 25: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0161] Compound 26: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0162] Compound 27: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclophen

[0163] [Tyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3one

[0164] Compound 28: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0165] Compound 29: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0166] Compound 30: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0167] Compound 31: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0168] Compound 32: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0169] Compound 33: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0170] Compound 34: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0171] Compound 35: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0172] Compound 36: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0173] Compound 37: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0174] Compound 38: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0175] Compound 39: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0176] Compound 40: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0177] Compound 41: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0178] Compound 42: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0179] Compound 43: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0180] Compound 44: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0181] Compound 45: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0182] Compound 46: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0183] Compound 47: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-ethyl-1,2,4-triazole-3-one;

[0184] Compound 48: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0185] Compound 49: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0186] Compound 50: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-one;

[0187] Compound 51: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0188] Compound 52: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0189] Compound 53: 2-[6-[[(1S,3S)-3-[[5-(2,2,2-trifluoroethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0190] Compound 54: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0191] Compound 55: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0192] Compound 56: 2-[6-[[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0193] Compound 57: 2-[6-[[(1S,3S)-3-[(5-chlorpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0194] Compound 58: 4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0195] Compound 59: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0196] Compound 60: 4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0197] Compound 61: 2-[6-[[(1S,3S)-3-[(5-methylpyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0198] Compound 62: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0199] Compound 63: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0200] Compound 64: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0201] Compound 65: 5-methoxy-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0202] Compound 66: 2-[6-[[(1S,3S)-3-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0203] Compound 67: tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate;

[0204] Compound 68: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0205] Compound 69: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0206] Compound 70: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0207] Compound 71: 4-ethyl-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0208] Compound 72: 2-[6-[[(1S,3S)-3-([1,3]oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0209] Compound 73: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one;

[0210] Compound 74: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one;

[0211] Compound 75: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0212] Compound 76: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0213] Compound 77: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0214] Compound 78: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0215] Compound 79: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0216] Compound 80: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0217] Compound 81: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-propan-2-ylpyrazole-3-one;

[0218] Compound 82: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-ethylpyrazole-3-one;

[0219] Compound 83: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0220] Compound 84: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0221] Compound 85: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0222] Compound 86: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0223] Compound 87: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0224] Compound 88: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0225] Compound 89: 5-ethoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0226] Compound 90: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0227] Compound 91: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0228] Compound 92: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0229] Compound 93: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0230] Compound 94: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0231] Compound 95: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0232] Compound 96: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0233] Compound 97: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0234] Compound 98: 2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0235] Compound 99: 5-ethoxy-2-[5-fluoro-6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0236] Compound 100: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0237] Compound 101: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0238] Compound 102: 1-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0239] Compound 103: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0240] Compound 104: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0241] Compound 105: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0242] Compound 106: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0243] Compound 107: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0244] Compound 108: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0245] Compound 109: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0246] Compound 110: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0247] Compound 111: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0248] Compound 112: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0249] Compound 113: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0250] Compound 114: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one;

[0251] Compound 115: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0252] Compound 116: 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[0253] Compound 117: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0254] Compound 118: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0255] Compound 119: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; and

[0256] Compound 120: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one.

[0257]

[0258] 16. A pharmaceutical composition for the prevention or treatment of PCSK9-related diseases, comprising as an active ingredient the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof.

[0259]

[0260] 17. In any one of the preceding paragraphs above,

[0261] A pharmaceutical composition in which PCSK9-related diseases are lipid or lipoprotein metabolic disorders.

[0262]

[0263] 18. In any one of the preceding paragraphs above,

[0264] Lipid or lipoprotein metabolic disorders include atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmias, low HDL levels, high LDL levels, sudden death, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, and chronic Chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, arterial occlusive disease,A pharmaceutical composition comprising one or more selected from the group consisting of cerebral arteriosclerosis, cerebrovascular disorder, myocardial ischemia, nonalcoholic steatohepatitis (NASH), and diabetic autonomic neuropathy.

[0265]

[0266] 19. In any one of the preceding paragraphs above,

[0267] The above pharmaceutical composition is a pharmaceutical composition that inhibits the activity of PCSK9.

[0268]

[0269] 20. A composition for inhibiting the activity of PCSK9, comprising as an active ingredient the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof.

[0270]

[0271] 21. A composition for promoting lipid or lipoprotein metabolism, comprising as an active ingredient the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof.

[0272]

[0273] 22. A pharmaceutical composition for co-administration for the prevention or treatment of PCSK9-related diseases, comprising as an active ingredient the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof.

[0274]

[0275] 23. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps:

[0276] A first step of preparing an example represented by Chemical Formula 3 by SnAr reaction of 2-fluoro-5-iodopyridine with an example represented by Chemical Formula 2 above;

[0277] A second step of preparing an example represented by Chemical Formula 5 by subjecting an example represented by Chemical Formula 3 and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction;

[0278] A third step of preparing an example represented by Chemical Formula 6 by reacting an example represented by Chemical Formula 5 with trifluoroacetic acid for deprotection;

[0279] Step 4, preparing an example represented by Chemical Formula 1-1' by SnAr reaction of an example represented by Chemical Formula 6 and an example represented by Chemical Formula 7,

[0280] [Chemical Formula 1-1']

[0281]

[0282] [Chemical Formula 2]

[0283]

[0284] [Chemical Formula 3]

[0285]

[0286] [Chemical Formula 4]

[0287]

[0288] [Chemical Formula 5]

[0289]

[0290] [Chemical Formula 6]

[0291]

[0292] [Chemical Formula 7]

[0293]

[0294] In the above reaction equation,

[0295] A, V, R1, R4, R5, R6, R9, and n are as defined in Clause 9.

[0296]

[0297] 24. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps:

[0298] Step 1' of preparing an example represented by Chemical Formula 8 by subjecting 2-fluoro-5-iodopyridine and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction;

[0299] Step 2' of preparing an example represented by Chemical Formula 1-1' by subjecting an example represented by Chemical Formula 8 and an example represented by Chemical Formula 9 to a Suzuki reaction or a Ullmann reaction,

[0300] [Chemical Formula 1-1']

[0301]

[0302] [Chemical Formula 4]

[0303]

[0304] [Chemical Formula 8]

[0305]

[0306] [Chemical Formula 9]

[0307]

[0308] In the above reaction equation,

[0309] A, V, R1, R4, R5, R6, R9 and n are as defined in Clause 10.

[0310]

[0311] 25. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps:

[0312] A first “step” of preparing an example represented by Chemical Formula 10 by reacting the example represented by Chemical Formula 3 with trifluoroacetic acid for deprotection;

[0313] A second “step” of preparing an example represented by Chemical Formula 11 by SnAr reaction between an example represented by Chemical Formula 10 below and an example represented by Chemical Formula 7 above;

[0314] A third step of preparing an example represented by Chemical Formula 1-1 by subjecting an example represented by Chemical Formula 11 to a Suzuki reaction or a Ullmann reaction with an example represented by Chemical Formula 4,

[0315] [Chemical Formula 1-1']

[0316]

[0317] [Chemical Formula 3]

[0318]

[0319] [Chemical Formula 6]

[0320]

[0321] [Chemical Formula 7]

[0322]

[0323] [Chemical Formula 10]

[0324]

[0325] [Chemical Formula 11]

[0326]

[0327] In the above reaction equation,

[0328] A, V, R1, R4, R5, R6, R9 and n are as defined in Clause 10.

[0329]

[0330] 26. A method for the prevention or treatment of a PCSK9-related disease, comprising the step of administering to an individual the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof.

[0331]

[0332] 27. Use of any of the compounds of the preceding paragraph, or any of the pharmaceutically acceptable salts, hydrates, solvates, tautomers, isotopic variants, enantiomers, or diastereomers thereof for the prevention or treatment of PCSK9-related diseases.

[0333]

[0334] 28. Use of the compound of any one of the preceding paragraphs, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer for the preparation of a pharmaceutical composition for the prevention or treatment of PCSK9-related diseases.

[0335]

[0336] The compound or pharmaceutically acceptable salt thereof provided in one aspect of the present invention may be usefully used for the prevention, improvement, or treatment of dyslipidemia and related cardiovascular diseases associated with PCSK9 activity.

[0337]

[0338] The present invention will be described in detail below.

[0339] Unless otherwise stated below, the “compound represented by Chemical Formula 1” of the present invention includes all of its pharmaceutically acceptable salts, hydrates, solvates, tautomers, isotopic variants, enantiomers, and / or diastereomers, all of which should be interpreted as being included within the scope of the present invention. For convenience of explanation, the term may be simply abbreviated in this specification as “compound of Chemical Formula 1,” etc.

[0340] Furthermore, unless otherwise defined, all technical terms used herein have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Additionally, although the present invention has been described in relation to specific methods and samples, analogs or equivalents thereof must be within the scope of the present invention. Furthermore, numerical values ​​described herein are deemed to include the meaning of “about” unless explicitly stated otherwise. All publications and other references mentioned herein are incorporated herein in their entirety by reference.

[0341]

[0342] Definition of Terms

[0343] As used in this specification, the term “pharmaceuticalally acceptable salt” refers to a salt form of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. In the case of the present invention, it may collectively refer to any salt that possesses equivalent biological efficacy and properties of the compound of Formula 1 and is desirable in terms of pharmaceutical, biological, or other properties.

[0344] The above "pharmaceutically acceptable salt" includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc., organic carboxylic acids like 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., and sulfonic acids like 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., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, 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 conventional methods.

[0345] As used herein, the term “hydrate” means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0346] As used herein, the term “solvate” means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0347] As used herein, the term “tautomer” refers to a type of structural isomer having the same chemical or molecular formula but different arrangements of constituent atoms, meaning that the structure changes by continuously switching back and forth between the two isomers, such as in a keto-eno structure.

[0348] As used herein, the term “isotope variant” refers to a compound containing isotopes in a non-natural proportion in one or more atoms constituting the compound. Examples of isotopes that may be incorporated into the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as 2H (deuterium), 3H, 11C, 13C, 14C, 18F, 123I, or 125I, etc., which may be naturally occurring or non-naturally occurring isotopes.

[0349] As used herein, the terms “enantiomer” or “diastereomer” refer to isomers that have the same chemical formula or molecular formula but differ in the spatial arrangement of atoms within the molecule. The term “enantiomer” refers to an isomer that does not overlap with its mirror image, much like the relationship between a right hand and a left hand. Additionally, “diastereomer” refers to a stereoisomer that is not in a mirror image relationship, such as the trans form and the cis form; in this invention, this is limited to pharmaceutically acceptable diastereomers. All of these isomers and mixtures thereof are also included within the scope of this invention.

[0350] As used herein, the term “alkyl” refers to an aliphatic hydrocarbon group. The alkyl may include branched, straight-chain, or cyclic forms, and also includes structural isomers. For example, in the case of a C3 alkyl, it may mean propyl or isopropyl. In the present invention, the alkyl is C 1-20 , C 1-15 , C 1-12 , C 1-10 , C 1-8 , C 1-6 , C1-5 , C 1-4 , C 1-3 , or C 1-2 It may be an alkyl, but is not limited thereto. For example, in the present invention, the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, etc.

[0351] As used herein, the term “heteroalkyl” refers to an alkyl group comprising at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.) in addition to carbon and hydrogen. Like alkyls, heteroalkyls may also include branched, straight-chain, or cyclic forms and include structural isomers.

[0352] As used herein, the term "alkenyl" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon double bond, and "alkynyl" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon triple bond. In the present invention, the alkene or alkyne is C 2-20 , C 2-15 , C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-5 , C 2-4 , or C 2-3 It may be an alkene or alkyne, but is not limited thereto.

[0353] As used herein, the term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein "alkyl" is defined as above. "Halo" indicates -F, -Cl, -Br, or -I, and the term is used interchangeably with the term "halogen."

[0354] As used in this specification, the term “oxo” refers to a functional group in which an oxygen atom exists in the form of a double bond with another atom, i.e., =O.

[0355] As used in this specification, the term “hydroxy” refers to -OH, and “hydroxyalkyl” means an alkyl bonded to -OH, wherein the alkyl is defined as above.

[0356] As used in this specification, the term “cyano” refers to -CN, and “cyanoalkyl” refers to an alkyl group substituted with -CN, wherein the alkyl is defined as above.

[0357] As used herein, the term “alkoxy” refers to a substituent having a structure in which an alkyl group is connected through an oxygen atom. In the present invention, the alkoxy is C 1-20 , C 1-15 , C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , or C 1-2 It may be an alkoxy, but is not limited thereto. In addition, the alkoxy may be a halogenated alkoxy substituted with one or more, two or more, three or more, or more halogen atoms, but is not limited thereto.

[0358] As used in this specification, the term “amino” refers to -NH2; and “nitro” refers to -NO2. “Aminoalkyl” means an alkyl group substituted with one or more amino groups, wherein the alkyl is defined as above.

[0359] The term “deuterium (hereinafter also referred to as Deuterium, Deuteriun, or D)” as used in this specification refers to an isotope of hydrogen and is characterized by having one proton and one neutron in its atomic nucleus. “Deuterium-substituted alkyl” means an alkyl group substituted with one or more, two or more, three or more, or more deuteriums, wherein alkyl is defined as above.

[0360] As used herein, the terms “ring,” “cycle,” and “cyclic” refer to cyclic hydrocarbon groups and encompass concepts including monocyclic, bicyclic, tricyclic, or polycyclic structures. Additionally, as used herein, the term “ring” encompasses both fully saturated and partially unsaturated rings, and includes both aromatic and non-aromatic rings. “Heteroring” or “heterocycle” refers to a ring containing one or more heteroatoms. The term “membered,” used in conjunction with “ring,” refers to the number of skeletal atoms constituting the ring.

[0361] As used herein, the term “cycloalkyl” refers to a cyclic saturated hydrocarbon group. In the present invention, the cycloalkyl is C 3-20 , C 3-15 , C 3-12 , C 3-10 , C 3-8 , C 3-6 , C 3-5 , C 3-4 ...or may be a C3 cycloalkyl, and more specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The cycloalkyl comprises monocyclic, bicyclic, tricyclic, or more than one polycyclic alkyl. In addition, the cycloalkyl according to the present invention may also be a fused or bridged cycloalkyl.

[0362] As used herein, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or more than one polycyclic alkyl comprising one or more heteroatoms selected from N, O, and S, for example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom. Additionally, the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl. The above heterocycloalkyl may be 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4 heterocycloalkyl, but is not limited thereto. Examples of non-aromatic rings include azetidinyl, oxetanil, tetrahydrothienyl, tetrahydrofuranil, pyrrolinyl, pyrrolidinyl, imidazolininyl, imidazolidinyl, oxazolininyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolininyl, pyrazolidinyl, thiazolininyl, thiazolidinyl, tetrahydrofuranil, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyranil, dihydropyranil, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranil, Includes, but is not limited to, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomophorinyl, azephanyl, diazephanyl, N-oxide, azadamantanil, diazamantanil, etc. Attachment of heterocycloalkyl substituents may occur through carbon atoms or heteroatoms.

[0363] As used herein, the term “aryl” refers to an aromatic hydrocarbon group having a shared pi electron system and at least one ring. In the present invention, aryl is C 5-12 , C 5-11 , C 5-10 , C 5-9 , C 5-8 , C 5-7 , C 5-6 , C 6-12 , C 6-11 , C 6-10 , C 6-9 , C 6-8 , or C 6-7 It may be an aryl, but is not limited thereto. The aryl includes monocyclic, bicyclic, tricyclic, or more polycyclic aryls. That is, the aryl may include a bicyclic radical comprising an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups include benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, etc., but are not limited thereto.

[0364] As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, tricyclic, or more aromatic group comprising one or more heteroatoms selected from N, O, and S, for example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom. The above heteroaryls may be 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 5 to 15, 5 to 14, 5 to 15, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7, or 5 to 6 heteroaryls, but are not limited thereto. Examples of heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, etc. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisooxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furinyl, propyridinyl, octahydropyranopyridine, benzodioxolyl, and similar groups thereof.

[0365] In this specification, “condensation ring” or “fusion ring” refers to a polycyclic ring in which two or more rings are connected by sharing one or more atoms or bonds. The condensation ring may be a 4 to 15-membered, 4 to 14-membered, 4 to 14-membered, 4 to 12-membered, 4 to 11-membered, 4 to 10-membered, 4 to 9-membered, 4 to 8-membered, 4 to 7-membered, 4 to 6-membered, 4 to 5-membered, 5 to 15-membered, 5 to 14-membered, 5 to 15-membered, 5 to 12-membered, 5 to 11-membered, 5 to 10-membered, 5 to 9-membered, 5 to 8-membered, 5 to 7-membered, or 5 to 6-membered condensation ring, but is not limited thereto. In addition, the condensed ring may be a hydrocarbon group composed of carbon and hydrogen, or it may be a heterocondensed ring comprising one or more heteroatoms selected from N, O, and S, for example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom. In the present invention, the condensed ring may be formed by the condensation of two or more of the rings described above. That is, in the present invention, the condensed ring may be formed by the condensation of two or more, three or more, or four or more rings selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In addition, the condensed ring may be a ring that is entirely saturated or an unsaturated ring that is partially saturated.

[0366] In the present invention, the term "substitution" refers to the introduction of a hydrogen atom in place of another atomic group when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to the introduced atomic group. That is, in the present invention, the substitution of any functional group means that one or more hydrogen atoms of the said functional group are replaced by another atomic group. In the present invention, each functional group may independently have one or more hydrogen atoms substituted by another atomic group. "Independently substituted" means that when the number of substitutable hydrogens is two or more, each hydrogen may be substituted with the same or different substituents. In the present invention, "substitution" includes single substitution, double substitution, triple substitution, quadruple substitution, or more substitutions.

[0367] Terms other than those described above may be interpreted in the sense commonly understood by those skilled in the art to which the present invention pertains.

[0368]

[0369] Compound of Chemical Formula 1

[0370] In the following, “loop” or “cycle” refers to a monocyclic loop unless otherwise noted.

[0371] The present invention provides a compound represented by the following chemical formula 1, and a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof:

[0372] [Chemical Formula 1]

[0373]

[0374] In the above formula

[0375] A is a tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring, wherein the tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S;

[0376] L is a six-membered heteroarylene comprising 1 to 3 heteroatoms selected from the group consisting of bonded, substituted, or unsubstituted N, O, and S;

[0377] B is a 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring, wherein the 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S;

[0378] R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Each is independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos;

[0379] R2 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Aryl, 4- to 12-membered heteroaryl, halo, -NH-C(=O)-R 3, Each is independently selected from the group consisting of -C(=O)-NH-(CH2)p-OR3 or -C(=O)OR3, wherein p is an integer from 0 to 3, and R3 is hydrogen or C 1-6 It is alkyl;

[0380] n is an integer from 0 to 4;

[0381] m is an integer from 0 to 4.

[0382]

[0383] Each structure and substituent is explained in more detail.

[0384] In one embodiment of the present invention, A is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring may comprise 1 to 3 selected from the group consisting of N, O, and S.

[0385]

[0386] In one embodiment of the present invention, A may be any one selected from the group consisting of:

[0387]

[0388]

[0389] .

[0390] In the above formula, “ " refers to the part that combines with other groups, and the same applies to other chemical structures below.

[0391]

[0392] In one embodiment of the present invention, R1 is hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-4 Thioalkyl, C 3-4 Cycloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-4 Alkyl, quaternary to hexavalent heterocycloalkyl, C 6-10 Each is independently selected from the group consisting of aryls, tetroaryls, and halos, wherein the tetrocycloalkyl or tetroaryls may comprise 1 to 3 selected from the group consisting of N, O, and S. In this case, the tetrocycloalkyl or tetroaryls may be substituted with or unsubstituted with oxos.

[0393]

[0394] In one embodiment of the present invention, R1 is hydrogen, F, Cl, -CH3, -C2H5, , -CH=CH2, -C≡CH, -CF2H, -CF3, -OCH3, -OCF2H, -OCH2CF3, or It could be.

[0395]

[0396] In one embodiment of the present invention, L may be a bonded, substituted, or unsubstituted pyridylene. In a more specific embodiment, the substituted pyridylene is a deuterium, halo, cyano, or C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 Pyridylene substituted with hydroxyalkyl, more specifically, may be substituted with deuterium, F, Cl, cyano, vinyl, -CH3 or -OCH3.

[0397]

[0398] In one embodiment of the present invention, B is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring may comprise 1 to 3 selected from the group consisting of N, O, and S.

[0399]

[0400] In one embodiment of the present invention, R2 may be any one selected from the group consisting of:

[0401]

[0402] .

[0403]

[0404] In one embodiment of the present invention, B-(R2) mcan be any one selected from the group consisting of .

[0405]

[0406]

[0407] In the above formula,

[0408] R2 and m are as defined in the above Chemical Formula 1, and

[0409] V is C, O, S, or N, and

[0410] If there are multiple R2s, each R2 may be the same or different from the others.

[0411]

[0412] In one embodiment of the present invention, B-(R2) m can be any one selected from the group consisting of .

[0413] , , , , , , , , , ,

[0414] , , , , , , , , , , .

[0415] , , , .

[0416]

[0417] The present invention also provides a compound represented by the structure of Formula 1-1 below, its optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0418] [Chemical Formula 1-1]

[0419]

[0420] In the above formula,

[0421] The definitions of A, R1, and n are the same as the definitions of Chemical Formula 1;

[0422] V is C, O, S, or N, and represents a single or double bond, wherein if V is O and S, R4 does not exist;

[0423] The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, or

[0424] R4 and R5 or R5 and R6 together comprise a 4- to 7-membered heterocycle or C comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S. 4-8 Forms a cycloalkyl group, wherein the above 4 to 7-membered heterocycle or C 4-8The cycloalkyl group of can be unsubstituted or substituted by 1 to 3 R7 groups, and

[0425] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and

[0426] R9 is hydrogen, deuterium (hereinafter also referred to as “D”), halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It can be a hydroxyalkyl.

[0427]

[0428] In one embodiment of the present invention, may be a compound, its optical isomer, solvate, isotopic variant, or pharmaceutically acceptable salt selected from the group consisting of the following:

[0429]

[0430]

[0431] In the above formula,

[0432] The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos,

[0433] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and

[0434] p is an integer from 0 to 4.

[0435]

[0436] The present invention also provides a compound represented by the structure of Formula 1-2 below, its optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0437] [Chemical Formula 1-2]

[0438]

[0439]

[0440] In the above formula,

[0441] The definitions of A, R1, and n are the same as the definitions of Chemical Formula 1;

[0442] D is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of;

[0443] V is C, O, S, or N;

[0444] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0445] R9 is hydrogen, deuterium (hereinafter also referred to as “D”), halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It may be a hydroxyalkyl;

[0446] p is an integer from 0 to 4.

[0447]

[0448] The present invention also provides a compound represented by the structure of Formula 1-3 below, its optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0449]

[0450] [Chemical Formula 1-3]

[0451]

[0452] In the above formula,

[0453] The definitions of A, R1, and n are the same as the definitions of Chemical Formula 1;

[0454] E is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of;

[0455] V is C, O, S, or N;

[0456] R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0457] R9 is hydrogen, deuterium (hereinafter also referred to as “D”), halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4haloalkyl, or C 1-4 It may be a hydroxyalkyl;

[0458] p is an integer from 0 to 4.

[0459]

[0460] The present invention also provides a compound represented by the structure of the following formulas 1-4, its optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts:

[0461] [Chemical Formula 1-4]

[0462]

[0463] In the above formula,

[0464] The definitions of A, R1, and n are the same as the definitions of Chemical Formula 1;

[0465] V is C, O, S, or N;

[0466] R8 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos;

[0467] q is an integer from 0 to 4.

[0468]

[0469] As a specific embodiment, the compounds of Formula 1 according to the present invention may be one or more selected from the group consisting of compounds 1 to 120 below, but are not limited thereto.

[0470] Compound 1: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0471] Compound 2: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0472] Compound 3: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0473] Compound 4: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0474] Compound 5: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0475] Compound 6: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one;

[0476] Compound 7: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one;

[0477] Compound 8: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one;

[0478] Compound 9: 1-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one;

[0479] Compound 10: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0480] Compound 11: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0481] Compound 12: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0482] Compound 13: 2-[6-[[(1S,3S)-3-(5,7-dihydrothieno[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0483] Compound 14: 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0484] Compound 15: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid;

[0485] Compound 16: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-N-(2-hydroxyethyl)-1,3-benzothiazole-6-carboxamide;

[0486] Compound 17: 2-[6-[[(1S,3S)-3-[[5-(2-oxozetidine-1-yl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0487] Compound 18: 1-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one;

[0488] Compound 19: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one;

[0489] Compound 20: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one;

[0490] Compound 21: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-diethyl-1,2,4-triazole-3-one;

[0491] Compound 22: 2-[6-[,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0492] Compound 23: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0493] Compound 24: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methyl-1-propan-2-ylpyrazole-3-one;

[0494] Compound 25: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0495] Compound 26: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0496] Compound 27: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclophen

[0497] [Tyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3one

[0498] Compound 28: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0499] Compound 29: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0500] Compound 30: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0501] Compound 31: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0502] Compound 32: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0503] Compound 33: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0504] Compound 34: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0505] Compound 35: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0506] Compound 36: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0507] Compound 37: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0508] Compound 38: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0509] Compound 39: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0510] Compound 40: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0511] Compound 41: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one;

[0512] Compound 42: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0513] Compound 43: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0514] Compound 44: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0515] Compound 45: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one;

[0516] Compound 46: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0517] Compound 47: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-ethyl-1,2,4-triazole-3-one;

[0518] Compound 48: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0519] Compound 49: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0520] Compound 50: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-one;

[0521] Compound 51: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0522] Compound 52: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0523] Compound 53: 2-[6-[[(1S,3S)-3-[[5-(2,2,2-trifluoroethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one;

[0524] Compound 54: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0525] Compound 55: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0526] Compound 56: 2-[6-[[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0527] Compound 57: 2-[6-[[(1S,3S)-3-[(5-chlorpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0528] Compound 58: 4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0529] Compound 59: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0530] Compound 60: 4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0531] Compound 61: 2-[6-[[(1S,3S)-3-[(5-methylpyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0532] Compound 62: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0533] Compound 63: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one;

[0534] Compound 64: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0535] Compound 65: 5-methoxy-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0536] Compound 66: 2-[6-[[(1S,3S)-3-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0537] Compound 67: tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate;

[0538] Compound 68: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0539] Compound 69: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one;

[0540] Compound 70: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one;

[0541] Compound 71: 4-ethyl-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0542] Compound 72: 2-[6-[[(1S,3S)-3-([1,3]oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0543] Compound 73: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one;

[0544] Compound 74: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one;

[0545] Compound 75: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0546] Compound 76: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0547] Compound 77: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0548] Compound 78: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0549] Compound 79: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0550] Compound 80: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0551] Compound 81: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-propan-2-ylpyrazole-3-one;

[0552] Compound 82: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-ethylpyrazole-3-one;

[0553] Compound 83: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0554] Compound 84: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0555] Compound 85: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0556] Compound 86: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0557] Compound 87: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0558] Compound 88: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0559] Compound 89: 5-ethoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one;

[0560] Compound 90: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0561] Compound 91: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0562] Compound 92: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0563] Compound 93: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0564] Compound 94: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0565] Compound 95: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0566] Compound 96: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one;

[0567] Compound 97: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0568] Compound 98: 2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0569] Compound 99: 5-ethoxy-2-[5-fluoro-6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one;

[0570] Compound 100: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one;

[0571] Compound 101: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one;

[0572] Compound 102: 1-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one;

[0573] Compound 103: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0574] Compound 104: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0575] Compound 105: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0576] Compound 106: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0577] Compound 107: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0578] Compound 108: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0579] Compound 109: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0580] Compound 110: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0581] Compound 111: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one;

[0582] Compound 112: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0583] Compound 113: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0584] Compound 114: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one;

[0585] Compound 115: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one;

[0586] Compound 116: 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[0587] Compound 117: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0588] Compound 118: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one;

[0589] Compound 119: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; and

[0590] Compound 120: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one.

[0591]

[0592] In a specific embodiment according to the present invention, the binding strength of PCSK9 to a compound represented by Formula 2 according to the present invention was evaluated, and excellent binding strength was confirmed. In addition, excellent activity was also shown in cell activity evaluating the improvement of LDL-C uptake capacity in liver cells.

[0593] A compound or a pharmaceutically acceptable salt thereof provided in one aspect of the present invention possesses advantageous features compared to a compound of prior patents with respect to a conventional PCSK9 inhibitor. For example, the compound of the present application has activity similar to that of a compound of prior patents and possesses more advantageous pharmacokinetic properties (e.g., as measured by Cmax and AUC), and can be usefully employed for the prevention, improvement, and / or treatment of diseases related to PCSK9 activity, such as diseases that may be induced by the overactivity or overexpression of PCSK9. The PCSK9-related disease may preferably be a disease related to lipid or lipoprotein metabolic disorders (e.g., dyslipidemia or related diseases).

[0594]

[0595] For the prevention, improvement, and / or treatment of diseases

[0596] The present invention provides a composition for the prevention, improvement, and / or treatment of PCSK9-related diseases, comprising as an active ingredient a compound represented by the above-described formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof. The composition may be a pharmaceutical composition and / or a food composition.

[0597] In addition, the present invention provides a method for the prevention, improvement, and / or treatment of a PCSK9-related disease, comprising the step of administering a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof to a subject in need thereof. The method may further comprise the step of identifying a subject in need of the prevention, improvement, and / or treatment of a PCSK9-related disease prior to the step of administration.

[0598] In addition, the present invention provides the use of a compound represented by Formula 1, and its pharmaceutically acceptable salts, hydrates, solvates, tautomers, isotopic variants, enantiomers, or diastereomers for the prevention, improvement, and / or treatment of PCSK9-related diseases.

[0599] In addition, the present invention provides the use of a compound represented by Formula 1, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer for the manufacture of a drug for the prevention, improvement, and / or treatment of PCSK9-related diseases.

[0600] In this specification, "prevention" refers to any act of suppressing or delaying the onset of a disease (disease) by administering a composition according to one example, "treatment" refers to any act of improving or beneficially changing the symptoms of an individual suspected of or suffering from a disease by administering a composition according to one example, and "improvement" may refer to any act of at least reducing parameters related to the state in which the disease is treated, such as the degree of symptoms, by administering a composition according to one example. The disease may be a PCSK9-related disease or a lipid or lipoprotein metabolic disorder.

[0601] In the present invention, “PCSK9-related disease” includes all diseases that may be caused by PCSK9 expression, activity, or function abnormalities. The disease may be a disease caused by PCSK9 overactivity and / or overexpression, or a disease that can be prevented, improved, and / or treated by inhibiting PCSK9 activity and / or function. More specifically, the PCSK9-related disease may be a lipid and / or lipoprotein metabolic disorder.

[0602] In the present invention, “lipid and / or lipoprotein metabolic disorder” refers to a disease in which abnormal metabolism of lipids and / or lipoproteins may be a direct or indirect cause. In particular, the said disease may be a disease that can be induced by a decrease in lipid and / or lipoprotein metabolism. The lipid and / or lipoprotein metabolic disorder includes dyslipidemia, including primary hypercholesterolemia induced by abnormal PCSK9 activity, as well as dyslipidemia-related cardiovascular disease. More specifically, the lipid and / or lipoprotein metabolic disorders mentioned above include atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmias, low HDL levels, high LDL levels, sudden death, stable angina, coronary heart disease, acute myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia (including heterozygous and homozygous familial hypercholesterolemia), stroke, hyperlipidemia, and hyperlipoproteinemia. Chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral arterial disease,It may be one or more selected from the group consisting of diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, arterial occlusive disease, cerebral arteriosclerosis, cerebrovascular disorder, myocardial ischemia, non-alcoholic fatty liver disease (NLLD), nonalcoholic steatohepatitis (NASH), and diabetic autonomic neuropathy, but is not limited thereto.

[0603] The pharmaceutical composition according to the present invention may further include a suitable carrier, excipient, and diluent commonly used in the manufacture of pharmaceutical compositions. The excipient may be one or more selected from the group consisting of, for example, diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

[0604] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric granules, liquids, eye drops, oxylic agents, emulsions, suspensions, ethanol tablets, troches, fragrances, limonene adzes, tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, warning agents, lotions, pastes, sprays, inhalants, patches, sterile injectable solutions, or aerosols, according to conventional methods, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, or cataplasms.

[0605] Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0606] When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0607] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined according to factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0608] The dosage of the pharmaceutical composition of the present invention is determined by the type of active ingredient drug, along with various relevant factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and the severity of the disease. Specifically, the effective dosage of the composition according to the present invention may vary depending on the patient's age, gender, and weight, and generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0609] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all the above-mentioned factors, and this can be easily determined by a person skilled in the art to which the present invention belongs.

[0610] In the present invention, “administration” means providing a specific compound of the present invention to an individual by any appropriate method. The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration may be anticipated, for example, by oral administration, subcutaneous injection, intraperitoneal administration, intramuscular injection, intrathecal (intradural) injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spray through the mouth or nose, skin administration, transdermal administration, etc.

[0611] The subjects of administration of the composition of the present invention may be one or more mammals selected from primates such as humans and monkeys, rodents such as mice and rats, livestock such as dogs, cats, pigs, cattle, horses, sheep, goats, etc., and poultry such as chickens, ducks, geese, pheasants, quails, and turkeys, or cells, tissues, or cultures derived from these.

[0612] The composition according to the present invention can inhibit the expression, activity, and / or function of PCSK9. Accordingly, the composition of the present invention can exhibit preventive, remedial, and / or therapeutic activity for lipid or lipoprotein metabolic disorders by inhibiting the expression, activity, and / or function of PCSK9.

[0613]

[0614] Uses of PCSK9 activity inhibitor

[0615] The present invention provides a composition for inhibiting the activity of PCSK9, comprising as an active ingredient a compound of Formula 1 described above, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof. The composition may be a pharmaceutical composition and / or a food composition.

[0616] In addition, the present invention provides a method for inhibiting the activity of PCSK9, comprising the step of administering a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof to a subject requiring such a compound. The method may further comprise the step of identifying a subject requiring inhibition of PCSK9 activity prior to the step of administering the compound.

[0617] In addition, the present invention provides the use of a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof for inhibiting the activity of PCSK9.

[0618] In addition, the present invention provides the use of a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof for inhibiting the activity of PCSK9.

[0619] The description of the composition and other terms is the same as that described above, so it is omitted.

[0620]

[0621] Uses for promoting lipid or lipoprotein metabolism

[0622] The present invention provides a composition for promoting lipid or lipoprotein metabolism, comprising as an active ingredient a compound of Formula 1 described above, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof. The composition may be a pharmaceutical composition and / or a food composition.

[0623] In addition, the present invention provides a method for promoting lipid or lipoprotein metabolism, comprising the step of administering a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof to a subject requiring such a compound. The method may further comprise the step of identifying a subject requiring lipid or lipoprotein metabolism promotion prior to the step of administering the compound.

[0624] In addition, the present invention provides the use of a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof for promoting lipid or lipoprotein metabolism.

[0625] In addition, the present invention provides the use of a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof for promoting lipid or lipoprotein metabolism.

[0626] The description of the composition and other terms is the same as that described above, so it is omitted.

[0627]

[0628] Manufacturing method

[0629] In another aspect, the present invention relates to a method for preparing the novel compound. An example of Formula 1 may be synthesized by the synthesis route described herein. In certain embodiments, methods widely known in the chemical field, either in light of the disclosures contained herein or otherwise, may be used. Starting materials are generally available from commercial sources or are readily prepared using methods widely known to those skilled in the art.

[0630] Embodiments of the present invention may be prepared from commercially available starting materials using the general methods illustrated herein. For exemplary purposes, Reaction Schemes 1 through 3 shown below provide routes for synthesizing examples of compounds of Formula 1, more specifically compounds of Formula 1-1. For more detailed disclosure of individual reaction steps, refer to the Examples section below. Those skilled in the art will recognize that other synthesis routes are available and may be used. Although specific starting materials and reagents are shown in the reaction schemes and described below, other starting materials and reagents may be substituted to provide various derivatives and / or reaction conditions. Furthermore, many examples prepared by the methods described below may be further modified in light of the present invention using conventional chemicals known to those skilled in the art.

[0631]

[0632] An example of a compound of Formula 1-1', which is a stereoisomer of Formula 1-1, as a compound of Formula 1 above, can be prepared by a manufacturing method comprising the following steps:

[0633] A first step of preparing an example represented by Chemical Formula 3 by SnAr reaction of 2-fluoro-5-iodopyridine with an example represented by Chemical Formula 2 above;

[0634] A second step of preparing an example represented by Chemical Formula 5 by subjecting an example represented by Chemical Formula 3 and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction;

[0635] A third step of preparing an example represented by Chemical Formula 6 by reacting an example represented by Chemical Formula 5 with trifluoroacetic acid for deprotection;

[0636] Step 4: Preparing an example represented by Chemical Formula 1-1' by SnAr reaction of an example represented by Chemical Formula 6 and an example represented by Chemical Formula 7.

[0637]

[0638] As a specific example, in the first step above, an example represented by Chemical Formula 2 and 2-fluoro-5-iodopyridine are dissolved in dimethyl sulfoxide, potassium carbonate is added dropwise, and Chemical Formula 3 is prepared by stirring at 120°C for 16 hours.

[0639] As a specific example, in the second step above, the example represented by Chemical Formulas 3 and 4 is dissolved in dimethyl sulfoxide, then N,N'-dimethylcyclohexane-1,2-diamine, copper(I) iodide, and potassium carbonate are added dropwise and stirred at 120°C for 16 hours to prepare Chemical Formula 17.

[0640] As a specific example, in the third step above, an example represented by Chemical Formula 5 is dissolved in dichloromethane, then trifluoroacetic acid is slowly added dropwise and stirred at room temperature for 16 hours to prepare Chemical Formula 6.

[0641] As a specific example, in the fourth step above, the example represented by Chemical Formula 6 and Chemical Formula 7 is dissolved in dimethyl sulfoxide, N,N-diisopropylethylamine is added dropwise, and the mixture is stirred at 100°C for 16 hours to prepare Chemical Formula 1-1'.

[0642]

[0643] Specifically, the above manufacturing method can be represented by the following reaction scheme 1.

[0644] [Reaction Equation 1]

[0645]

[0646] In the above reaction equation,

[0647] A, V, R1, R4, R5, R6, R7, R9, and n are as defined in the above chemical formula 1-1.

[0648]

[0649] An example of the above chemical formula 1-1' can be prepared by a manufacturing method comprising the following steps:

[0650] Step 1' of preparing an example represented by Chemical Formula 8 by subjecting 2-fluoro-5-iodopyridine and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction;

[0651] Step 2' of preparing an example represented by Chemical Formula 1-1' by subjecting an example represented by Chemical Formula 8 and an example represented by Chemical Formula 9 to a Suzuki reaction or a Ullmann reaction.

[0652]

[0653] As a specific example, in the first step above, 2-fluoro-5-iodopyridine and an example represented by Formula 4 are dissolved in 1,4-dioxane, then N,N'-dimethylcyclohexane-1,2-diamine, copper(I) iodide, and potassium carbonate are added dropwise and stirred at 120°C for 16 hours to prepare Formula 8.

[0654] As a specific example, in the above 2' step, the example represented by Chemical Formula 8 and the example represented by Chemical Formula 9 are dissolved in dimethyl sulfoxide, then N,N-diisopropylethylamine is added dropwise and stirred at 130°C for 16 hours to prepare Chemical Formula 1-1'.

[0655]

[0656] Specifically, the above manufacturing method can be represented by the following reaction scheme 2.

[0657] [Reaction Equation 2]

[0658]

[0659] In the above reaction equation,

[0660] A, V, R1, R4, R5, R 6, R9 and n are as defined in the above chemical formula 1-1.

[0661]

[0662] An example of the above chemical formula 1-1' can be prepared by a manufacturing method comprising the following steps:

[0663] A first “step” of preparing an example represented by Chemical Formula 10 by reacting the example represented by Chemical Formula 3 with trifluoroacetic acid for deprotection;

[0664] A second “step” of preparing an example represented by Chemical Formula 11 by SnAr reaction between an example represented by Chemical Formula 10 below and an example represented by Chemical Formula 7 above;

[0665] Step 3” of preparing an example represented by Chemical Formula 1-1’ by subjecting an example represented by Chemical Formula 11 below to a Suzuki reaction or a Ullmann reaction with an example represented by Chemical Formula 4.

[0666]

[0667] As a specific example, in the following first step, an example represented by Chemical Formula 3 and trifluoroacetic acid are added dropwise and stirred at room temperature for 16 hours to prepare Chemical Formula 10.

[0668] As a specific example, in the following step 2”, an example represented by Chemical Formula 10 and Chemical Formula 7 is dissolved in dimethyl sulfoxide, N,N-diisopropylethylamine is added dropwise, and Chemical Formula 11 is prepared by stirring at 130°C for 16 hours.

[0669] As a specific example, in the following step 3”, an example represented by Chemical Formula 11 and Chemical Formula 4 is dissolved in dimethyl sulfoxide, then N,N'-dimethylcyclohexane-1,2-diamine, copper(I) iodide, and potassium carbonate are added dropwise and stirred at 120°C for 16 hours to prepare Chemical Formula 1-1'.

[0670]

[0671] Specifically, the above manufacturing method can be represented by the following reaction scheme 3.

[0672] [Reaction Equation 3]

[0673]

[0674] In the above reaction equation,

[0675] A, V, R1, R4, R5, R6, R9, and n are as defined in the above chemical formula 1-1.

[0676]

[0677] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the present invention and do not limit the present invention.

[0678]

[0679] When preparing the compounds of the present invention, the reaction order can be appropriately changed. That is, any reaction step may be performed first, any change in substituent may be inserted, and any reagent other than the exemplified reagent may be used as needed.

[0680] Various synthesis methods for starting materials for synthesizing the compounds of the present invention are known, and if the starting materials are commercially available, they may be purchased from suppliers. Reagent suppliers include companies such as Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Combi-Blocks, and Dae-Jung, but are not limited thereto. Furthermore, unless otherwise specified, all commercially available materials were used without additional purification.

[0681] First, the compounds used in the synthesis in the following examples were prepared as in the following manufacturing examples. The following examples may be appropriately modified or changed by those skilled in the art within the scope of the present invention.

[0682]

[0683] The following manufacturing examples are examples of the embodiment represented by Chemical Formula 1-1 of Reaction Scheme 1 above, and can be appropriately modified to correspond to the structure of the embodiment to be manufactured.

[0684]

[0685] Preparation Example 1-1) tert-butyl N-[(1S,3S)-3-[(5-iodo-2-pyridinyl)amino]cyclopentyl]carbamate

[0686]

[0687] Dimethyl sulfoxide (50 mL) was added to 2-fluoro-5-iodopyridine (1.00 g, 4.39 mmol), tert-butyl((1S,3S)-3-aminocyclopentyl)carbamate (907.42 mg, 4.39 mmol), and potassium carbonate (1.22 g, 8.79 mmol), and the mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by MPLC to obtain tert-butyl N-[(1S,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]carbamate (1.30 g, 3.22 mmol, 73%) as a white solid.

[0688] ESI-MS m / z: 389.05 [M+H] + .

[0689]

[0690] Preparation Example 1-2) tert-butyl N-[(1S,3S)-3-[[5-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-2-pyridinyl]amino ]cyclopentyl]carbamate

[0691]

[0692] Dimethyl sulfoxide (4 mL) was added to 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (51.30 mg, 0.37 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (7.05 mg, 0.049 mmol), tert-butyl N-[(1S,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]carbamate (100 mg, 0.25 mmol), copper(I) iodide (9.45 mg, 0.049 mmol), and potassium carbonate (103.34 mg, 0.74 mmol), and stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate:methanol (10:1), and then extracted and washed with distilled water. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was purified by MPLC and washed with dichloromethane and hexane to obtain tert-butyl N-[(1S,3S)-3-[[5-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-2-pyridinyl]amino ]cyclopentyl]carbamate (80.00 mg, 0.19 mmol, 79%) as a white solid.

[0693] ESI-MS m / z: 411.21 [M+H] + .

[0694] 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (d, 1H, J=7.3 Hz), 8.24 (s, 2H), 8.10 (dd, 1H, J=1.6, 3.8 Hz), 8.0-8.0 (m, 1H), 7.92 (td, 1H, J=1.3, 8.0 Hz), 7.7-7.8 (m, 1H), 7.4-7.6 (m, 3H), 7.22 (s, 1H), 7.11 (dd, 1H, J=1.6, 9.5 Hz), 7.04 (s, 1H), 6.85 (s, 1H), 4.3-4.5 (m, 1H), 4.1-4.6 (m, 1H), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.5-1.7 (m, 2H).

[0695]

[0696] Preparation Example 1-3) 2-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0697]

[0698] Dichloromethane (10 mL) was added to tert-butyl N-[(1S,3S)-3-[[5-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-2-pyridinyl]amino]cyclopentyl]carbamate (300.00 mg, 0.081 mmol). Trifluoroacetic acid (1683.5 mg, 14.61 mmol) was slowly added to the reaction mixture and stirred at room temperature for 16 hours. An aqueous sodium hydroxide solution was slowly added to the reaction mixture to adjust the pH to 10.0. The example was extracted by adding dichloromethane, and the obtained organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified using MPLC (column: amine column) to obtain 2-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one (160 mg, 0.51 mmol, 70%).

[0699] ESI-MS m / z: 311.15 [M+H] + .

[0700]

[0701] Preparation Example 1-4) 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0702]

[0703] Dimethyl sulfoxide (5 mL) was added to 2-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one (25.00 mg, 0.081 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (22.26 mg, 0.12 mmol), and N,N-diisopropylethylamine (31.55 mg, 0.24 mmol), and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with distilled water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by PTLC to obtain 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one (80.00 mg, 0.17 mmol, 34%) as a white solid.

[0704] ESI-MS m / z: 454.17 [M+H] + .

[0705] 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (d, 1H, J=2.6 Hz), 8.23 ​​(s, 2H), 7.91 (td, 1H, J=1.1, 7.1 Hz), 7.86 (dd, 1H, J=2.8, 9.0 Hz), 7.47 (d, 1H, J=7.3 Hz), 7.2-7.3 (m, 2H), 6.8-7.2 (m, 2H), 6.6-6.7 (m, 2H), 4.31 (sxt, 2H, J=6.6 Hz), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0706]

[0707]

[0708] The following manufacturing examples are examples of the embodiment represented by Chemical Formula 1-1 of Reaction Scheme 2 above, and can be appropriately modified to correspond to the structure of the embodiment to be manufactured.

[0709]

[0710] Preparation Example 2-1) 2-(6-fluoro-3-pyridinyl)pyridazine-3-one

[0711]

[0712] 1,4-dioxane (4 mL) was added to 2-fluoro-5-iodopyridine (1000 mg, 4.39 mmol), 1H-pyridazine-6-one (646.37 mg, 6.59 mmol), N,N'-dimethylcyclohexane-1,2-diamine (62.51 mg, 0.44 mmol), copper(I) iodide (167.4 mg, 0.88 mmol), and potassium carbonate (1831.40 mg, 13.18 mmol), and stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. This residue was purified by MPLC to obtain 2-(6-fluoro-3-pyridinyl)pyridazine-3-one (613 mg, 3.21 mmol, 73%) as a yellow solid (or oil).

[0713] ESI-MS m / z: 192.05 [M+H] + .

[0714]

[0715] Preparation Example 2-2) 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0716]

[0717] Dimethyl sulfoxide (2 mL) was added to trans-(1S,3S)-3-N-pyrrolo[2,1-f][1,2,4]triazine-2-ylcyclopentane-1,3-diamine trifluoroacetic acid (100.00 mg, 0.30 mmol), 2-(6-fluoro-3-pyridinyl)pyridazine-3-one (69.24 mg, 0.36 mmol), and N,N-diisopropylethylamine (118.22 mg, 0.91 mmol), and stirred at 130°C for 6 hours. After cooling the reaction mixture to room temperature, the mixture was purified by prep-HPLC to obtain 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one (12.00 mg, 0.031 mmol, 10%) as a yellow solid.

[0718] ESI-MS m / z: 389.18 [M+H]+.

[0719] 1H NMR (DMSO-d6, 400 MHz) δ 8.77 (s, 1H), 8.11 (d, 1H, J=2.6 Hz), 8.02 (dd, 1H, J=1.6, 3.9 Hz), 7.60 (ddd, 1H, J=0.8, 1.4, 2.3 Hz), 7.52 (dd, 1H, J=2.7,8.9 Hz), 7.46 (dd, 1H, J=3.9, 9.5 Hz), 7.03 (dd, 1H, J=1.6, 9.5 Hz), 6.94 (br d, 1H, J=7.0 Hz), 6.91 (br d, 1H, J=7.0 Hz), 6.68 (dd, 1H, J=1.5, 4.5 Hz), 6.59 (dd, 1H, J=2.4, 4.5 Hz), 6.54 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[0720]

[0721]

[0722] The following manufacturing examples are examples of the embodiment represented by Chemical Formula 1-1 of Reaction Scheme 3 above, and can be appropriately modified to correspond to the structure of the embodiment to be manufactured.

[0723]

[0724] Preparation Example 3-1) (1S,3S)-N1-(5-iodopyridine-2-yl)cyclopentane-1,3-diamine

[0725]

[0726] Dichloromethane (20 mL) was added to tert-butyl N-[(1S,3S)-3-[(5-iodo-2-pyridinyl)amino]cyclopentyl]carbamate (2.00 g, 4.95 mmol) to dissolve the mixture, and then trifluoroacetic acid (7.67 mL, 99.19 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain (1S,3S)-N1-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (1.42 g, 4.68 mmol, 94%), which was used in the next step without further purification.

[0727] ESI-MS m / z: 304.02[M+H]+.

[0728]

[0729] Preparation Example 3-2) Trans-(1S,3S)-3-N-(5-cyclopropylpyrimidine-2-yl)-1-N-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine

[0730]

[0731] (1S,3S)-N1-(5-iodopyridine-2-yl)cyclopentane-1,3-diamine (765.00 mg, 2.52 mmol), 2-chloro-5-cyclopropylpyrimidine (429.16 mg, 2.77 mmol), and N,N-diisopropylethylamine (1.36 mL, 7.57 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at room temperature for 16 hours. Distilled water (30 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by MPLC to produce trans-(1S,3S)-3-N-(5-cyclopropylpyrimidine-2-yl)-1-N-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine (600.00 mg, 1.42 mmol, 56%).

[0732] ESI-MS m / z: 422.08[M+H]+.

[0733]

[0734] Preparation Example 3-3) 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[0735]

[0736] Trans-(1S,3S)-3-N-(5-cyclopropylpyrimidine-2-yl)-1-N-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine (100.00 mg, 0.23 mmol), 4-methyl-1H-1,2,4-triazole-5-one (35.28 mg, 0.35 mmol), potassium carbonate (98.91 mg, 0.71 mmol), copper(I) iodide (9.04 mg, 0.04 mmol), and trans-N,N'-dimethylcyclohexane-1,2-diamine (6.75 mg, 0.04 mmol) were dissolved in dimethyl sulfoxide (2 mL) and stirred at 120°C for 16 hours. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to prepare 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one (25.00 mg, 0.06 mmol, 26%).

[0737] ESI-MS m / z: 393.21[M+H]+.

[0738] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.0-8.1 (m, 3H), 7.68 (dd, 1H, J=2.6, 9.0 Hz), 6.99 (d, 1H, J=7.3 Hz), 6.73 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.29 (dt, 2H, J=7.0, 14.4 Hz), 3.24 (s, 3H), 2.0-2.2 (m, 2H), 1.7-1.9 (m, 3H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.5-0.7 (m, 2H).

[0739] The following examples were synthesized with reference to the above manufacturing example.

[0740]

[0741] Example 1: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0742]

[0743] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one [Example 1] (34%) was prepared by a method similar to that of Preparation Examples 1-4.

[0744] ESI-MS m / z: 454.17 [M+H] + .

[0745] 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (d, 1H, J=2.6 Hz), 8.23 ​​(s, 2H), 7.91 (td, 1H, J=1.1, 7.1 Hz), 7.86 (dd, 1H, J=2.8, 9.0 Hz), 7.47 (d, 1H, J=7.3 Hz), 7.2-7.3 (m, 2H), 6.8-7.2 (m, 2H), 6.6-6.7 (m, 2H), 4.31 (sxt, 2H, J=6.6 Hz), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0746]

[0747] Example 2: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0748]

[0749] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one [Example 2] (60%) was prepared by a method similar to that of Preparation Examples 1-4.

[0750] ESI-MS m / z: 434.23[M+H] + .

[0751] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.4 Hz), 8.06 (s, 2H), 7.69 (dd, 1H, J=2.6, 9.0 Hz), 6.99 (d, 1H, J=7.4 Hz), 6.68 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=8.6 Hz), 4.2-4.4 (m, 2H), 3.53 (t, 2H, J=6.1 Hz), 2.6-2.7 (m, 2H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 4H), 1.8-1.8 (m, 2H), 1.7-1.7 (m, 1H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0752]

[0753] Example 3: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[0754]

[0755] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 3] (68%) was prepared by a method similar to that of Preparation Examples 1-4.

[0756] ESI-MS m / z: 462.17[M+H] + .

[0757] 1H NMR (DMSO-d6, 400 MHz) δ 8.2-8.3 (m, 3H), 7.66 (dd, 1H, J=2.8, 9.0 Hz), 7.46 (d, 1H, J=7.1 Hz), 6.8-7.3 (m, 1H), 6.69 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.28 (qd, 2H, J=6.6, 12.8 Hz), 3.70 (t, 2H, J=7.1 Hz), 2.8-2.8 (m, 2H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0758]

[0759] Example 4: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0760]

[0761] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 4] (32%) was prepared by a method similar to that of Preparation Examples 1-4.

[0762] ESI-MS m / z: 446.18[M+H] + .

[0763] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 4H, J=2.5 Hz), 8.23 ​​(s, 7H), 7.68 (dd, 4H, J=2.8, 9.0 Hz), 7.47 (d, 4H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.75 (d, 4H, J=6.9 Hz), 6.54 (d, 4H, J=8.9 Hz), 4.70 (s, 8H), 4.2-4.4 (m, 8H), 4.01 (t, 8H, J=5.4 Hz), 3.63 (t, 9H, J=5.4 Hz), 2.0-2.2 (m, 9H), 1.8-1.9 (m, 8H), 1.4-1.6 (m, 8H).

[0764]

[0765] Example 5: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0766]

[0767] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one [Example 5] (68%) was prepared by a method similar to that of Preparation Examples 1-4.

[0768] ESI-MS m / z: 460.10[M+H] + .

[0769] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.6 Hz), 8.23 ​​(s, 2H), 7.69 (dd, 1H, J=2.7, 8.9 Hz), 7.47 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.69 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=8.9 Hz), 4.2-4.4 (m, 2H), 3.53 (t, 2H, J=6.1 Hz), 2.6-2.7 (m, 2H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 4H), 1.7-1.8 (m, 2H), 1.4-1.6 (m, 2H).

[0770]

[0771] Example 6: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one

[0772]

[0773] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one [Example 6] (62%) was prepared in a manner similar to that of Preparation Examples 1-4.

[0774] ESI-MS m / z: 407.22[M+H] + .

[0775] 1H NMR (DMSO-d6, 400 MHz) δ 8.1-8.1 (m, 3H), 7.47 (dd, 1H, J=2.7, 8.9 Hz), 6.99 (d, 1H, J=7.4 Hz), 6.76 (d, 1H, J=6.9 Hz), 6.50 (d, 1H, J=9.0 Hz), 5.64 (s, 1H), 4.29 (qd, 2H, J=6.9, 13.9 Hz), 3.84 (s, 3H), 2.1-2.2 (m, 5H), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0776]

[0777] Example 7: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one

[0778] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one [Example 7] (60%) was prepared in a manner similar to that of Preparation Examples 1-4.

[0779] ESI-MS m / z: 433.18[M+H] + .

[0780] 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 2H), 8.07 (d, 1H, J=2.6 Hz), 7.4-7.5 (m, 2H), 7.22 (t, 1H, J=1.0 Hz), 6.77 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=8.9 Hz), 5.64 (s, 1H), 4.30 (quind, 2H, J=7.0, 14.1 Hz), 3.84 (s, 3H), 2.1-2.2 (m, 5H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0781]

[0782] Example 8: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one

[0783]

[0784] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one [Example 8] (23%) was prepared by a method similar to that of Preparation Examples 1-4.

[0785] ESI-MS m / z: 430.20[M+H] + .

[0786] 1H NMR (DMSO-d6, 400 MHz) δ 8.48 (d, 1H, J=2.3 Hz), 8.07 (s, 2H), 7.92 (td, 1H, J=1.2, 7.0 Hz), 7.8-7.9 (m, 1H), 7.3-7.3 (m, 2H), 7.01 (d, 1H, J=7.3 Hz), 6.86 (d, 1H, J=6.9 Hz), 6.67 (ddd, 1H, J=2.2, 5.2, 7.2 Hz), 6.59 (d, 1H, J=9.1 Hz), 4.31 (td, 2H, J=6.3, 13.1 Hz), 2.12 (ddd, 2H, J=4.6, 7.5, 18.3 Hz), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0787]

[0788] Example 9: Synthesis of 1-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0789]

[0790] 1-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one [Example 9] (60%) was prepared in a manner similar to that of Preparation Examples 1-4.

[0791] ESI-MS m / z: 374.17[M+H] + .

[0792] 1H NMR (DMSO-d6, 400 MHz) δ 8.32 (br s, 2H), 7.85 (d, 1H, J=2.6 Hz), 7.71 (d, 1H, J=7.4 Hz), 7.53 (d, 1H, J=6.6 Hz), 7.41 (ddd, 1H, J=2.1, 6.7, 9.1 Hz), 7.32 (dd, 1H, J=2.6, 8.9 Hz), 6.85 (d, 1H, J=6.9 Hz), 6.46 (d, 1H, J=8.9 Hz), 6.37 (d, 1H, J=9.3 Hz), 6.20 (dt, 1H, J=1.3, 6.7 Hz), 4.2-4.4 (m, 2H), 4.16 (s, 1H), 2.0-2.1 (m, 2H), 1.7-1.9 (m, 2H), 1.4-1.5 (m, 2H).

[0793]

[0794] Example 10: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0795]

[0796] 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 10] (28%) was prepared by a method similar to that of Preparation Examples 1-4.

[0797] ESI-MS m / z: 392.19[M+H] + .

[0798] 1H NMR (DMSO-d6, 400 MHz) δ 8.1-8.2 (m, 2H), 8.02 (dd, 1H, J=1.6, 3.9 Hz), 7.51 (dd, 1H, J=2.6, 8.9 Hz), 7.46 (dd, 1H, J=3.8, 9.4 Hz), 7.0-7.1 (m, 2H), 6.93 (br d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.1-4.4 (m, 4H), 2.5-2.5 (m, 2H), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0799]

[0800] Example 11: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0801]

[0802] 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 11] (14%) was prepared by a method similar to that of Preparation Examples 1-4.

[0803] ESI-MS m / z: 392.19[M+H] + .

[0804] 1H NMR (DMSO-d6, 400 MHz) δ 8.1-8.1 (m, 2H), 8.02 (dd, 1H, J=1.6, 3.8 Hz), 7.51 (dd, 1H, J=2.7, 8.9 Hz), 7.46 (dd, 1H, J=3.8, 9.4 Hz), 7.03 (dd, 1H,

[0805] J=1.6, 9.5 Hz), 6.93 (d, 2H, J=7.6 Hz), 6.53 (d, 1H, J=8.9 Hz), 4.3-4.4 (m, 2H), 2.70 (dt, 4H, J=4.1, 7.5 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 4H), 1.4-1.6 (m, 2H).

[0806]

[0807] Example 12: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0808]

[0809] 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 12] (6%) was prepared by a method similar to that of Preparation Examples 1-4.

[0810] ESI-MS m / z: 408.15[M+H] + .

[0811] 1H NMR (DMSO-d6, 400 MHz) Shift 8.1-8.1 (m, 2H), 8.02 (dd, 1H, J=1.6, 3.9 Hz), 7.4-7.5 (m, 2H), 7.0-7.1 (m, 2H), 6.92 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=8.6 Hz), 4.3-4.4 (m, 2H), 3.27 (s, 2H), 3.1-3.1 (m, 2H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0812]

[0813] Example 13: Synthesis of 2-[6-[[(1S,3S)-3-(5,7-dihydrothieno[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0814]

[0815] 2-[6-[[(1S,3S)-3-(5,7-dihydrothieno[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 13] (14%) was prepared in a manner similar to Preparation Examples 1-4.

[0816] ESI-MS m / z: 408.15[M+H] + .

[0817] 1H NMR (DMSO-d6, 400 MHz) Shift 8.24 (s, 1H), 8.10 (d, 1H, J=2.5 Hz), 8.02 (dd, 1H, J=1.6, 3.9 Hz), 7.4-7.6 (m, 2H), 7.27 (d, 1H, J=7.3 Hz), 7.03 (dd, 1H, J=1.6, 9.4 Hz), 6.93 (d, 1H, J=6.9 Hz), 6.54 (s, 1H), 6.52 (d, 1H, J=4.5 Hz), 4.35 (br dd, 1H, J=7.3, 14.0 Hz), 4.02 (br d, 3H, J=3.3 Hz), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[0818]

[0819] Example 14: Synthesis of 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0820]

[0821] 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 14] (10%) was prepared in the same manner as in Preparation Example 2-2.

[0822] ESI-MS m / z: 389.18 [M+H]+.

[0823] 1H NMR (DMSO-d6, 400 MHz) δ 8.77 (s, 1H), 8.11 (d, 1H, J=2.6 Hz), 8.02 (dd, 1H, J=1.6, 3.9 Hz), 7.60 (ddd, 1H, J=0.8, 1.4, 2.3 Hz), 7.52 (dd, 1H, J=2.7,8.9 Hz), 7.46 (dd, 1H, J=3.9, 9.5 Hz), 7.03 (dd, 1H, J=1.6, 9.5 Hz), 6.94 (br d, 1H, J=7.0 Hz), 6.91 (br d, 1H, J=7.0 Hz), 6.68 (dd, 1H, J=1.5, 4.5 Hz), 6.59 (dd, 1H, J=2.4, 4.5 Hz), 6.54 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[0824]

[0825] Example 15: Synthesis of 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid

[0826]

[0827]

[0828] Ethyl 2-[[(1R)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylate (43.50 mg, 0.10 mmol) synthesized in Preparation Example 3-2 was dissolved in ethanol (0.7 mL) and water (0.5 mL), then lithium hydroxide (22.5 mg, 0.51 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 4 by adding 1 N aqueous hydrochloric acid solution dropwise, and the reaction mixture was filtered to prepare 2-[[(1R,3R)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid (19.6 mg, 0.04 mmol, 48%).

[0829] ESI-MS m / z: 398.12[M+H] + .

[0830] 1H NMR (DMSO-d6, 400 MHz) Shift 8.54 (br d, 1H, J=6.8 Hz), 8.27 (d, 1H, J=1.6 Hz), 8.24 (s, 1H), 7.81 (dd, 1H, J=1.8, 8.4 Hz), 7.40 (d, 2H, J=8.4 Hz), 4.92 (s, 2H), 4.73 (s, 2H), 4.38 (br dd, 2H, J=6.0, 12.3 Hz), 2.1-2.3 (m, 2H), 1.97 (t, 2H, J=6.8 Hz), 1.5-1.6 (m, 2H).

[0831]

[0832] Example 16: Synthesis of 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-N-(2-hydroxyethyl)-1,3-benzothiazole-6-carboxamide

[0833]

[0834]

[0835]

[0836] 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid (30.00 mg, 0.08 mmol) was dissolved in dimethylformamide (1 mL), then N,N-diisopropylethylamine (19.71 mg, 0.15 mmol) and HATU (32.21 mg, 0.08 mmol) were added and stirred at room temperature for 30 minutes. After stirring, 2-aminoethanol (6.05 mg, 0.10 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours and 30 minutes. After concentrating the reaction mixture, 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-N-(2-hydroxyethyl)-1,3-benzothiazole-6-carboxamide [Example 16] (7.50 mg, 0.02 mmol, 23%) was prepared by purifying via prep-LC.

[0837] ESI-MS m / z: 441.16[M+H]+.

[0838] 1H NMR (DMSO-d6, 400 MHz) Shift 8.37 (d, 1H, J=6.8 Hz), 8.29 (t, 1H, J=5.6 Hz), 8.24 (s, 1H), 8.17 (d, 1H, J=1.6 Hz), 7.74 (dd, 1H, J=1.8, 8.4 Hz), 7.3-7.4 (m, 2H), 4.92 (s, 2H), 4.72 (s, 3H), 4.3-4.4 (m, 2H), 3.4-3.6 (m, 2H), 3.3-3.3 (m, 2H), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[0839]

[0840] Example 17: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(2-oxozetidine-1-yl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0841] 2-[6-[[(1S,3S)-3-[[5-(2-oxozetidine-1-yl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 17] (13%) was prepared by a method similar to that of Preparation Example 2-2.

[0842] ESI-MS m / z: 419.19[M+H] + .

[0843] 1H NMR (DMSO-d6, 400 MHz) δ 8.4-8.4 (m, 2H), 8.10 (d, 1H, J=2.6 Hz), 8.02 (dd, 1H, J=1.6, 3.8 Hz), 7.4-7.5 (m, 2H), 7.25 (d, 1H, J=7.4 Hz), 7.03 (dd, 1H, J=1.6, 9.5 Hz), 6.93 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.3-4.4 (m, 2H), 3.59 (t, 2H, J=4.4 Hz), 3.07 (t, 2H, J=4.3 Hz), 2.1-2.2 (m, 2H), 1.8-1.9 (m,2H), 1.4-1.6 (m, 2H).

[0844]

[0845] Example 18: Synthesis of 1-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one

[0846]

[0847] 1-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one [Example 18] (8%) was prepared by a method similar to that of Preparation Example 2-2.

[0848] ESI-MS m / z: 388.18[M+H] + .

[0849] 1H NMR (DMSO-d6, 400 MHz) δ 8.77 (s, 1H), 7.92 (d, 1H, J=2.6 Hz), 7.6-7.6 (m, 2H), 7.48 (ddd, 1H, J=2.1, 6.7, 9.1 Hz), 7.40 (dd, 1H, J=2.8, 8.9 Hz), 6.91 (dd, 2H, J=7.3, 9.8 Hz), 6.68 (dd, 1H, J=1.4, 4.5 Hz), 6.59 (dd, 1H, J=2.4, 4.5 Hz), 6.54 (d, 1H, J=8.9 Hz), 6.45 (d, 1H, J=8.6 Hz), 6.28 (dt, 1H, J=1.4, 6.7 Hz), 4.3-4.4 (m, 1H), 4.1-4.2 (m, 1H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0850]

[0851] Example 19: Synthesis of 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one

[0852]

[0853] 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one [Example 19] (26%) was prepared by a method similar to that of Preparation Example 2-2.

[0854] ESI-MS m / z: 392.18[M+H] + .

[0855] 1H NMR (DMSO-d6, 400 MHz) δ 8.23 ​​(s, 1H), 8.10 (d, 1H, J=2.5 Hz), 8.02 (dd, 1H, J=1.7, 3.8 Hz), 7.4-7.5 (m, 2H), 7.30 (br d, 1H, J=7.4 Hz), 7.03 (dd, 1H, J=1.6, 9.4 Hz), 6.93 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.92 (s, 2H), 4.72 (s, 2H), 4.3-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0856]

[0857] Example 20: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[0858]

[0859] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 20] (26%) was prepared in the same manner as in Preparation Example 3-3.

[0860] ESI-MS m / z: 393.21[M+H]+.

[0861] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.0-8.1 (m, 3H), 7.68 (dd, 1H, J=2.6, 9.0 Hz), 6.99 (d, 1H, J=7.3 Hz), 6.73 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.29 (dt, 2H, J=7.0, 14.4 Hz), 3.24 (s, 3H), 2.0-2.2 (m, 2H), 1.7-1.9 (m, 3H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.5-0.7 (m, 2H).

[0862]

[0863] Example 21: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-diethyl-1,2,4-triazole-3-one

[0864]

[0865]

[0866] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-diethyl-1,2,4-triazole-3-one [Example 21] (6%) was prepared in a manner similar to that of Preparation Example 3-3.

[0867] ESI-MS m / z: 462.21[M+H] + .

[0868] 1H NMR (DMSO-d6, 400 MHz) δ 8.32 (d, 1H, J=2.8 Hz), 8.23 ​​(s, 2H), 7.69 (dd, 1H, J=2.7, 8.9 Hz), 7.46 (d, 1H, J=7.1 Hz), 6.8-7.2 (m, 1H), 6.70 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.1 Hz), 4.29 (dt, 2H, J=6.8, 12.8 Hz), 3.66 (q, 2H, J=7.2 Hz), 2.6-2.7 (m, 3H), 2.5-2.6 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H), 1.2-1.2 (m, 7H).

[0869]

[0870] Example 22: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one

[0871]

[0872] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one [Example 22] (39%) was prepared by a method similar to that of Preparation Example 3-3.

[0873] ESI-MS m / z: 450.17[M+H] + .

[0874] 1H NMR (DMSO-d6, 400 MHz) δ 8.23 ​​(s, 2H), 7.97 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=7.1 Hz), 7.38 (dd, 1H, J=2.6, 8.9 Hz), 6.8-7.2 (m, 2H), 6.53 (d, 1H, J=9.0 Hz), 4.3-4.4 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0875]

[0876] Example 23: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[0877]

[0878] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one [Example 23] (17%) was prepared by a method similar to that of Preparation Example 3-3.

[0879] ESI-MS m / z: 449.23[M+H] + .

[0880] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.0-8.1 (m, 3H), 7.68 (dd, 1H, J=2.6, 9.0 Hz), 6.98 (d, 1H, J=7.3 Hz), 6.73 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.1 Hz), 4.2-4.4 (m, 2H), 2.0-2.2 (m, 2H), 1.7-1.9 (m, 3H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0881]

[0882] Example 24: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methyl-1-propan-2-ylpyrazole-3-one

[0883]

[0884] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methyl-1-propan-2-ylpyrazole-3-one [Example 24] (4%) was prepared in a manner similar to that of Preparation Example 3-3.

[0885] ESI-MS m / z: 435.25[M+H] + .

[0886] 1H NMR (DMSO-d6, 400 MHz) δ 8.0-8.1 (m, 2H), 7.83 (d, 1H, J=2.5 Hz), 7.21 (d, 1H, J=8.9 Hz), 6.99 (d, 1H, J=7.1 Hz), 6.85 (d, 1H, J=6.9 Hz), 6.51 (d,

[0887] 1H, J=8.9 Hz), 5.25 (s, 1H), 4.2-4.3 (m, 2H), 3.9-3.9 (m, 1H), 2.2-2.3 (m, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.5 (m, 2H), 1.07 (d, 6H, J=6.9 Hz), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0888]

[0889] Example 25: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[0890]

[0891] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 25] (95%) was prepared by a method similar to that of Preparation Example 3-3.

[0892] ESI-MS m / z: 436.21[M+H] + .

[0893] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.06 (s, 2H), 7.67 (dd, 1H, J=2.8, 9.0 Hz), 6.99 (d, 1H, J=7.3 Hz), 6.74 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.70 (s, 2H), 4.2-4.3 (m, 2H), 4.01 (t, 2H, J=5.3 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.72 (tt, 1H, J=5.2, 8.4 Hz), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.7 (m, 2H).

[0894]

[0895] Example 26: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0896]

[0897] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 26] (95%) was prepared by a method similar to that of Preparation Example 3-3.

[0898] ESI-MS m / z: 420.22[M+H] + .

[0899] 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, 1H, J=2.6 Hz), 8.06 (s, 2H), 7.66 (dd, 1H, J=2.7, 8.9 Hz), 6.99 (d, 1H, J=7.3 Hz), 6.68 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.70 (t, 2H, J=7.0 Hz), 2.8-2.8 (m, 2H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[0900]

[0901] Example 27: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclophen

[0902] Synthesis of thyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3one

[0903]

[0904] 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclophen

[0905] [Example 27] (13%) was prepared in a manner similar to Preparation Examples 1-4.

[0906] ESI-MS m / z: 403.19[M+H] + .

[0907] 1H NMR (DMSO-d6, 400 MHz) δ 8.3-8.5 (m, 2H), 8.27 (d, 1H, J=2.6 Hz), 7.7-7.8 (m, 1H), 7.67 (dd, 1H, J=2.6, 9.0 Hz), 6.6-6.8 (m, 1H), 6.51 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 4.23 (s, 1H), 3.69 (d, 2H, J=7.1 Hz), 2.79 (d, 2H, J=8.0 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0908]

[0909] Example 28: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0910]

[0911] 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 28] (2%) was prepared by a method similar to that of Preparation Examples 1-4.

[0912] ESI-MS m / z: 393.21[M+H] + .

[0913] 1H NMR 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (d, 1H, J=2.6 Hz), 8.11 (d, 2H, J=0.6 Hz), 7.66 (dd, 1H, J=2.6, 9.0 Hz), 6.95 (d, 1H, J=7.4 Hz), 6.68 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=9.0 Hz), 5.3-5.3 (m, 2H), 4.30 (s, 1H), 3.70 (t, 2H, J=7.0 Hz), 2.8-2.9 (m, 2H), 2.1-2.1 (m, 1H), 2.04 (s, 3H), 2.0-2.0 (m, 1H), 1.7-1.9 (m, 2H), 1.4-1.5 (m, 2H).

[0914]

[0915] Example 29: Synthesis of 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0916]

[0917] 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 29] (4%) was prepared in a manner similar to Preparation Examples 1-4.

[0918] ESI-MS m / z: 421.24[M+H] + .

[0919] 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (d, 1H, J=2.5 Hz), 8.17 (s, 2H), 7.66 (dd, 1H, J=2.6, 9.0 Hz), 7.00 (d, 1H, J=7.4 Hz), 6.68 (d, 1H, J=7.0 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 3.6-3.8 (m, 2H), 2.7-2.8 (m, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H), 1.17 (d, 6H, J=7.0 Hz).

[0920]

[0921] Example 30: Synthesis of 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0922]

[0923] 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 30] (13%) was prepared in a manner similar to Preparation Examples 1-4.

[0924] ESI-MS m / z: 421.20[M+H] + .

[0925] 1H NMR (DMSO-d6, 400 MHz) δ 8.2-8.3 (m, 1H), 8.1-8.4 (m, 1H), 7.66 (dd, 1H, J=2.7, 8.9 Hz), 7.2-7.4 (m, 1H), 6.69 (d, 1H, J=7.0 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.91 (s, 2H), 4.71 (s, 2H), 4.2-4.4 (m, 2H), 3.6-3.7 (m, 2H), 3.17 (d, 1H, J=4.5 Hz), 2.7-2.9 (m, 2H), 2.4-2.5 (m, 2H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0926]

[0927] Example 31: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0928]

[0929] 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 31] (23%) was prepared by a method similar to that of Preparation Examples 1-4.

[0930] ESI-MS m / z: 429.19[M+H] + .

[0931] 1H NMR 1H NMR (DMSO-d6, 400 MHz) δ 8.4-8.5 (m, 2H), 8.2-8.3 (m, 1H), 7.8-7.9 (m, 1H), 7.6-7.7 (m, 1H), 6.92 (s, 1H), 6.7-6.7 (m, 1H), 6.52 (d, 1H, J=9.0 Hz), 4.2-4.5 (m, 2H), 3.69 (d, 1H, J=7.1 Hz), 2.8-2.9 (m, 2H), 2.46 (d, 2H, J=7.6 Hz), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0932]

[0933] Example 32: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0934]

[0935] 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 32] (11%) was prepared in a manner similar to Preparation Examples 1-4.

[0936] ESI-MS m / z: 419.22[M+H] + .

[0937] 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (d, 1H, J=2.6 Hz), 8.07 (s, 1H), 7.66 (dd, 1H, J=2.7, 8.9 Hz), 6.91 (d, 1H, J=7.4 Hz), 6.67 (s, 1H), 6.51 (d, 1H, J=9.0 Hz), 3.6-3.8 (m, 2H), 2.7-2.9 (m, 2H), 2.5-2.7 (m, 6H), 2.3-2.5 (m, 3H), 1.8-2.0 (m, 5H), 1.24 (br s, 2H).

[0938]

[0939] Example 33: Synthesis of 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one

[0940]

[0941] 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]okzine-3-one [Example 33] (61%) was prepared by a method similar to that of Preparation Examples 1-4.

[0942] ESI-MS m / z: 419.19[M+H] + .

[0943] 1H NMR (DMSO-d6, 400 MHz) δ 8.39 (br s, 2H), 8.30 (d, 1H, J=2.6 Hz), 7.77 (d, 1H, J=7.4 Hz), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 6.76 (d, 1H, J=7.0 Hz), 6.54 (d, 1H, J=9.0 Hz), 4.71 (s, 2H), 4.3-4.4 (m, 1H), 4.3-4.3 (m, 1H), 4.23 (s, 1H), 4.01 (dd, 2H, J=4.9, 5.9 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0944]

[0945] Example 34: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[0946]

[0947] 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 34] (62%) was prepared by a method similar to that of Preparation Examples 1-4.

[0948] ESI-MS m / z: 409.20[M+H] + .

[0949] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.11 (d, 2H, J=0.6 Hz), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 6.95 (d, 1H, J=7.3 Hz), 6.74 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.01 (dd, 2H, J=4.9, 5.9 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 2.04 (s, 3H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0950]

[0951] Example 35: Synthesis of 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one

[0952]

[0953] 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one [Example 35] (82%) was prepared by a method similar to that of Preparation Examples 1-4.

[0954] ESI-MS m / z: 437.23[M+H] + .

[0955] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.17 (s, 2H), 7.68 (dd, 1H, J=2.6, 9.0 Hz), 7.00 (d, 1H, J=7.3 Hz), 6.74 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.01 (dd, 2H, J=4.9, 5.9 Hz), 3.63 (t, 2H, J=5.3 Hz), 2.7-2.8 (m, 1H), 2.0-2.1 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 2H), 1.17 (d, 6H, J=7.0 Hz).

[0956]

[0957] Example 36: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one

[0958]

[0959] 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one [Example 36] (31%) was prepared by a method similar to that of Preparation Examples 1-4.

[0960] ESI-MS m / z: 435.22[M+H] + .

[0961] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.07 (s, 1H), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 6.91 (d, 1H, J=7.4 Hz), 6.74 (d, 1H, J=6.9 Hz), 6.53 (dd, 1H, J=0.6, 9.0 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.01 (dd, 2H, J=4.9, 5.9 Hz), 3.63 (t, 2H, J=5.3 Hz), 2.69 (dt, 4H, J=4.7, 7.4 Hz), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 2H).

[0962]

[0963] Example 37: Synthesis of 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one

[0964]

[0965] 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one [Example 37] (46%) was prepared by a method similar to that of Preparation Examples 1-4.

[0966] ESI-MS m / z: 437.20[M+H] + .

[0967] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.22 (s, 1H), 7.67 (dd, 1H, J=2.6, 9.0 Hz), 7.29 (br d, 1H, J=7.3 Hz), 6.75 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.91 (s, 2H), 4.7-4.7 (m, 4H), 4.3-4.4 (m, 1H), 4.2-4.3 (m, 1H), 4.01 (dd, 2H, J=4.8, 5.8 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[0968]

[0969] Example 38: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one

[0970]

[0971] 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one [Example 38] (22%) was prepared by a method similar to that of Preparation Examples 1-4.

[0972] ESI-MS m / z: 425.20 [M+H] + .

[0973] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.10 (s, 2H), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 6.83 (d, 1H, J=7.3 Hz), 6.74 (d, 1H, J=6.9 Hz), 6.53 (dd, 1H, J=0.6, 9.0 Hz), 4.71 (s, 2H), 4.2-4.3 (m, 2H), 4.0-4.0 (m, 2H), 3.74 (s, 3H), 3.63 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 2H).

[0974]

[0975] Example 39: Synthesis of 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one

[0976]

[0977] 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one [Example 39] (74%) was prepared by a method similar to that of Preparation Examples 1-4.

[0978] ESI-MS m / z: 421.20[M+H] + .

[0979] 1H NMR (DMSO-d6, 400 MHz) δ 8.41 (s, 2H), 8.30 (d, 1H, J=2.5 Hz), 7.68 (dd, 1H, J=2.6, 8.9 Hz), 7.42 (d, 1H, J=7.3 Hz), 6.75 (d, 1H, J=7.0 Hz), 6.5-6.6 (m, 2H), 5.69 (d, 1H, J=17.8 Hz), 5.07 (d, 1H, J=11.3 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.00 (t, 2H, J=5.4 Hz), 3.63 (t, 2H, J=5.3 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0980]

[0981] Example 40: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one

[0982]

[0983] 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]okzine-3-one [Example 40] (62%) was prepared by a method similar to that of Preparation Examples 1-4.

[0984] ESI-MS m / z: 445.18[M+H] + .

[0985] 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (br s, 2H), 8.30 (d, 1H, J=2.8 Hz), 7.86 (d, 1H, J=7.3 Hz), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 6.7-7.1 (m, 2H), 6.54 (d, 1H, J=9.0 Hz), 4.71 (s, 2H), 4.40 (sxt, 1H, J=7.0 Hz), 4.2-4.4 (m, 1H), 4.01 (t, 2H, J=5.4 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[0986]

[0987] Example 41: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one

[0988]

[0989] 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one [Example 41] (72%) was prepared by a method similar to that of Preparation Examples 1-4.

[0990] ESI-MS m / z: 429.15[M+H] + .

[0991] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.03 (d, 1H, J=1.4 Hz), 7.72 (d, 1H, J=1.4 Hz), 7.7-7.7 (m, 1H), 7.39 (d, 1H, J=6.8 Hz), 6.78 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.01 (dd, 2H, J=4.9, 5.9 Hz), 3.63 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.88 (t, 2H, J=6.7 Hz), 1.4-1.6 (m, 2H).

[0992]

[0993] Example 42: Synthesis of 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0994]

[0995] 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 42] (3%) was prepared in a manner similar to Preparation Examples 1-4.

[0996] ESI-MS m / z: 437.18[M+H] + .

[0997] 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (d, 1H, J=2.5 Hz), 8.08 (s, 1H), 7.65 (d, 1H, J=2.6 Hz), 7.0-7.1 (m, 1H), 6.6-6.7 (m, 1H), 6.51 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.70 (s, 2H), 3.29 (t, 2H, J=7.8 Hz), 3.09 (s, 2H), 2.80 (s, 2H), 2.4-2.5 (m, 2H), 2.0-2.1 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 2H).

[0998]

[0999] Example 43: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[1000]

[1001] 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 43] (33%) was prepared by a method similar to that of Preparation Examples 1-4.

[1002] ESI-MS m / z: 413.15[M+H] + .

[1003] 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, 1H, J=2.6 Hz), 8.03 (d, 1H, J=1.4 Hz), 7.72 (d, 1H, J=1.4 Hz), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 7.40 (d, 1H, J=6.8 Hz), 6.72 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.70 (t, 2H, J=7.0 Hz), 2.79 (d, 2H, J=7.9 Hz), 2.47 (s, 2H), 2.1-2.2 (m, 2H), 1.87 (t, 2H, J=6.7 Hz), 1.4-1.5 (m, 2H).

[1004]

[1005] Example 44: Synthesis of 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[1006]

[1007] 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 44] (19%) was prepared by a method similar to that of Preparation Examples 1-4.

[1008] ESI-MS m / z: 405.21[M+H] + .

[1009] 1H NMR (DMSO-d6, 400 MHz) δ 8.41 (s, 2H), 8.27 (d, 1H, J=2.5 Hz), 7.66 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=7.4 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.4-6.6 (m, 2H), 5.69 (dd, 1H, J=0.8, 17.8 Hz), 5.0-5.2 (m, 1H), 4.2-4.4 (m, 2H), 3.70 (t, 2H, J=7.0 Hz), 3.51 (s, 1H), 2.79 (d, 2H, J=7.9 Hz), 2.4-2.5 (m, 2H), 2.12 (br dd, 2H, J=7.2, 14.6 Hz), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1010]

[1011] Example 45: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[1012]

[1013] 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one [Example 45] (10%) was prepared in a manner similar to Preparation Examples 1-4.

[1014] ESI-MS m / z: 409.20[M+H] + .

[1015] 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (d, 1H, J=2.6 Hz), 8.10 (s, 2H), 7.66 (dd, 1H, J=2.6, 9.0 Hz), 6.83 (d, 1H, J=7.1 Hz), 6.68 (d, 1H, J=7.0 Hz), 6.51 (dd, 1H, J=0.6, 9.0 Hz), 4.2-4.3 (m, 2H), 3.7-3.7 (m, 5H), 2.79 (d, 2H, J=8.0 Hz), 2.4-2.5 (m, 2H), 2.0-2.1 (m, 2H), 1.85 (br d, 2H, J=6.8 Hz), 1.4-1.5 (m, 2H).

[1016]

[1017] Example 46: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one

[1018]

[1019] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one [Example 46] (27%) was prepared by a method similar to that of Preparation Example 3-3.

[1020] ESI-MS m / z: 407.22[M+H] + .

[1021] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.8 Hz), 8.06 (s, 2H), 7.68 (dd, 1H, J=2.6, 9.0 Hz), 6.99 (d, 1H, J=7.3 Hz), 6.68 (d, 1H, J=6.9 Hz), 6.52 (dd, 1H, J=0.6, 9.0 Hz), 4.2-4.3 (m, 2H), 3.17 (s, 3H), 2.24 (s, 3H), 2.10 (dddd, 2H, J=2.8, 7.0, 12.0, 19.3 Hz), 1.8-1.9 (m, 2H), 1.72 (tt, 1H, J=5.2, 8.5 Hz), 1.4-1.5 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1022]

[1023] Example 47: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-ethyl-1,2,4-triazole-3-one

[1024]

[1025] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-ethyl-1,2,4-triazole-3-one [Example 47] (51%) was prepared by a method similar to that of Preparation Example 3-3.

[1026] ESI-MS m / z: 407.22[M+H] + .

[1027] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.6 Hz), 8.19 (s, 1H), 8.06 (s, 2H), 7.69 (dd, 1H, J=2.7, 8.9 Hz), 6.99 (d, 1H, J=7.4 Hz), 6.73 (d, 1H, J=7.0 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.29 (sxtd, 2H, J=7.0, 14.4 Hz), 3.66 (q, 2H, J=7.3 Hz), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.71 (tt, 1H, J=5.1, 8.4 Hz), 1.4-1.6 (m, 2H), 1.27 (t, 3H, J=7.3 Hz), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1028] Example 48: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one

[1029]

[1030] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one [Example 48] (29%) was prepared by a method similar to that of Preparation Example 3-3.

[1031] ESI-MS m / z: 430.20[M+H] + .

[1032] 1H NMR (DMSO-d6, 400 MHz) Shift 8.98 (d, 1H, J=1.6 Hz), 8.48 (d, 1H, J=2.6 Hz), 8.07 (s, 2H), 7.9-8.0 (m, 1H), 7.8-7.9 (m, 1H), 7.59 (d, 1H, J=4.9 Hz), 6.9-7.1 (m, 2H), 6.6-6.6 (m, 1H), 4.3-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1033]

[1034] Example 49: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one

[1035]

[1036] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one [Example 49] (31%) was prepared by a method similar to that of Preparation Example 3-3.

[1037] ESI-MS m / z: 433.18[M+H] + .

[1038] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.8 Hz), 8.23 ​​(s, 2H), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 7.47 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.70 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 3.18 (s, 3H), 2.24 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1039]

[1040] Example 50: Synthesis of 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-one

[1041]

[1042] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-one [Example 50] (23%) was prepared by a method similar to that of Preparation Example 3-3.

[1043] ESI-MS m / z: 433.18[M+H] + .

[1044] 1H NMR (DMSO-d6, 400 MHz) δ 8.32 (d, 1H, J=2.8 Hz), 8.23 ​​(s, 2H), 8.19 (s, 1H), 7.70 (dd, 1H, J=2.6, 9.0 Hz), 7.47 (d, 1H, J=7.1 Hz), 6.8-7.2 (m, 1H), 6.75 (d, 1H, J=6.9 Hz), 6.54 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.66 (q, 2H, J=7.3 Hz), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H), 1.27 (t, 3H, J=7.3 Hz).

[1045]

[1046] Example 51: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1047]

[1048] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 51] (34%) was prepared by a method similar to that of Preparation Example 3-3.

[1049] ESI-MS m / z: 419.17[M+H] + .

[1050] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.5 Hz), 8.23 ​​(s, 2H), 8.10 (s, 1H), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 7.46 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.74 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=8.9 Hz), 4.2-4.4 (m, 2H), 3.23 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1051]

[1052] Example 52: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one

[1053]

[1054] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one [Example 52] (17%) was prepared by a method similar to that of Preparation Example 3-3.

[1055] ESI-MS m / z: 423.22[M+H] + .

[1056] 1H NMR (DMSO-d6, 400 MHz) δ 10.08 (s, 1H), 8.43 (s, 1H), 7.98 (br d, 2H, J=7.8 Hz), 7.59 (s, 1H), 7.53 (dd, 1H, J=1.5, 8.4 Hz), 7.4-7.5 (m, 3H), 7.2-7.3 (m, 1H), 7.1-7.2 (m, 2H), 4.49 (br dd, 1H, J=3.3, 8.0 Hz), 3.6-3.7 (m, 1H), 3.5-3.5 (m, 1H), 3.06 (td, 1H, J=6.9, 13.9 Hz), 2.1-2.2 (m, 4H), 1.9-2.1 (m, 4H), 1.17 (d, 6H, J=7.0 Hz).

[1057]

[1058] Example 53: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(2,2,2-trifluoroethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one

[1059]

[1060] 2-[6-[[(1S,3S)-3-[[5-(2,2,2-trifluoroethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one [Example 53] (91%) was prepared by a method similar to that of Preparation Examples 1-4.

[1061] ESI-MS m / z: 493.18[M+H] + .

[1062] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, 1H, J=2.6 Hz), 8.20 (s, 2H), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 7.08 (d, 1H, J=7.1 Hz), 6.74 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.7-4.7 (m, 4H), 4.2-4.3 (m, 2H), 4.0-4.0 (m, 2H), 3.63 (t, 2H, J=5.4 Hz), 3.34 (br s, 1H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 2H), 1.86 (dd, 2H, J=7.4, 14.8 Hz), 1.4-1.6 (m, 2H), 1.24 (s, 1H).

[1063]

[1064] Example 54: Synthesis of 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1065]

[1066] 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 54] (7%) was prepared in a manner similar to that of Preparation Examples 1-4.

[1067] ESI-MS m / z: 425.23[M+H] + .

[1068] 1H NMR (DMSO-d6, 400 MHz) δ 8.17 (s, 2H), 7.97 (d, 1H, J=2.9 Hz), 7.38 (dd, 1H, J=2.7, 8.9 Hz), 7.02 (d, 2H, J=7.4 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.7-2.8 (m, 1H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 3H), 1.24 (s, 2H), 1.17 (d, 6H, J=6.9 Hz).

[1069]

[1070] Example 55: Synthesis of 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one

[1071]

[1072] 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one [Example 55] (11%) was prepared by a method similar to that of Preparation Examples 1-4.

[1073] ESI-MS m / z: 409.2[M+H] + .

[1074] 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (s, 2H), 7.97 (d, 1H, J=2.6 Hz), 7.44 (d, 1H, J=7.3 Hz), 7.38 (dd, 1H, J=2.7, 8.9 Hz), 7.03 (d, 1H, J=6.9 Hz), 6.5-6.6 (m, 2H), 5.69 (dd, 1H, J=0.9, 17.8 Hz), 5.1-5.1 (m, 1H), 4.3-4.4 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[1075]

[1076] Example 56: Synthesis of 2-[6-[[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1077]

[1078] 2-[6-[[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 56] (5%) was prepared in a manner similar to Preparation Examples 1-4.

[1079] ESI-MS m / z: 383.19[M+H] + .

[1080] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.1-8.1 (m, 3H), 7.68 (dd, 1H, J=2.8, 9.0 Hz), 6.83 (d, 1H, J=7.3 Hz), 6.73 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.74 (s, 3H), 3.24 (s, 3H), 2.0-2.2 (m, 2H), 1.85 (dd, 2H, J=7.3, 14.2 Hz), 1.4-1.6 (m, 2H).

[1081]

[1082] Example 57: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chlorpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1083]

[1084] 2-[6-[[(1S,3S)-3-[(5-chlorpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 57] (10%) was prepared in a manner similar to Preparation Examples 1-4.

[1085] ESI-MS m / z: 387.14[M+H] + .

[1086] 1H NMR (DMSO-d6, 400 MHz) δ 8.3-8.3 (m, 3H), 8.11 (s, 1H), 7.69 (dd, 1H, J=2.8, 9.0 Hz), 7.56 (d, 1H, J=7.3 Hz), 6.75 (d, 1H, J=6.9 Hz), 6.53 (d, 1H, J=9.0 Hz), 4.29 (spt, 2H, J=6.7 Hz), 3.24 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1087]

[1088] Example 58: Synthesis of 4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1089]

[1090] 4-methyl-2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 58] (16%) was prepared by a method similar to that of Preparation Examples 1-4.

[1091] ESI-MS m / z: 395.22[M+H] + .

[1092] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.6 Hz), 8.17 (s, 2H), 8.11 (s, 1H), 7.68 (dd, 1H, J=2.8, 9.0 Hz), 7.00 (d, 1H, J=7.3 Hz), 6.74 (d, 1H, J=6.9 Hz), 6.54 (dd, 1H, J=0.6, 9.0 Hz), 4.2-4.4 (m, 2H), 3.24 (s, 3H), 2.7-2.8 (m, 1H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H), 1.17 (d, 6H, J=7.0 Hz).

[1093]

[1094] Example 59: Synthesis of 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1095]

[1096] 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 59] (11%) was prepared in a manner similar to Preparation Examples 1-4.

[1097] ESI-MS m / z: 379.19[M+H] + .

[1098] 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (s, 2H), 8.31 (d, 1H, J=2.8 Hz), 8.11 (s, 1H), 7.69 (dd, 1H, J=2.8, 9.0 Hz), 7.43 (d, 1H, J=7.4 Hz), 6.75 (d, 1H, J=7.0 Hz), 6.5-6.6 (m, 2H), 5.69 (dd, 1H, J=0.9, 17.8 Hz), 5.1-5.1 (m, 1H), 4.3-4.4 (m, 1H), 4.2-4.3 (m, 1H), 3.24 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1099]

[1100] Example 60: Synthesis of 4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1101]

[1102] 4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 60] (15%) was prepared by a method similar to that of Preparation Examples 1-4.

[1103] ESI-MS m / z: 421.16[M+H] + .

[1104] 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (br d, 2H, J=14.8 Hz), 8.31 (d, 1H, J=2.6 Hz), 8.19 (d, 1H, J=7.3 Hz), 8.11 (s, 1H), 7.69 (dd, 1H, J=2.6, 9.0 Hz), 6.77 (d, 1H, J=6.9 Hz), 6.54 (dd, 1H, J=0.6, 9.0 Hz), 4.42 (sxt, 1H, J=7.0 Hz), 4.30 (sxt, 1H, J=6.5 Hz), 3.24 (s, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[1105]

[1106] Example 61: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methylpyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1107]

[1108] 2-[6-[[(1S,3S)-3-[(5-methylpyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 61] (5%) was prepared by a method similar to that of Preparation Examples 1-4.

[1109] ESI-MS m / z: 409.20[M+H] + .

[1110] 1H NMR (DMSO-d6, 400 MHz) Shift 8.30 (d, 1H, J=2.6 Hz), 7.8-7.9 (m, 2H), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 6.85 (d, 1H, J=6.9 Hz), 6.77 (d, 1H, J=6.9 Hz), 6.53 (dd, 1H, J=0.6, 9.0 Hz), 4.70 (s, 2H), 4.2-4.4 (m, 2H), 4.00 (d, 2H, J=5.6 Hz), 3.63 (s, 2H), 2.24 (s, 3H), 2.14 (br d, 2H, J=2.9 Hz), 1.86 (t, 2H, J=6.8 Hz), 1.47 (td, 2H, J=3.0, 4.6 Hz).

[1111]

[1112] Example 62: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one

[1113]

[1114] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one [Example 62] (15%) was prepared by a method similar to that of Preparation Example 3-3.

[1115] ESI-MS m / z: 456.16[M+H] + .

[1116] 1H NMR (DMSO-d6, 400 MHz) Shift 8.98 (d, 1H, J=1.8 Hz), 8.49 (d, 1H, J=2.8 Hz), 8.24 (s, 2H), 7.94 (dd, 1H, J=1.7, 4.8 Hz), 7.8-7.9 (m, 1H), 7.60 (s, 1H), 7.4-7.5 (m, 1H), 6.8-7.2 (m, 2H), 6.6-6.6 (m, 1H), 4.3-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[1117]

[1118] Example 63: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one

[1119]

[1120] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one [Example 63] (11%) was prepared in a manner similar to Preparation Examples 1-4.

[1121] ESI-MS m / z: 417.15[M+H] + .

[1122] 1H NMR (DMSO-d6, 400 MHz) Shift 8.32 (s, 2H), 7.9-8.1 (m, 1H), 7.5-7.6 (m, 1H), 7.4-7.4 (m, 1H), 7.3-7.4 (m, 1H), 7.0-7.1 (m, 1H), 6.53 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1123]

[1124] Example 64: Synthesis of 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1125]

[1126] 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 64] (10%) was prepared by a method similar to that of Preparation Examples 1-4.

[1127] ESI-MS m / z: 451.17[M+H] + .

[1128] 1H NMR (DMSO-d6, 400 MHz) Shift 8.5-8.7 (m, 2H), 8.1-8.3 (m, 1H), 7.98 (d, 1H, J=2.6 Hz), 7.3-7.5 (m, 1H), 6.9-7.1 (m, 1H), 6.54 (d, 1H, J=8.9 Hz), 4.2-4.5 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.5-1.7 (m, 2H).

[1129]

[1130] Example 65: Synthesis of 5-methoxy-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1131]

[1132] 5-methoxy-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 65] (8%) was prepared by a method similar to that of Preparation Examples 1-4.

[1133] ESI-MS m / z: 413.20[M+H] + .

[1134] 1H NMR (DMSO-d6, 400 MHz) Shift 8.10 (s, 2H), 7.97 (d, 1H, J=2.5 Hz), 7.3-7.4 (m, 1H), 7.0-7.0 (m, 1H), 6.8-6.9 (m, 1H), 6.4-6.6 (m, 1H), 4.2-4.4 (m, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.10 (br d, 2H, J=12.1 Hz), 1.86 (dd, 2H, J=7.3, 14.1 Hz), 1.4-1.5 (m, 2H).

[1135]

[1136] Example 66: Synthesis of 2-[6-[[(1S,3S)-3-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1137]

[1138] 2-[6-[[(1S,3S)-3-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 66] (10%) was prepared in a manner similar to Preparation Examples 1-4.

[1139] ESI-MS m / z: 451.16[M+H] + .

[1140] 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (br d, 1H, J=6.8 Hz), 8.32 (d, 1H, J=2.4 Hz), 8.08 (br d, 1H, J=3.9 Hz), 7.6-7.7 (m, 2H), 7.23 (dd, 1H, J=4.8, 8.1 Hz), 6.81 (d, 1H, J=7.0 Hz), 6.55 (d, 1H, J=9.0 Hz), 4.70 (s, 2H), 4.3-4.4 (m, 2H), 4.0-4.1 (m, 2H), 3.63 (t, 2H, J=5.3 Hz), 2.1-2.3 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.7 (m, 2H).

[1141]

[1142] Example 67: Synthesis of tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate

[1143]

[1144] tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate [Example 67] (11%) was prepared by a method similar to that of Preparation Example 2-2.

[1145] ESI-MS m / z: 560.25[M+H] + .

[1146] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.54 (d, 1H, J=2.5 Hz), 8.18 (s, 2H), 7.90 (dd, 1H, J=2.4, 8.9 Hz), 6.60 (s, 1H), 6.44 (s, 1H), 6.42 (s, 1H), 6.24 (s, 1H), 5.3-5.3 (m, 2H), 4.62 (s, 2H), 4.42 (sxt, 1H, J=6.9 Hz), 4.24 (sxt, 1H, J=6.5 Hz), 3.84 (t, 2H, J=5.3 Hz), 3.75 (t, 2H, J=5.4 Hz), 2.3-2.4 (m, 2H), 2.0-2.1 (m, 2H), 1.5-1.6 (m, 2H), 1.52 (s, 9H).

[1147]

[1148] Example 68: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-one

[1149]

[1150] tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate (30.00 mg, 0.082 mmol), which is Example 67 synthesized as in Preparation Example 2-2, was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (123.49 mg, 1.07 mmol) was added at room temperature and stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 11 using a 4N aqueous sodium hydroxide solution. The organic layer was extracted with ethyl acetate, dried with sodium sulfate, filtered, and concentrated. The residue was purified by MPLC to produce 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-one [Example 68] (15.00 mg, 0.032 mmol, 60%).

[1151] ESI-MS m / z: 460.19[M+H] + .

[1152] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=3.1 Hz), 8.23 ​​(s, 2H), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 7.47 (d, 1H, J=7.3 Hz), 7.22 (s, 1H), 7.03 (s, 1H), 6.85 (s, 1H), 6.71 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=9.0 Hz), 4.2-4.3 (m, 2H), 3.77 (d, 2H, J=6.1 Hz), 3.47 (t, 2H, J=5.6 Hz), 3.03 (q, 2H, J=5.6 Hz), 2.63 (br t, 1H, J=6.3 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H), 1.2-1.3 (m, 1H).

[1153]

[1154] Example 69: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one

[1155]

[1156] 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one [Example 69] (15%) was prepared by a method similar to that of Preparation Example 3-3.

[1157] ESI-MS m / z: 420.18[M+H] + .

[1158] 1H NMR (DMSO-d6, 400 MHz) δ 8.98 (d, 1H, J=1.6 Hz), 8.48 (d, 1H, J=2.6 Hz), 8.10 (s, 2H), 7.93 (dd, 1H, J=1.8, 4.9 Hz), 7.84 (dd, 1H, J=2.8, 9.0 Hz), 7.59 (d, 1H, J=4.9 Hz), 6.96 (d, 1H, J=7.0 Hz), 6.85 (d, 1H, J=7.3 Hz), 6.60 (d, 1H, J=9.0 Hz), 4.2-4.4 (m, 2H), 3.74 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.5-1.5 (m, 2H).

[1159]

[1160] Example 70: Synthesis of 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one

[1161]

[1162] 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one [Example 70] (43%) was prepared by a method similar to that of Preparation Example 3-3.

[1163] ESI-MS m / z: 397.20[M+H] + .

[1164] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.5 Hz), 8.10 (s, 2H), 7.68 (dd, 1H, J=2.7, 8.9 Hz), 6.83 (d, 1H, J=7.1 Hz), 6.68 (d, 1H, J=7.0 Hz), 6.52 (d, 1H, J=9.0 Hz), 4.26 (br d, 2H, J=6.9 Hz), 3.74 (s, 3H), 3.18 (s, 3H), 2.24 (s, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1165]

[1166] Example 71: Synthesis of 4-ethyl-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1167]

[1168] 4-ethyl-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 71] (24%) was prepared by a method similar to that of Preparation Example 3-3.

[1169] ESI-MS m / z: 397.20[M+H] + .

[1170] 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 1H, J=2.8 Hz), 8.19 (s, 1H), 8.10 (s, 2H), 7.68 (s, 1H), 6.83 (d, 1H, J=7.3 Hz), 6.73 (d, 1H, J=6.9 Hz), 6.53 (dd, 1H, J=0.6, 9.0 Hz), 4.2-4.3 (m, 2H), 3.74 (s, 3H), 3.66 (d, 2H, J=7.3 Hz), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 2H), 1.27 (t, 3H, J=7.3 Hz).

[1171]

[1172] Example 72: Synthesis of 2-[6-[[(1S,3S)-3-([1,3]oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1173]

[1174] 2-[6-[[(1S,3S)-3-([1,3]oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 72] (11%) was prepared by a method similar to that of Preparation Examples 1-4.

[1175] ESI-MS m / z: 435.18[M+H] + .

[1176] 1H NMR (DMSO-d6, 400 MHz) δ 8.39 (d, 1H, J=7.0 Hz), 8.31 (d, 1H, J=2.6 Hz), 7.83 (dd, 1H, J=1.5, 5.0 Hz), 7.70 (dd, 1H, J=2.6, 9.0 Hz), 7.58 (dd, 1H, J=1.6, 7.7 Hz), 7.16 (dd, 1H, J=5.1, 7.7 Hz), 6.81 (d, 1H, J=6.9 Hz), 6.55 (d, 1H, J=9.0 Hz), 4.71 (s, 2H), 4.2-4.4 (m, 2H), 4.01 (t, 2H, J=5.4 Hz), 3.63 (t, 2H, J=5.3 Hz), 2.1-2.2 (m, 2H), 1.9-2.1 (m, 2H), 1.6-1.7 (m, 1H), 1.5-1.6 (m, 1H).

[1177]

[1178] Example 73: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one

[1179]

[1180] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one [Example 73] (35%) was prepared by a method similar to that of Preparation Example 3-3.

[1181] ESI-MS m / z: 437.23[M+H] + .

[1182] 1H NMR (DMSO-d6, 400 MHz) δ 8.3-8.3 (m, 1H), 8.07 (s, 2H), 7.67 (dd, 1H, J=2.8, 9.0 Hz), 7.00 (d, 1H, J=7.3 Hz), 6.75 (d, 1H, J=7.0 Hz), 6.54 (d, 1H, J=9.0 Hz), 4.42 (s, 2H), 4.29 (qt, 2H, J=6.8, 14.1 Hz), 3.32 (s, 3H), 3.24 (s, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.72 (tt, 1H, J=5.2, 8.4 Hz), 1.3-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.5-0.7 (m, 2H).

[1183]

[1184] Example 74: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one

[1185]

[1186] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one [Example 74] (54%) was prepared by a method similar to that of Preparation Example 3-3.

[1187] ESI-MS m / z: 463.19[M+H] + .

[1188] 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=2.6 Hz), 8.23 ​​(s, 2H), 7.67 (dd, 1H, J=2.7, 8.9 Hz), 7.47 (d, 1H, J=7.3 Hz), 7.22 (s, 1H), 7.03 (s, 1H), 6.85 (s, 1H), 6.77 (d, 1H, J=6.9 Hz), 6.54 (d, 1H, J=9.1 Hz), 4.42 (s, 2H), 4.2-4.3 (m, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H).

[1189]

[1190] Example 75: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1191]

[1192] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 75] (74%) was prepared by a method similar to that of Preparation Example 3-3.

[1193] ESI-MS m / z: 453.21[M+H] + .

[1194] 1H NMR (DMSO-d6, 400 MHz) δ 8.23 ​​(d, 1H, J=2.1 Hz), 8.11 (br d, 2H, J=1.4 Hz), 7.71 (dd, 1H, J=2.2, 12.3 Hz), 6.99 (br s, 1H), 6.71 (d, 1H, J=6.1 Hz), 4.72 (s, 2H), 4.4-4.5 (m, 1H), 4.3-4.4 (m, 1H), 4.01 (t, 2H, J=5.4 Hz), 3.64 (t, 2H, J=5.3 Hz), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.72 (s, 1H), 1.5-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.5-0.6 (m, 2H).

[1195]

[1196] Example 76: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1197]

[1198] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 76] (10%) was prepared by a method similar to that of Preparation Example 3-3.

[1199] ESI-MS m / z: 411.20[M+H] + .

[1200] 1H NMR (DMSO-d6, 400 MHz) δ 8.25 (d, 1H, J=2.1 Hz), 8.16 (s, 1H), 8.07 (s, 2H), 7.73 (dd, 1H, J=2.1, 12.3 Hz), 6.99 (d, 1H, J=7.4 Hz), 6.7-6.7 (m, 1H), 4.4-4.5 (m, 1H), 4.32 (sxt, 1H, J=6.9 Hz), 3.25 (s, 3H), 2.1-2.1 (m, 2H), 1.90 (dt, 2H, J=1.8, 7.0 Hz), 1.7-1.7 (m, 1H), 1.5-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1201]

[1202] Example 77: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1203]

[1204] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 77] (68%) was prepared by a method similar to that of Preparation Example 3-3.

[1205] ESI-MS m / z: 479.17[M+H] + .

[1206] 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, 1H, J=2.1 Hz), 8.23 ​​(s, 2H), 8.15 (s, 1H), 7.73 (dd, 1H, J=2.1, 12.3 Hz), 7.46 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.72 (d, 1H, J=6.1 Hz), 4.4-4.6 (m, 1H), 4.3-4.4 (m, 1H), 3.25 (s, 3H), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[1207]

[1208] Example 78: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1209]

[1210] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 78] (87%) was prepared by a method similar to that of Preparation Example 3-3.

[1211] ESI-MS m / z: 437.16[M+H] + .

[1212] 1H NMR (DMSO-d6, 400 MHz) δ 8.2-8.3 (m, 3H), 7.72 (dd, 1H, J=2.2, 12.3 Hz), 7.46 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 1H), 6.7-6.8 (m, 1H), 4.71 (s, 2H), 4.48 (br d, 1H, J=7.0 Hz), 4.32 (br d, 1H, J=6.9 Hz), 4.01 (t, 2H, J=5.3 Hz), 3.64 (t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.55 (dt, 2H, J=2.1, 4.7 Hz).

[1213]

[1214] Example 79: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1215]

[1216] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 79] (33%) was prepared by a method similar to that of Preparation Example 3-3.

[1217] ESI-MS m / z: 470.18[M+H] + .

[1218] 1H NMR (DMSO-d6, 400 MHz) δ 8.4-8.5 (m, 1H), 8.24 (s, 2H), 7.8-7.9 (m, 2H), 7.48 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 3H), 6.59 (d, 1H, J=9.0 Hz), 4.3-4.4 (m, 2H), 2.43 (s, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.5-1.6 (m, 2H).

[1219]

[1220] Example 80: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1221]

[1222] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 80] (18%) was prepared by a method similar to that of Preparation Example 3-3.

[1223] ESI-MS m / z: 444.22[M+H] + .

[1224] 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (d, 1H, J=2.6 Hz), 8.07 (s, 2H), 7.8-7.9 (m, 2H), 7.14 (d, 1H, J=9.8 Hz), 7.01 (d, 1H, J=7.3 Hz), 6.88 (d, 1H, J=7.0 Hz), 6.59 (d, 1H, J=9.0 Hz), 4.31 (spt, 2H, J=6.7 Hz), 2.43 (s, 3H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.72 (tt, 1H, J=5.2, 8.5 Hz), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1225]

[1226] Example 81: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-propan-2-ylpyrazole-3-one

[1227]

[1228] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-propan-2-ylpyrazole-3-one [Example 81] (20%) was prepared by a method similar to that of Preparation Examples 1-4.

[1229] ESI-MS m / z: 420.24[M+H] + .

[1230] 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 2H), 7.98 (d, 1H, J=3.6 Hz), 7.87 (d, 1H, J=2.6 Hz), 7.26 (dd, 1H, J=2.6, 8.9 Hz), 7.00 (d, 1H, J=7.3 Hz), 6.92 (d, 1H, J=6.9 Hz), 6.54 (d, 1H, J=8.9 Hz), 5.40 (d, 1H, J=3.6 Hz), 4.2-4.4 (m, 2H), 3.6-3.7 (m, 1H), 3.4-3.4 (m, 1H), 3.3-3.3 (m, 2H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.7-1.8 (m, 1H), 1.4-1.6 (m, 2H), 1.24 (s, 2H), 1.14 (d, 6H, J=6.6 Hz), 0.8-0.9 (m, 2H), 0.5-0.7 (m, 2H).

[1231] Example 82: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-ethylpyrazole-3-one

[1232]

[1233] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-ethylpyrazole-3-one [Example 82] (15%) was prepared by a method similar to that of Preparation Examples 1-4.

[1234] ESI-MS m / z: 406.23[M+H] + .

[1235] 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 2H), 7.9-7.9 (m, 2H), 7.27 (dd, 1H, J=2.7, 8.8 Hz), 7.00 (d, 1H, J=7.3 Hz), 6.93 (d, 1H, J=7.0 Hz), 6.55 (d, 1H, J=8.9 Hz), 5.35 (d, 1H, J=3.5 Hz), 4.2-4.4 (m, 2H), 3.51 (d, 2H, J=7.1 Hz), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 2H), 1.86 (dd, 2H, J=7.3, 14.2 Hz), 1.72 (s, 1H), 1.4-1.6 (m, 2H), 0.94 (t, 3H, J=7.1 Hz), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1236]

[1237] Example 83: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1238]

[1239] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 83] (38%) was prepared by a method similar to that of Preparation Example 3-3.

[1240] ESI-MS m / z: 456.16[M+H] + .

[1241] 1H NMR (DMSO-d6, 400 MHz) δ 8.48 (d, 1H, J=2.6 Hz), 8.32 (dd, 1H, J=1.4, 4.1 Hz), 8.2-8.3 (m, 2H), 7.87 (ddd, 2H, J=2.1, 9.3, 16.7 Hz), 7.48 (d, 1H, J=7.3 Hz), 6.8-7.2 (m, 3H), 6.6-6.6 (m, 1H), 4.3-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.5-1.6 (m, 2H).

[1242]

[1243] Example 84: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one

[1244]

[1245] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one [Example 84] (33%) was prepared by a method similar to that of Preparation Example 3-3.

[1246] ESI-MS m / z: 437.23[M+H] + .

[1247] 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, 1H, J=2.6 Hz), 8.06 (s, 2H), 7.65 (dd, 1H, J=2.6, 9.0 Hz), 6.98 (d, 1H, J=7.3 Hz), 6.65 (d, 1H, J=6.9 Hz), 6.51 (d, 1H, J=9.0 Hz), 4.3-4.4 (m, 2H), 4.2-4.3 (m, 2H), 3.07 (s, 3H), 2.0-2.2 (m, 2H), 1.7-1.9 (m, 3H), 1.4-1.5 (m, 2H), 1.38 (t, 3H, J=7.1 Hz), 0.8-0.9 (m, 2H), 0.6-0.6 (m, 2H).

[1248]

[1249] Example 85: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one

[1250]

[1251] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one [Example 85] (29%) was prepared by a method similar to that of Preparation Example 3-3.

[1252] ESI-MS m / z: 463.19[M+H] + .

[1253] 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, 1H, J=2.8 Hz), 8.23 ​​(s, 2H), 7.66 (dd, 1H, J=2.6, 9.0 Hz), 7.46 (d, 1H, J=7.3 Hz), 7.21 (s, 1H), 7.03 (s, 1H), 6.84 (s, 1H), 6.66 (d, 1H, J=6.9 Hz), 6.52 (d, 1H, J=9.0 Hz), 4.3-4.4 (m, 2H), 4.2-4.3 (m, 2H), 3.07 (s, 3H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.6 (m, 2H), 1.38 (t, 3H, J=7.1 Hz).

[1254]

[1255] Example 86: Synthesis of 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1256]

[1257] 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 86] (53%) was prepared by a method similar to that of Preparation Example 3-3.

[1258] ESI-MS m / z: 430.20[M+H] + .

[1259] 1H NMR (DMSO-d6, 400 MHz) δ 8.47 (d, 1H, J=2.5 Hz), 8.32 (dd, 1H, J=1.4, 4.0 Hz), 8.07 (s, 2H), 7.87 (dd, 1H, J=9.4, 15.8 Hz), 7.87 (dd, 1H, J=9.3, 19.9 Hz), 7.19 (dd, 1H, J=4.0, 9.6 Hz), 7.01 (d, 1H, J=7.3 Hz), 6.91 (d, 1H, J=6.9 Hz), 6.60 (d, 1H, J=9.1 Hz), 4.3-4.4 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.9 (m, 2H), 1.72 (tt, 1H, J=5.1, 8.4 Hz), 1.4-1.6 (m, 2H), 0.8-0.9 (m, 2H), 0.5-0.7 (m, 2H).

[1260]

[1261] Example 87: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[1262]

[1263] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one [Example 87] (51%) was prepared by a method similar to that of Preparation Example 3-3.

[1264] ESI-MS m / z: 474.20[M+H] + .

[1265] 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 2H), 7.88 (d, 1H, J=2.6 Hz), 7.48 (d, 1H, J=7.3 Hz), 7.27 (dd, 1H, J=2.6, 8.9 Hz), 7.22 (s, 1H), 7.03 (s, 1H), 6.91 (d, 1H, J=6.9 Hz), 6.85 (s, 1H), 6.54 (d, 1H, J=8.9 Hz), 4.57 (s, 2H), 4.3-4.4 (m, 2H), 3.80 (t, 2H, J=5.5 Hz), 2.89 (s, 3H), 2.26 (br t, 2H, J=5.4 Hz), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[1266]

[1267] Example 88: Synthesis of 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1268]

[1269] 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 88] (81%) was prepared by a method similar to that of Preparation Example 3-3.

[1270] ESI-MS m / z: 432.22[M+H] + .

[1271] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J=2.63 Hz, 1 H) 8.32 (dd, J=4.00, 1.50 Hz, 1 H) 8.18 (s, 2 H) 7.87 (ddd, J=17.32, 9.32, 2.00 Hz, 2 H) 7.17 - 7.22 (m, 1 H) 7.02 (d, J=7.25 Hz, 1 H) 6.91 (d, J=6.88 Hz, 1 H) 6.60 (d, J=9.01 Hz, 1 H) 4.32 (dquin, J=14.04, 7.00, 7.00, 7.00, 7.00 Hz, 2 H) 2.73 (quin, J=6.94 Hz, 1 H) 2.06 - 2.20 (m, 2 H) 1.83 - 1.95 (m, 2 H) 1.45 - 1.57 (m, 2 H) 1.17 (d, J=6.88 Hz, 6 H).

[1272]

[1273] Example 89: Synthesis of 5-ethoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one

[1274]

[1275] 5-ethoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one [Example 89] (80%) was prepared by a method similar to that of Preparation Example 3-3.

[1276] ESI-MS m / z: 439.25[M+H] + .

[1277] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J=2.50 Hz, 1 H) 8.17 (s, 2 H) 7.66 (dd, J=9.01, 2.63 Hz, 1 H) 7.00 (d, J=7.25 Hz, 1 H) 6.65 (d, J=6.88 Hz, 1 H) 6.52 (d, J=9.01 Hz, 1 H) 4.34 - 4.40 (m, 2 H) 4.21 - 4.34 (m, 2 H) 3.07 (s, 3 H) 2.67 - 2.78 (m, 1 H) 2.05 - 2.18 (m, 2 H) 1.79 - 1.92 (m, 2 H) 1.43 - 1.56 (m, 2 H) 1.38 (t, J=7.07 Hz, 3 H) 1.17 (d, J=7.00 Hz, 6 H).

[1278]

[1279] Example 90: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1280]

[1281] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 90] (31%) was prepared by a method similar to that of Preparation Example 3-3.

[1282] ESI-MS m / z: 424.13[M+H] + .

[1283] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J=2.50 Hz, 1 H) 8.32 (s, 3 H) 7.89 (br dd, J=9.57, 1.19 Hz, 2 H) 7.58 (br d, J=7.13 Hz, 1 H) 7.20 (dd, J=9.63, 4.00 Hz, 2 H) 6.66 (br d, J=8.63 Hz, 1 H) 4.25 - 4.39 (m, 2 H) 2.05 - 2.23 (m, 2 H) 1.82 - 2.00 (m, 2 H) 1.45 - 1.60 (m, 2 H).

[1284]

[1285] Example 91: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one

[1286]

[1287] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one [Example 91] (34%) was prepared by a method similar to that of Preparation Example 3-3.

[1288] ESI-MS m / z: 431.16[M+H] + .

[1289] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 2 H) 8.29 (d, J=2.38 Hz, 1 H) 7.66 (dd, J=9.01, 2.63 Hz, 1 H) 7.56 (d, J=7.25 Hz, 1 H) 6.66 (d, J=6.88 Hz, 1 H) 6.52 (d, J=9.01 Hz, 1 H) 4.36 (q, J=7.00 Hz, 2 H) 4.28 (br dd, J=13.13, 6.50 Hz, 2 H) 3.07 (s, 3 H) 2.03 - 2.19 (m, 2 H) 1.87 (qt, J=12.92; 6.57 Hz, 2 H) 1.42 - 1.59 (m, 2 H) 1.38 (t, J=7.07 Hz, 3 H).

[1290]

[1291] Example 92: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[1292]

[1293] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one [Example 92] (31%) was prepared by a method similar to that of Preparation Example 3-3.

[1294] ESI-MS m / z: 442.17[M+H] + .

[1295] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 2 H) 7.88 (d, J=2.88 Hz, 1 H) 7.57 (d, J=7.25 Hz, 1 H) 7.27 (dd, J=8.88, 2.63 Hz, 1 H) 6.92 (d, J=6.88 Hz, 1 H) 6.54 (d, J=8.88 Hz, 1 H) 4.57 (s, 2 H) 4.25 - 4.36 (m, 2 H) 3.80 (t, J=5.50 Hz, 2 H) 2.89 (s, 3 H) 2.26 (t, J=5.38 Hz, 2 H) 2.07 - 2.17 (m, 2 H) 1.82 - 1.95 (m, 2 H) 1.46 - 1.59 (m, 2 H).

[1296]

[1297] Example 93: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1298]

[1299] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 93] (49%) was prepared by a method similar to that of Preparation Example 3-3.

[1300] ESI-MS m / z: 442.12[M+H] + .

[1301] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=1.75 Hz, 1 H) 8.29 - 8.36 (m, 3 H) 7.84 - 7.94 (m, 2 H) 7.57 (br d, J=7.25 Hz, 1 H) 7.22 (dd, J=9.63, 4.00 Hz, 1 H) 6.91 (br d, J=7.00 Hz, 1 H) 4.47 - 4.58 (m, 1 H) 4.27 - 4.38 (m, 1 H) 2.05 - 2.21 (m, 2 H) 1.95 (br t, J=7.00 Hz, 2 H) 1.48 - 1.66 (m, 2 H).

[1302]

[1303] Example 94: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one

[1304]

[1305] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one [Example 94] (40%) was prepared by a method similar to that of Preparation Example 3-3.

[1306] ESI-MS m / z: 449.15[M+H] + .

[1307] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 2 H) 8.22 (d, J=2.00 Hz, 1 H) 7.68 (dd, J=12.44, 2.06 Hz, 1 H) 7.55 (d, J=7.25 Hz, 1 H) 6.63 (br d, J=6.88 Hz, 1 H) 4.42 - 4.50 (m, 1 H) 4.39 (q, J=7.09 Hz, 2 H) 4.27 - 4.34 (m, 1 H) 3.07 (s, 3 H) 2.07 - 2.15 (m, 2 H) 1.92 (t, J=7.00 Hz, 2 H) 1.48 - 1.62 (m, 2 H) 1.39 (t, J=7.07 Hz, 3 H).

[1308]

[1309] Example 95: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[1310]

[1311] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one [Example 95] (38%) was prepared by a method similar to that of Preparation Example 3-3.

[1312] ESI-MS m / z: 460.16[M+H] + .

[1313] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 2 H) 7.80 (d, J=1.88 Hz, 1 H) 7.56 (d, J=7.13 Hz, 1 H) 7.36 (dd, J=11.88, 2.00 Hz, 1 H) 6.90 (br d, J=6.75 Hz, 1 H) 4.57 (s, 2 H) 4.46 - 4.54 (m, 1 H) 4.28 - 4.36 (m, 1 H) 3.80 (t, J=5.38 Hz, 2 H) 2.92 (s, 3 H) 2.26 (br t, J=5.19 Hz, 2 H) 2.07 - 2.18 (m, 2 H) 1.94 (td, J=6.82, 3.50 Hz, 2 H) 1.50 - 1.65 (m, 2 H).

[1314]

[1315] Example 96: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one

[1316]

[1317] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one [Example 96] (51%) was prepared by a method similar to that of Preparation Example 3-3.

[1318] ESI-MS m / z: 447.14[M+H] + .

[1319] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 2 H) 8.24 (d, J=2.00 Hz, 1 H) 7.72 (dd, J=12.32, 2.06 Hz, 1 H) 7.56 (d, J=7.25 Hz, 1 H) 6.73 (br d, J=6.88 Hz, 1 H) 4.72 (s, 2 H) 4.48 (sxt, J=6.80 Hz, 1 H) 4.31 (sxt, J=6.80 Hz, 1 H) 4.01 (t, J=5.32 Hz, 2 H) 3.64 (t, J=5.32 Hz, 2 H) 2.04 - 2.19 (m, 2 H) 1.92 (t, J=7.13 Hz, 2 H) 1.47 - 1.63 (m, 2 H).

[1320]

[1321] Example 97: Synthesis of 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1322]

[1323] 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 97] (58%) was prepared by a method similar to that of Preparation Example 3-3.

[1324] ESI-MS m / z: 405.13[M+H] + .

[1325] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 2 H) 8.26 (d, J=2.00 Hz, 1 H) 8.16 (s, 1 H) 7.73 (dd, J=12.26, 2.13 Hz, 1 H) 7.56 (d, J=7.13 Hz, 1 H) 6.73 (br d, J=6.88 Hz, 1 H) 4.42 - 4.54 (m, 1 H) 4.31 (sxt, J=6.68 Hz, 1 H) 3.25 (s, 3 H) 2.06 - 2.18 (m, 2 H) 1.92 (t, J=7.13 Hz, 2 H) 1.49 - 1.62 (m, 2 H).

[1326]

[1327] Example 98: Synthesis of 2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1328]

[1329] 2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 98] (59%) was prepared by a method similar to that of Preparation Example 3-3.

[1330] ESI-MS m / z: 450.21[M+H] + .

[1331] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 - 8.44 (m, 1 H) 8.33 (d, J=2.88 Hz, 1 H) 8.18 (s, 2 H) 7.84 - 7.94 (m, 2 H) 7.22 (dd, J=9.63, 4.00 Hz, 1 H) 7.03 (br d, J=7.13 Hz, 1 H) 6.89 (br d, J=6.88 Hz, 1 H) 4.46 - 4.56 (m, 1 H) 4.29 - 4.40 (m, 1 H) 2.73 (dt, J=13.85, 6.89 Hz, 1 H) 2.04 - 2.21 (m, 2 H) 1.93 (br t, J=6.88 Hz, 2 H) 1.46 - 1.66 (m, 2 H) 1.17 (d, J=7.00 Hz, 6 H).

[1332]

[1333] Example 99: Synthesis of 5-ethoxy-2-[5-fluoro-6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one

[1334]

[1335] 5-ethoxy-2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one [Example 99] (14%) was prepared by a method similar to that of Preparation Example 3-3.

[1336] ESI-MS m / z: 457.24[M+H] + .

[1337] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, J=2.00 Hz, 1 H) 8.17 (s, 2 H) 7.68 (dd, J=12.38, 2.00 Hz, 1 H) 6.99 (d, J=7.25 Hz, 1 H) 6.61 (br d, J=6.63 Hz, 1 H) 4.42 - 4.48 (m, 1 H) 4.39 (q, J=7.05 Hz, 2 H) 4.29 - 4.35 (m, 1 H) 3.07 (s, 3 H) 2.73 (dt, J=13.88, 6.94 Hz, 1 H) 2.05 - 2.16 (m, 2H) 1.90 (t, J=7.00 Hz, 2 H) 1.48 - 1.61 (m, 2 H) 1.39 (t, J=7.07 Hz, 3 H) 1.17 (d, J=6.88 Hz, 6 H).

[1338]

[1339] Example 100: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one

[1340]

[1341] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one [Example 100] (60%) was prepared by a method similar to that of Preparation Example 3-3.

[1342] ESI-MS m / z: 474.15[M+H] + .

[1343] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J=1.88 Hz, 1 H) 8.31 - 8.35 (m, 1 H) 8.24 (s, 2 H) 7.86 - 7.93 (m, 2 H) 7.48 (d, J=7.13 Hz, 1 H) 6.83 - 7.27 (m, 3 H) 4.52 (sxt, J=6.88 Hz, 1 H) 4.28 - 4.39 (m, 1 H) 2.07 - 2.20 (m, 2 H) 1.91 - 1.99 (m, 2 H) 1.49 - 1.66 (m, 2 H).

[1344]

[1345] Example 101: Synthesis of 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one

[1346]

[1347] 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one [Example 101] (56%) was prepared by a method similar to that of Preparation Example 3-3.

[1348] ESI-MS m / z: 481.18[M+H] + .

[1349] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 ​​(s, 2 H) 8.22 (d, J=2.00 Hz, 1 H) 7.68 (dd, J=12.38, 2.00 Hz, 1 H) 7.46 (d, J=7.13 Hz, 1 H) 6.82 - 7.24 (m, 1 H) 6.63 (br d, J=6.88 Hz, 1 H) 4.42 - 4.50 (m, 1 H) 4.39 (q, J=7.13 Hz, 2 H) 4.26 - 4.34 (m, 1 H) 3.07 (s, 3 H) 2.07 - 2.18 (m, 2 H) 1.92 (t, J=7.00 Hz, 2 H) 1.48 - 1.63 (m, 2 H) 1.39 (t, J=7.07 Hz, 3 H).

[1350]

[1351] Example 102: Synthesis of 1-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one

[1352]

[1353] 1-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one [Example 102] (50%) was prepared by a method similar to that of Preparation Example 3-3.

[1354] ESI-MS m / z: 476.19[M+H] + .

[1355] 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (br d, 2H, J=16.4 Hz), 8.20 (d, 1H, J=7.3 Hz), 7.89 (d, 1H, J=2.6 Hz), 7.28 (dd, 1H, J=2.6, 8.9 Hz), 6.94 (d, 1H, J=6.9 Hz), 6.55 (d, 1H, J=8.9 Hz), 4.57 (s, 2H), 4.4-4.5 (m, 1H), 4.3-4.4 (m, 1H), 3.80 (t, 2H, J=5.5 Hz), 2.89 (s, 3H), 2.2-2.3 (m, 2H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H).

[1356]

[1357] Example 103: Synthesis of 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one

[1358]

[1359] 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one [Example 103] (28%) was prepared in a manner similar to Preparation Examples 1-4.

[1360] ESI-MS m / z: 412.99[M+H] + .

[1361] 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 2.6 Hz, 1H), 8.20 (s, 2H), 7.95 (d, J = 9.0 Hz, 1H), 6.45 (d, J = 9.1 Hz, 1H), 5.27 (d, J = 7.0 Hz, 1H), 4.45 - 4.36 (m, 1H), 4.20 - 4.12 (m, 1H), 3.85 - 3.80 (m, 2H), 2.88 (dd, J = 8.2, 7.2 Hz, 2H), 2.61 - 2.55 (m, 2H), 2.33 - 2.28 (m, 2H), 2.13 - 1.94 (m, 3H), 1.63 - 1.52 (m, 2H).

[1362]

[1363] Example 104: Synthesis of 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one

[1364]

[1365] 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one [Example 104] (33%) was prepared by a method similar to that of Preparation Examples 1-4.

[1366] ESI-MS m / z: 447.08[M+H] + .

[1367] 1H NMR (500 MHz, CDCl3) δ 8.52 - 8.38 (m, 3H), 7.95 (dd, J = 8.9, 2.5 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.23 (s, 1H), 3.87 - 3.80 (m, 2H), 2.89 (dd, J = 8.3, 7.1 Hz, 2H), 2.64 - 2.55 (m, 2H), 2.38 - 2.28 (m, 2H), 2.14 - 1.93 (m, 3H), 1.63 - 1.58 (m, 2H).

[1368]

[1369] Example 105: Synthesis of 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1370]

[1371] 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 105] (32%) was prepared by a method similar to that of Preparation Example 3-3.

[1372] ESI-MS m / z: 428.99[M+H] + .

[1373] 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 2.6 Hz, 1H), 8.21 (s, 2H), 7.90 (dd, J = 9.0, 2.6 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 5.20 (d, J = 7.1 Hz, 1H), 4.79 (s, 1H), 4.72 (s, 2H), 4.39 (q, J = 6.8 Hz, 1H), 4.21 (t, J = 6.5 Hz, 1H), 4.05 (dd, J = 6.0, 4.6 Hz, 2H), 3.77 (dd, J = 6.1, 4.6 Hz, 2H), 2.36 - 2.27 (m, J = 6.8 Hz, 2H), 2.02 (ddd, J = 10.4, 7.1, 4.9 Hz, 2H), 1.56 (dt, J = 13.0, 6.7 Hz, 2H).

[1374]

[1375] Example 106: Synthesis of 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1376]

[1377] 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 106] (22%) was prepared by a method similar to that of Preparation Example 3-3.

[1378] ESI-MS m / z: 463.15[M+H] + .

[1379] 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.47 (s, 2H), 7.94 (dd, J = 9.0, 2.5 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H), 5.59 (d, J = 7.1 Hz, 1H), 4.72 (s, 2H), 4.51 (q, J = 6.8 Hz, 1H), 4.26 - 4.18 (m, 1H), 4.05 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.37 - 2.31 (m, 2H), 2.12 - 2.00 (m, 3H), 1.64 - 1.57 (m, 2H).

[1380]

[1381] Example 107: Synthesis of 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1382]

[1383] 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 107] (52%) was prepared by a method similar to that of Preparation Examples 1-4.

[1384] ESI-MS m / z: 413.19[M+H] + .

[1385] 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 2.6 Hz, 1H), 8.17 (s, 2H), 7.90 (dd, J = 9.2, 2.6 Hz, 1H), 6.43 (d, J = 9.0 Hz, 1H), 5.10 (d, J = 7.0 Hz, 1H), 4.72 (s, 2H), 4.37 (h, J = 6.8 Hz, 1H), 4.21 (q, J = 6.4 Hz, 1H), 4.05 (dd, J = 6.1, 4.6 Hz, 2H), 3.77 (t, J = 5.4 Hz, 2H), 2.32 (dq, J = 10.3, 4.9 Hz, 2H), 2.08 - 1.95 (m, 3H), 1.56 (d, J = 4.6 Hz, 2H).

[1386]

[1387] Example 108: Synthesis of 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1388]

[1389] 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 108] (51%) was prepared by a method similar to that of Preparation Examples 1-4.

[1390] ESI-MS m / z: 434.22[M+H] + .

[1391] 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 0.8 Hz, 1H), 8.53 - 8.51 (m, 1H), 7.89 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (dt, J = 2.4, 1.0 Hz, 1H), 6.64 (dd, J = 4.6, 1.4 Hz, 1H), 6.61 (dd, J = 4.6, 2.4 Hz, 1H), 6.45 - 6.41 (m, 1H), 4.71 (s, 2H), 4.69 (d, J = 6.8 Hz, 2H), 4.32 (q, J = 6.6 Hz, 1H), 4.22 (q, J = 6.4 Hz, 1H), 4.04 (dd, J = 6.1, 4.6 Hz, 2H), 3.77 (dd, J = 6.1, 4.6 Hz, 2H), 2.38 - 2.29 (m, 2H), 2.07 (t, J = 6.7 Hz, 2H), 1.59 (tdd, J) = 8.4, 7.1, 3.6 Hz, 2H).

[1392]

[1393] Example 109: Synthesis of 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one

[1394]

[1395] 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one [Example 109] (41%) was prepared by a method similar to that of Preparation Examples 1-4.

[1396] ESI-MS m / z: 457.12[M+H] + .

[1397] 1H NMR (500 MHz, CDCl3) δ 8.77 (dd, J = 2.6, 0.7 Hz, 1H), 8.51 (s, 2H), 8.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.22 - 7.13 (m, 2H), 6.59 - 6.53 (m, 1H), 6.51 (dd, J = 9.0, 0.8 Hz, 1H), 5.61 (d, J = 7.3 Hz, 1H), 4.87 (s, 1H), 4.60 - 4.50 (m, 1H), 4.37 - 4.24 (m, 1H), 2.45 - 2.31 (m, 2H), 2.18 - 2.02 (m, 2H), 1.69 - 1.58 (m, 2H).

[1398]

[1399] Example 110: Synthesis of 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one

[1400]

[1401] 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one [Example 110] (37%) was prepared by a method similar to that of Preparation Examples 1-4.

[1402] ESI-MS m / z: 423.03[M+H] + .

[1403] 1H NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 2.7, 0.7 Hz, 1H), 8.24 (s, 2H), 8.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.21 - 7.13 (m, 2H), 6.59 - 6.53 (m, 1H), 6.50 (dd, J = 9.0, 0.8 Hz, 1H), 5.23 (d, J = 7.1 Hz, 1H), 4.85 (s, 1H), 4.49 - 4.38 (m, 1H), 4.31 - 4.23 (m, 1H), 2.41 - 2.29 (m, 2H), 2.14 - 2.02 (m, 2H), 1.66 - 1.55 (m, 2H).

[1404]

[1405] Example 111: Synthesis of 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one

[1406]

[1407] 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one [Example 111] (31%) was prepared by a method similar to that of Preparation Examples 1-4.

[1408] ESI-MS m / z: 407.09[M+H] + .

[1409] 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J = 2.5 Hz, 1H), 8.20 (s, 2H), 8.14 (dd, J = 9.0, 2.7 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.21 - 7.14 (m, 2H), 6.59 - 6.54 (m, 1H), 6.51 (d, J = 9.1 Hz, 1H), 5.14 (d, J = 7.0 Hz, 1H), 4.98 (s, 1H), 4.47 - 4.37 (m, 1H), 4.32 - 4.22 (m, 1H), 2.44 - 2.28 (m, 2H), 2.14 - 2.01 (m, 2H), 1.70 - 1.55 (m, 2H).

[1410]

[1411] Example 112: Synthesis of 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one

[1412]

[1413] 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one [Example 112] (24%) was prepared by a method similar to that of Preparation Examples 1-4.

[1414] ESI-MS m / z: 397.11[M+H] + .

[1415] 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 2.6 Hz, 1H), 8.17 (s, 2H), 7.90 (dd, J = 8.9, 2.6 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 5.12 (d, J = 7.0 Hz, 1H), 4.43 - 4.32 (m, 1H), 4.23 - 4.12 (m, 1H), 3.83 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.64 - 2.54 (m, 2H), 2.37 - 2.26 (m, 2H), 2.09 - 1.97 (m, 3H), 1.63 - 1.50 (m, 2H).

[1416]

[1417] Example 113: Synthesis of 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one

[1418]

[1419] 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one [Example 113] (19%) was prepared by a method similar to that of Preparation Examples 1-4.

[1420] ESI-MS m / z: 420.02[M+H] + .

[1421] 1H NMR (500 MHz, CDCl3) δ 8.53 - 8.47 (m, 1H), 8.02 (s, 1H), 7.88 (dd, J = 9.0, 2.6 Hz, 1H), 6.41 (d, J = 8.9 Hz, 1H), 5.15 (s, 1H), 4.61 (s, 1H), 4.53 - 4.46 (m, 1H), 4.28 - 4.21 (m, 1H), 3.86 - 3.80 (m, 2H), 2.88 (dd, J = 8.3, 7.2 Hz, 2H), 2.60 (d, J = 15.4 Hz, 3H), 2.40 - 2.29 (m, 2H), 2.10 - 2.02 (m, 2H), 2.01 - 1.92 (m, 1H), 1.59 - 1.58 (m, 2H), 1.12 - 1.05 (m, 2H), 1.05 - 0.98 (m, 2H).

[1422]

[1423] Example 114: Synthesis of 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one

[1424]

[1425] 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one [Example 114] (18%) was prepared by a method similar to that of Preparation Examples 1-4.

[1426] ESI-MS m / z: 486.12[M+H] + .

[1427] 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 7.0 Hz, 1H), 7.91 (d, J = 9.5 Hz, 1H), 7.66 (s, 1H), 6.99 (dd, J = 7.1, 1.9 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.67 (d, J = 6.9 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.26 - 4.20 (m, 1H), 3.87 - 3.80 (m, 2H), 2.89 (dd, J = 8.3, 7.2 Hz, 2H), 2.64 - 2.54 (m, 2H), 2.42 - 2.33 (m, 2H), 2.19 - 2.00 (m, 3H), 1.66 - 1.62 (m, 2H).

[1428]

[1429] Example 115: Synthesis of 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one

[1430]

[1431] 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one [Example 115] (48%) was prepared by a method similar to that of Preparation Examples 1-4.

[1432] ESI-MS m / z: 418.14[M+H] + .

[1433] 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.49 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 9.0, 2.6 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 4.6, 1.5 Hz, 1H), 6.62 (dd, J = 4.6, 2.4 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 6.6 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.22 - 4.16 (m, 1H), 3.83 (t, J = 7.1 Hz, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 - 2.54 (m, 2H), 2.39 - 2.32 (m, 2H), 2.13 - 1.96 (m, 3H), 1.67 - 1.56 (m, 2H).

[1434]

[1435] Example 116: Synthesis of 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1436]

[1437] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 116] (42%) was prepared by a method similar to that of Preparation Examples 1-4.

[1438] ESI-MS m / z: 451.83[M+H] + .

[1439] 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 2.6 Hz, 1H), 8.25 (t, J = 6.4 Hz, 1H), 7.88 (dd, J = 9.0, 2.6 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.61 (td, J = 7.4, 2.6 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 4.72 (s, 2H), 4.69 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.30 (q, J = 6.8 Hz, 1H), 4.26 - 4.20 (m, 1H), 4.05 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.34 (dt, J = 10.6, 6.0 Hz, 2H), 2.07 (dq, J = 14.3, 7.5, 7.1 Hz, 2H), 1.59 (dt, J) = 14.1, 8.9 Hz, 2H).

[1440]

[1441] Example 117: Synthesis of 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1442]

[1443] 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 117] (32%) was prepared by a method similar to that of Preparation Examples 1-4.

[1444] ESI-MS m / z: 502.20[M+H] + .

[1445] 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.41 (d, J = 7.1 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.66 (s, 1H), 6.98 (d, J = 6.5 Hz, 1H), 6.43 (d, J = 8.9 Hz, 1H), 4.72 (s, 2H), 4.65 (s, 2H), 4.34 (d, J = 6.7 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.05 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.36 (s, 2H), 2.16 - 2.06 (m, 2H), 1.41 (d, J = 15.7 Hz, 2H).

[1446]

[1447] Example 118: Synthesis of 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1448]

[1449] 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 118] (48%) was prepared by a method similar to that of Preparation Examples 1-4.

[1450] ESI-MS m / z: 436.32[M+H] + .

[1451] 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 2.6 Hz, 1H), 8.02 (s, 1H), 7.87 (dd, J = 8.9, 2.6 Hz, 1H), 6.41 (d, J = 9.0 Hz, 1H), 5.28 (s, 1H), 4.71 (s, 2H), 4.67 (d, J = 6.8 Hz, 1H), 4.49 (q, J = 6.8 Hz, 1H), 4.25 (q, J = 6.5 Hz, 1H), 4.04 (dd, J = 6.0, 4.7 Hz, 2H), 3.77 (dd, J = 6.2, 4.5 Hz, 2H), 2.39 - 2.30 (m, 2H), 2.06 (td, J = 6.8, 2.2 Hz, 2H), 1.96 (ddd, J = 8.3, 6.6, 4.2 Hz, 1H), 1.59 (dtd, J = 14.4, 8.7, 6.3 Hz, 2H), 1.08 (qd, J = 4.9, 2.0 Hz, 2H), 1.05 - 0.99 (m, 2H).

[1452]

[1453] Example 119: Synthesis of 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one

[1454]

[1455] 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one [Example 119] (32%) was prepared by a method similar to that of Preparation Examples 1-4.

[1456] ESI-MS m / z: 434.15[M+H] + .

[1457] 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 2.6 Hz, 1H), 8.31 (dt, J = 6.7, 1.1 Hz, 1H), 7.88 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 - 7.33 (m, 2H), 6.78 (td, J = 6.6, 1.8 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 4.71 (s, 3H), 4.59 (d, J = 7.1 Hz, 1H), 4.34 (q, J = 6.7 Hz, 1H), 4.23 (q, J = 6.5 Hz, 1H), 4.04 (dd, J = 6.1, 4.6 Hz, 2H), 3.76 (dd, J = 6.1, 4.6 Hz, 2H), 2.35 (td, J = 10.6, 5.6 Hz, 2H), 2.14 - 2.04 (m, 2H), 1.67 - 1.55 (m, 2H).

[1458]

[1459] Example 120: Synthesis of 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one

[1460]

[1461] 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one [Example 120] (13%) was prepared by a method similar to that of Preparation Examples 1-4.

[1462] ESI-MS m / z: 418.12[M+H] + .

[1463] 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 6.7 Hz, 1H), 7.88 (dd, J = 9.0, 2.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.81 - 6.77 (m, 1H), 6.42 (d, J = 8.9 Hz, 1H), 4.69 (s, 1H), 4.53 (d, J = 7.0 Hz, 1H), 4.34 (q, J = 6.6 Hz, 1H), 4.23 (s, 1H), 3.86 - 3.80 (m, 2H), 2.88 (dd, J = 8.3, 7.2 Hz, 2H), 2.58 (p, J = 7.4 Hz, 2H), 2.34 (tt, J = 12.6, 6.2 Hz, 2H), 2.14 - 2.05 (m, 2H), 1.58 (dd, J = 13.5, 8.0 Hz, 2H).

[1464] The following experiment was conducted on the example manufactured as described above.

[1465]

[1466] biological test

[1467] Experimental Example 1: Analysis of PCSK9 Ligand Binding Affinity

[1468] The PCSK9 binding of the compounds of the present invention was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. This TR-FRET assay measures the ability of the compounds of the present invention to compete for binding to a probe labeled with Alexa Fluor 647 against the recombinant protein of human PCSK9.

[1469] The experimental setup of the present invention is as follows. First, a solution containing PCSK9 and Streptavidin Europium (Strep-Eu) was prepared. To this end, Biotinylated PCSK9 at a concentration of 2 nM and Lance Strep-Eu at a concentration of 90 ng / mL were dissolved in a buffer composed of 50 mM HEPES (pH 7.4), 0.15 M NaCl, 5 mM CaCl, 0.01% BSA, and 0.01% Tween 20. A probe solution at a concentration of 60 nM was also prepared separately using the same buffer.

[1470] To perform the analysis, 15 μL of a mixed solution of biotinylated PCSK9 and Strep-Eu and 5 μL of the test compound were sequentially added to the plate. Subsequently, 10 μL of the probe solution was added to make the total reaction volume 30 μL. The concentrations of the final solution were PCSK9 0.5 nM, Strep-Eu 22.5 ng / mL, and probe 20 nM.

[1471] After reacting the reaction mixture at room temperature for at least 2 hours, the fluorescence signal was measured using an EnVision Multimode Plate Reader. Based on the experimental data, IC 50 The values ​​were derived through non-linear regression (sigmoidal dose-response curve), and the Ki values ​​were calculated using the probe's Km values; the results are shown in Table 1. In Table 1 below, A to D represent the PCSK9 binding strength (nM) and each signifies the following.

[1472] A: PCSK9 bonding strength (nM) Ki ≤ 100

[1473] B: PCSK9 bonding strength (nM) 100 ≤ Ki < 1000

[1474] C: PCSK9 bonding strength (nM) 1000 ≤ Ki < 10000

[1475] D: PCSK9 bond strength (nM) 10000 ≤ Ki

[1476]

[1477] Example Ki (nM) Example Ki (nM)1A61A2A62A3A63A4A64A5A65A6A66A7A67A8A68A9A69A10B70A11A71A12A72A13A73A14A74A15C75A16C76A17A 77A18A78A19A79A20A80A21A81A22A82A23A83A24A84A25A85A26A86A27A87A28A88A29A89A30A90A31A91A32A92A3 3A93A34A94A35A95A36A96A37A97A38A98A39A99A40A100A41A101A42A102A43A103A44A104A45A105A46A106A47A1 07A48A108A49A109A50A110A51A111A52A112A53A113A54A114A55A115A56A116A57A117A58A118A59A119A60A120A

[1478] Experimental Example 2: Evaluation of the efficacy of improving LDL-C absorption by PCSK9 inhibition

[1479] Human liver cells (HepG2) express LDL-C receptors and can absorb LDL-C into the cell; PCSK9 binds to LDL-C receptors, is internalized into the cell, and is degraded in lysosomes, thereby reducing the cellular LDL-C receptors and decreasing the intracellular absorption of LDL-C. The efficacy of the compounds of the present invention in improving LDL-C absorption by inhibiting PCSK9 was measured in HepG2 cells using fluorescently labeled LDL-C.

[1480] The experimental setup of the present invention is as follows. 2.5 x 10⁶ HepG2 cells in a 96-well plate 5Cells were seeded at a density of 10% FBS (Fetal Bivine Serum, Hyclone Inc.) and 5% Penicillin / streptomycin (WelGENE Inc.) in MEM (Minimum Essential Medium Eagle, WelGENE Inc.) and incubated overnight. The medium was replaced with 0.3% BSA (Bovine serum albumin, Gibco) in MEM serum-free media, and 2 pg / ml of recombinant human PCSK9 was added along with 50 μM of the test substance. After incubation for 24 hours, 10 pg / ml of bodily FL LDL (Invitrogen TM ...) was added and cultured for 4 more hours. Cell samples were analyzed for LDL-C uptake using a flow cytometer. For each treatment condition, the LDL-C uptake level was calculated as a % value, with the value of the control group not treated with PCSK9 set to 100% and the value of the group treated only with PCSK9 set to 0%. The results are shown in Table 2.

[1481] Cell activity evaluation example LDL-C uptake (%) example LDL-C uptake(%)1124.97042.7256.17156.2355.073101.2461.07439.7545.8 7561.76172.47680.7788.17830.18197.67996.8987.781111.02091.882 73.52250.38350.82354.28471.72479.286162.225157.28871.726157. 28965.82754.49225.429118.49331.93349.29521.33582.19768.13821. 598163.54122.89962.94441.110048.04540.410157.746297.810324.647232.710437.448188.410584.64962.41061185083.1109153.351128.0110140.652260.511232.954144.111337.95645.011422.957110.0116112.558163.011744.15949.6118108.960140.111954.862178.1120127.1

Claims

Compounds represented by the structure of Chemical Formula 1 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts: [Chemical Formula 1] In the above formula A is a tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring, wherein the tetrocycloalkyl, tetroaryl, or 7-to-12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S; L is a 6-membered heteroarylene comprising 1 to 3 heteroatoms that are bonded or substituted or unsubstituted and selected from the group consisting of N, O, and S; B is a 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring, wherein the 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, or 7- to 12-membered heterobicyclic ring comprises 1 to 4 selected from the group consisting of N, O, and S; R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Each is independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos; R2 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Aryl, 4- to 12-membered heteroaryl, halo, -NH-C(=O)-R 3, Each is independently selected from the group consisting of -C(=O)-NH-(CH2)p-OR3 or -C(=O)OR3, wherein p is an integer from 0 to 3, and R3 is hydrogen or C 1-6 It is alkyl; n is an integer from 0 to 4; m is an integer from 0 to 4. In paragraph 1, The above A is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring comprises 1 to 3 selected from the group consisting of N, O, and S. Compound, pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant. In paragraph 1, A is a compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant selected from the group consisting of the following: , , , , , , , , , , , , In paragraph 1, R1 is hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-4 Thioalkyl, C 3-4 Cycloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, oxo, deuterium, deuteride C 1-4 Alkyl, quaternary to hexavalent heterocycloalkyl, C 6-10 A compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant thereof, each independently selected from the group consisting of aryls, tetroaryls, and halos, wherein the tetrocycloalkyl or tetroaryls comprises 1 to 3 selected from the group consisting of N, O, and S. In paragraph 1, L is bonded, or deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 A compound, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant thereof, which is a pyridineylene substituted or unsubstituted with a hydroxyalkyl group. In paragraph 1, B is a 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring, wherein the 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 7- to 9-membered heterobicyclic ring comprises 1 to 3 selected from the group consisting of N, O, and S. Compound, pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotopic variant. In paragraph 1, R2 is any one of the following: a compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant: . In paragraph 1, B-(R2) m A compound, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotope variant selected from the group consisting of: In the above formula, R2 and m are as defined in Paragraph 1, and V is selected from the group consisting of C, O, S, and N, and If there are multiple R2s, each R2 may be the same or different from the others. In paragraph 1, B-(R2) m A compound, a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, hydrate, solvate, polymorph, or isotope variant selected from the group consisting of: , , , , , , , , , , , , , , , , , , . , , , . Compounds represented by the structure of Chemical Formula 1-1 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts: [Chemical Formula 1-1] In the above formula, The definitions of A, R1 and n are identical to the definitions in Paragraph 1; V is C, O, S, or N, and represents a single or double bond, wherein if V is O and S, R4 does not exist; The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, or R4 and R5 or R5 and R6 together comprise a 4- to 7-membered heterocycle or C comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S. 4-8 Forms a cycloalkyl group, wherein the above 4 to 7-membered heterocycle or C 4-8 The cycloalkyl group of can be unsubstituted or substituted by 1 to 3 R7 groups, and R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and R9 is hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl. In Paragraph 10, is any one selected from the group consisting of: a compound, its optical isomer, solvate, isotopic variant, or pharmaceutically acceptable salt: In the above formula, The above R4 to R6 are independently hydrogen, iodine, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, 4 to 12 heteroaryls, and halos, and p is an integer from 0 to 4. Compounds represented by the structures of Chemical Formula 1-2 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts: [Chemical Formula 1-2] In the above formula, The definitions of A, R1 and n are identical to the definitions in Paragraph 1; D is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of; V is C, O, S, N and; R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos; R9 is hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl; and p is an integer from 0 to 4. Compounds represented by the structures of Chemical Formulas 1-3 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts: [Chemical Formula 1-3] In the above formula, The definitions of A, R1 and n are identical to the definitions in Paragraph 1; E is a 4 to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or C 4-8 It is a cycloalkyl of; V is C, O, S, or N; R7 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos; R9 is hydrogen, deuterium (also referred to as "D" below), halo, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or C 1-4 It is a hydroxyalkyl; and p is an integer from 0 to 4. Compounds represented by the structures of Chemical Formulas 1-4 below, their optical isomers, solvates, isotopic variants, or pharmaceutically acceptable salts: [Chemical Formula 1-4] In the above formula, The definitions of A, R1 and n are identical to the definitions in Paragraph 1; V is C, O, S, or N; R8 is hydrogen, iodine, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Thioalkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Thioalkyl halides, carbonyl, acetyl, hydroxy, cyano, nitro, amino, thio, deuterium, deuteride C 1-6 Alkyl, quaternary to 12-membered heterocycloalkyl, C 6-10 Independently selected from the group consisting of aryls, quaternaryls to 12 heteroaryls, and halos; q is an integer from 0 to 4. In paragraph 1, The compound represented by the above chemical formula 1 is a compound selected from the group consisting of the compounds of 1 to 120 below, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a hydrate, a solvate, a polymorph, or an isotope variant: Compound 1: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; Compound 2: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one; Compound 3: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 4: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 5: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one; Compound 6: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one; Compound 7: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,5-dimethylpyrazole-3-one; Compound 8: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; Compound 9: 1-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one; Compound 10: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 11: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 12: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 13: 2-[6-[[(1S,3S)-3-(5,7-dihydrothieno[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 14: 2-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 15: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-1,3-benzothiazole-6-carboxylic acid; Compound 16: 2-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-N-(2-hydroxyethyl)-1,3-benzothiazole-6-carboxamide; Compound 17: 2-[6-[[(1S,3S)-3-[[5-(2-oxozetidine-1-yl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 18: 1-[6-[[(1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridin-2-one; Compound 19: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]pyridazine-3-one; Compound 20: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one; Compound 21: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-diethyl-1,2,4-triazole-3-one; Compound 22: 2-[6-[,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one; Compound 23: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one Compound 24: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methyl-1-propan-2-ylpyrazole-3-one; Compound 25: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 26: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 27: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclophen [Tyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3one Compound 28: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 29: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 30: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 31: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 32: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 33: 2-[6-[[(1S,3S)-3-[(5-ethynylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one; Compound 34: 2-[6-[[(1S,3S)-3-[(5-methylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 35: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one; Compound 36: 2-[6-[[(1S,3S)-3-(6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one; Compound 37: 2-[6-[[(1S,3S)-3-(5,7-dihydrofuro[3,4-d]pyrimidine-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one; Compound 38: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one; Compound 39: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one; Compound 40: 2-[6-[[(1S,3S)-3-[[5-(difluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one; Compound 41: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxtazine-3-one; Compound 42: 2-[6-[[(1S,3S)-3-(6,7-dihydrothieno[3,2-d]pyrimidine-2-ylamino)cyclopentyl]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 43: 2-[6-[[(1S,3S)-3-[(5-chloropyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 44: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 45: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-one; Compound 46: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one; Compound 47: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-ethyl-1,2,4-triazole-3-one; Compound 48: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one; Compound 49: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one; Compound 50: 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-one; Compound 51: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 52: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one; Compound 53: 2-[6-[[(1S,3S)-3-[[5-(2,2,2-trifluoroethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxin-3-one; Compound 54: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 55: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one; Compound 56: 2-[6-[[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 57: 2-[6-[[(1S,3S)-3-[(5-chlorpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 58: 4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 59: 2-[6-[[(1S,3S)-3-[(5-ethenylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 60: 4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 61: 2-[6-[[(1S,3S)-3-[(5-methylpyrazine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 62: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one; Compound 63: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-methoxy-4-methyl-1,2,4-triazole-3-one; Compound 64: 5-methoxy-4-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 65: 5-methoxy-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 66: 2-[6-[[(1S,3S)-3-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 67: tert-butyl 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-oxo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate; Compound 68: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-one; Compound 69: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine-3-one; Compound 70: 2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4,5-dimethyl-1,2,4-triazole-3-one; Compound 71: 4-ethyl-2-[6-[[(1S,3S)-3-[(5-methoxypyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 72: 2-[6-[[(1S,3S)-3-([1,3]oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 73: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one; Compound 74: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-(methoxymethyl)-4-methyl-1,2,4-triazole-3-one; Compound 75: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 76: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 77: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 78: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 79: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 80: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 81: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-propan-2-ylpyrazole-3-one; Compound 82: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-ethylpyrazole-3-one; Compound 83: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 84: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one; Compound 85: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one; Compound 86: 2-[6-[[(1S,3S)-3-[(5-cyclopropylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 87: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one; Compound 88: 2-[6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 89: 5-ethoxy-4-methyl-2-[6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1,2,4-triazole-3-one; Compound 90: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 91: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one; Compound 92: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one; Compound 93: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 94: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one; Compound 95: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-1-methyl-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one; Compound 96: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-one; Compound 97: 2-[6-[[(1S,3S)-3-[(5-chloropyrimidine-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 98: 2-[5-fluoro-6-[[(1S,3S)-3-[(5-propane-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 99: 5-ethoxy-2-[5-fluoro-6-[[(1S,3S)-3-[(5-propan-2-ylpyrimidine-2-yl)amino]cyclopentyl]amino]-3-pyridinyl]-4-methyl-1,2,4-triazole-3-one; Compound 100: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine-3-one; Compound 101: 2-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidine-2-yl]amino]cyclopentyl]amino]-5-fluoro-3-pyridinyl]-5-ethoxy-4-methyl-1,2,4-triazole-3-one; Compound 102: 1-methyl-2-[6-[[(1S,3S)-3-[[5-(trifluoromethyl)pyrimidine-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-3-one; Compound 103: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one; Compound 104: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one; Compound 105: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 106: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 107: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 108: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 109: 2-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one; Compound 110: 2-(6-(((1S,3S)-3-((5-chloropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one; Compound 111: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(4H)-one; Compound 112: 2-(6-(((1S,3S)-3-((5-fluoropyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one; Compound 113: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one; Compound 114: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one; Compound 115: 2-(6-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-one; Compound 116: 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one Compound 117: 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 118: 2-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; Compound 119: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazine-5-one; and Compound 120: 2-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridine-2-ylamino)cyclopentyl)amino)pyridine-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazolo-5-one. A pharmaceutical composition for the prevention or treatment of PCSK9-related diseases, comprising as an active ingredient a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof. In Paragraph 16, A pharmaceutical composition in which PCSK9-related diseases are lipid or lipoprotein metabolic disorders. In Paragraph 17, Lipid or lipoprotein metabolic disorders include atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmias, low HDL levels, high LDL levels, sudden death, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, and chronic Chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, arterial occlusive disease,A pharmaceutical composition comprising one or more selected from the group consisting of cerebral arteriosclerosis, cerebrovascular disorder, myocardial ischemia, nonalcoholic steatohepatitis (NASH), and diabetic autonomic neuropathy. In Paragraph 16, The above pharmaceutical composition is a pharmaceutical composition that inhibits the activity of PCSK9. A composition for inhibiting the activity of PCSK9, comprising as an active ingredient a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof. A composition for promoting lipid or lipoprotein metabolism, comprising as an active ingredient a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof. A pharmaceutical composition for co-administration for the prevention or treatment of PCSK9-related diseases, comprising as an active ingredient a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps: A first step of preparing an example represented by Chemical Formula 3 by SnAr reaction of 2-fluoro-5-iodopyridine with an example represented by Chemical Formula 2 above; A second step of preparing an example represented by Chemical Formula 5 by subjecting an example represented by Chemical Formula 3 and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction; A third step of preparing an example represented by Chemical Formula 6 by reacting an example represented by Chemical Formula 5 with trifluoroacetic acid for deprotection; Step 4, preparing an example represented by Chemical Formula 1-1' by SnAr reaction of an example represented by Chemical Formula 6 and an example represented by Chemical Formula 7, [Chemical Formula 1-1'] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] In the above reaction equation, A, V, R1, R4, R5, R6, R9, and n are as defined in Clause 9. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps: Step 1' of preparing an example represented by Chemical Formula 8 by subjecting 2-fluoro-5-iodopyridine and an example represented by Chemical Formula 4 to a Suzuki reaction or a Ullmann reaction; Step 2' of preparing an example represented by Chemical Formula 1-1' by subjecting an example represented by Chemical Formula 8 and an example represented by Chemical Formula 9 to a Suzuki reaction or a Ullmann reaction, [Chemical Formula 1-1'] [Chemical Formula 4] [Chemical Formula 8] [Chemical Formula 9] In the above reaction equation, A, V, R1, R4, R5, R6, R9 and n are as defined in Clause 10. A method for preparing a compound represented by the chemical formula 1-1', comprising the following steps: A first “step” of preparing an example represented by Chemical Formula 10 by reacting the example represented by Chemical Formula 3 with trifluoroacetic acid for deprotection; A second “step” of preparing an example represented by Chemical Formula 11 by SnAr reaction between an example represented by Chemical Formula 10 below and an example represented by Chemical Formula 7 above; A third step of preparing an example represented by Chemical Formula 1-1 by subjecting an example represented by Chemical Formula 11 to a Suzuki reaction or a Ullmann reaction with an example represented by Chemical Formula 4, [Chemical Formula 1-1'] [Chemical Formula 3] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 10] [Chemical Formula 11] In the above reaction equation, A, V, R1, R4, R5, R6, R9 and n are as defined in Clause 10. A method for the prevention or treatment of PCSK9-related diseases, comprising the step of administering to an individual a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer thereof. Use of a compound of any one of claims 1 to 15, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer for the prevention or treatment of PCSK9-related diseases. Use of a compound of any one of claims 1 to 15, its pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopic variant, enantiomer, or diastereomer in the preparation of a pharmaceutical composition for the prevention or treatment of PCSK9-related diseases.

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