Halogenated allylamine compounds and their applications

Abstract

The present invention relates to the field of pharmaceutical technology, specifically to halogenated allylamine compounds or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof, as well as pharmaceutical formulations and compositions containing these compounds and their application in the prevention and / or treatment of diseases associated with or induced by SSAO / VAP-1 protein. JPEG2022517085000369.jpg4273 (where R1, R2, R3, R4, R5, R6, L1, and Cy1 are as defined in the specification.)

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to halogenated allylamine compounds or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof, as well as pharmaceutical preparations and compositions containing these compounds, and their application in the prevention and / or treatment of diseases associated with or induced by SSAO / VAP-1 protein. [Background technology]

[0002] Semicarbazide-sensitive amine oxidase (SSAO) is an amine oxidase that is particularly sensitive to semicarbazide and is widely distributed throughout the body, including in cell membranes and plasma. SSAO is present in endothelial cells as vascular adhesion protein-1 (VAP-1). At present, the physiological function of SSAO in the body is thought to be primarily involved in amine metabolism, such as catalyzing the oxidative dehydrogenation of short-chain primary amines, such as methylamine and aminoacetone, to produce aldehydes, hydrogen peroxide, and ammonia. The SSAO structure contains a divalent copper ion and a quinonyl group as a coenzyme. SSAO does not have a dedicated substrate and primarily targets aliphatic and aromatic primary amines.

[0003] WO 2013163675A1 discloses 3-halogenated allylamine derivatives represented by formula I as SSAO / VAP-1 inhibitors having inhibitory activity against the SSAO / VAP-1 enzyme, and specifically discloses compound 23, also known as PXS-4728, having the following structure:

[0004] [ka]

[0005] At present, there are no commercially available SSAO / VAP-1 inhibitors. However, the SSAO / VAP-1 inhibitor of the present invention has good applicability because it can be used to effectively alleviate symptoms and lesions of ataxic conditions associated with overexpression of SSAO / VAP-1 in multiple types of diseases. Summary of the Invention

[0006] The applicant of the present invention has conducted in-depth studies in light of the above-mentioned problems in the art, and as a result, has developed novel halogenated allylamine compounds (hereinafter also referred to as "compounds according to the present invention") or pharmaceutically acceptable salts, esters, stereoisomers, and tautomers thereof as SSAO / VAP-1 inhibitors. These inhibitor compounds exhibit excellent inhibitory activity against SSAO / VAP-1 protein and are therefore applicable to the prevention and / or treatment of diseases associated with or induced by SSAO / VAP-1 protein.

[0007] Furthermore, the SSAO / VAP-1 inhibitor compounds of the present invention exhibit superior selective inhibitory effects on SSAO / VAP-1 protein compared to rhAOC1 protein and MAO protein, and therefore can prevent and / or treat diseases associated with or induced by SSAO / VAP-1 protein without causing any unwanted side effects.

[0008] Furthermore, the SSAO / VAP-1 inhibitor compounds of the present invention are less likely to pass through the blood-brain barrier than existing pharmaceuticals, and therefore have an extremely low risk of toxicity to the nervous system, demonstrating excellent pharmaceutical safety.

[0009] The present invention specifically provides the following embodiments.

[0010] Embodiment 1. A compound represented by Formula I below, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof:

[0011] [ka]

[0012] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0013] R3 and R4 are each independently hydrogen, C optionally substituted with a substituent A 1-6 or forms, together with the nitrogen atom bonded thereto, a nitrogen-containing 5- to 10-membered heterocyclic group optionally substituted with a substituent A.

[0014] R5 and R6 are each independently hydrogen, C optionally substituted with a substituent A; 1-6 It is selected from alkyl groups.

[0015] L1 is a bond, -CR'R''-, -NR'-, -S-, -SO2-, -S(O)-, -SONR'-, -SON2NR'-, or -NR'CONR'-, and R' and R'' are each independently hydrogen, C optionally substituted with a substituent A; 1-6 It is selected from alkyl groups.

[0016] C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (A), (a), (b) or (c) substituted with

[0017] [ka]

[0018] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0019] Y1, Y2, Y3, and Y4 are each independently CR c R c , N.R. d , O, and S.

[0020] X1, X2, X3, X4, X9, X 10 are each independently CR c R c , N.R.d , O, S, and X5, X6, X7, and X8 are each independently selected from CR c R c , N.R. d and at least one of X1, X2, and X3 is NR d is.

[0021] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 2-6 alkenyl group, optionally one or more R b C replaced with 2-6 an alkynyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 an alkylthio group, optionally one or more R b C replaced with 1-6 Alkylthio C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more Rb (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminosulfonyl group, optionally one or more R b (C 1-6 alkyl)2aminosulfonyl group, optionally one or more R b C replaced with 1-6 Alkylaminosulfonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2aminosulfonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylsulfonylamino group, optionally one or more R b C replaced with 1-6 Alkyl sulfonyl amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylsulfonyl group, optionally one or more R b C replaced with 1-6 Alkyl Sulfonyl C 1-6 alkyl group, optionally one or more R bCy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0022] Each Cy2 is independently selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 14-membered heteroaryl group.

[0023] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl group, (C 1-6 alkyl)2 aminosulfonyl group, C 1-6Alkylsulfonylamino group, C 1-6 alkylsulfonyl groups.

[0024] The substituents A each independently represent a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl group, (C 1-6 Alkyl)2 aminosulfonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, C 1-6 Alkylsulfonyl group, C 1-6 It is selected from an alkylthio group, a 3- to 12-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 12-membered heterocyclic group, a 5- to 14-membered heteroaryl group, and an oxo group.

[0025] R c is absent, or each occurrence is independently selected from a hydrogen atom, or two R c forms an oxo group.

[0026] R d is absent, or each occurrence is independently selected from a hydrogen atom.

[0027] [ka]

[0028] represents a single or double bond.

[0029] [ka]

[0030] indicates an optional double bond moiety in the ring structure.

[0031] As a condition, C y1 is formula (c), then formula (c) is one or more R a is replaced by

[0032] As a condition, C y1 is formula (b), X1, X2, X3, X9, X 10 is not C=O.)

[0033] Embodiment 2. A compound according to embodiment 1 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0034] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0035] R3 and R4 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0036] R5 and R6 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0037] L1 is a bond, -CR'R''-, -NR'-, or -S-, and R' and R'' are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0038] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0039] Y1, Y2, Y3, and Y4 are each independently CR c R c , N.R. d Selected from.

[0040] X1, X2, X3, X4, X9, X 10 are each independently CR c R c , N.R. d and at least one of X1, X2, and X3 is NR d is.

[0041] X5, X6, X7, and X8 are each independently CR c R c , N.R. d Selected from.

[0042] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 an alkylthio group, optionally one or more R b C replaced with 1-6 Alkylthio C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0043] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group.

[0044] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0045] The substituents A each independently represent a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, C 1-6It is selected from an alkylthio group, a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, a 5- to 10-membered heteroaryl group, and an oxo group.

[0046] Preferably, each R a are each independently a hydroxyl group, an amino group, a cyano group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-4 alkyl group, optionally one or more R b C replaced with 1-4 an alkoxy group, optionally one or more R b C replaced with 1-4 Alkoxy C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 Alkoxy C 1-4 an alkoxy group, optionally one or more R b C replaced with 1-4 an alkylthio group, optionally one or more R b C replaced with 1-4 Alkylthio C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylamino group, optionally one or more R b (C 1-4 alkyl)2 amino group, optionally one or more R b C replaced with 1-4 Alkylamino C 1-4 alkyl group, optionally one or more R b (C 1-4 Alkyl)2amino C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylaminocarbonyl group, optionally one or more R b (C 1-4 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-4 Alkylaminocarbonyl C 1-4 alkyl group, optionally one or more R b (C 1-4Alkyl)2 Aminocarbonyl C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylcarbonylamino group, optionally one or more R b C replaced with 1-4 Alkylcarbonylamino C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylcarbonyl group, optionally one or more R b C replaced with 1-4 Alkyl carbonyl C 1-4 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-4 alkyl group, optionally one or more R b Cy2-C substituted with 1-4 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0047] Preferably, each R b are each independently a hydroxyl group, an amino group, a cyano group, a halogen atom, an aminocarbonyl group, or C 1-4 Alkyl group, C 1-4 Alkoxy group, amino C 1-4 Alkyl groups, halogenated C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkoxy group, amino C 1-4 Alkoxy group, halogenated C 1-4 Alkoxy group, C 1-4 Alkylthio group, C 1-4 Alkylamino group, (C 1-4 alkyl)2 amino group, C 1-4 alkylaminocarbonyl group, (C 1-4alkyl)2 aminocarbonyl group, C 1-4 Alkylcarbonylamino group, C 1-4 It is selected from alkylcarbonyl groups.

[0048] Preferably, the substituents A are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-4 Alkyl group, C 1-4 Alkoxy group, amino C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkoxy group, amino C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 alkyl)2 amino group, C 1-4 alkylaminocarbonyl group, (C 1-4 alkyl)2 aminocarbonyl group, C 1-4 Alkylcarbonylamino group, C 1-4 Alkylcarbonyl group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, C 1-4 It is selected from an alkylthio group, a 3- to 6-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, a 5- to 10-membered heteroaryl group, and an oxo group.

[0049] Preferably, at least one of Y1, Y2, Y3, Y4 is C=O.

[0050] Preferably, for formula (A), R a When present, at least one of them is combined with any one of Y1, Y2, Y3, and Y4.

[0051] Preferably, for formula (a), R a When present, at least one of them is combined with any one of Y1, Y2, and Y3.

[0052] Preferably, for formula (c), R aAt least one of X5, X6, X7, and X8 is present, and at least one of X5, X6, X7, and X8 is combined with any one of X5, X6, X7, and X8.

[0053] Preferably, for formula (A), the L1 atom group is bonded to X1, X2 or X3 in formula (A).

[0054] Preferably, for formula (a), the L1 group is bonded to X1, X2 or X3 in formula (a).

[0055] Preferably, for formula (c), the L1 group is bonded to X1, X2, X3 or X4 in formula (c).

[0056] Preferably, the L1 group is attached to the nitrogen atom.

[0057] Embodiment 3. A compound according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0058] (However, C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (A-1), (A-2), (A-3), (a), (b) or (c) substituted with

[0059] [ka]

[0060] Embodiment 4. A compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0061] (However, C y1 is unsubstituted or contains one or more R a is an atomic group substituted with the following general formula (A-11), (a-1), (a-2), (b-1), (c-1) or (c-2):

[0062] [ka]

[0063] Here, m is an integer between 1 and 2.

[0064] Y1, Y2, and Y3 are each independently selected from CH2, NH, CH, and N.

[0065] X1, X2, X3, X4, and X9 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0066] As a condition, C y1 is the formula (c-1) or (c-2), the formula (c-1) or (c-2) is one or more R a is replaced by

[0067] As a condition, C y1 is the formula (b-1), X1, X2, X3, and X9 are not C=O.

[0068] Preferably, for formula (A-11), R a When present, at least one of them is bound to Y2.

[0069] Preferably, for formula (a-1), R a When present, at least one of them is bound to Y2.

[0070] Preferably, for formula (a-2), R a When present, at least one of them is bound to Y1.

[0071] Preferably, for formula (b-1), R a When present, at least one of them is bound to a ring carbon atom.

[0072] Preferably, for formulas (c-1) and (c-2), R a is present, and at least one of them is bonded to a benzene ring atom group.

[0073] Embodiment 5. A compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0074] (However, C y1 is unsubstituted or contains one or more R a is an atomic group substituted with the following general formula (A-11) or (a-1).

[0075] [ka]

[0076] m is an integer between 1 and 2.

[0077] Y2 and Y3 are each independently selected from CH2, NH, CH, and N.

[0078] X1, X2, and X3 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0079] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more Rb C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with

[0080] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group.

[0081] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0082] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 6-membered heteroaryl group.

[0083] Preferably, R a are each independently a halogen atom, a cyano group, optionally a halogen, C 1-6 Alkyl group, C 1-6 C substituted with at least one selected from an alkoxy group and a 3- to 6-membered cycloalkyl group 1-6 Alkyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6and 5-6 membered heteroaryl groups substituted with at least one selected from alkoxy groups.

[0084] More preferably, R a are each independently a halogen atom, a cyano group, optionally a halogen, C 1-6 Alkyl group, C 1-6 C substituted with at least one selected from an alkoxy group and a 3- to 5-membered cycloalkyl group 1-4 alkyl group; optionally halogen, C 1-6 Alkyl group, C 1-6 a 3- to 5-membered cycloalkyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- or 6-membered nitrogen-containing heteroaryl group substituted with at least one group selected from alkoxy groups.

[0085] Preferably, in formula (A-11), X1 and X2 are each independently selected from CH2, CH, N, and NH.

[0086] Preferably, in formula (a-1), X1 and X2 are each independently selected from CH2, CH, N, and NH.

[0087] Preferably, in formula (A-11) and formula (a-1), Y2 is NH.

[0088] Preferably, in formula (A-11) and formula (a-1), Y3 is CH2 or CH.

[0089] Preferably, in formula (A-11) and formula (a-1), R a If there is at least one R a is attached to the Y2 position.

[0090] Preferably, in formula (A-11) and formula (a-1), the L1 atomic group is bonded to X1, X2 or X3.

[0091] Preferably, in formula (A-11) and formula (a-1), the L1 atomic group is bonded to the nitrogen atom.

[0092] Embodiment 6. A compound according to embodiment 5 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0093] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0094] R3 and R4 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0095] R5 and R6 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0096] L1 is a bond.

[0097] C y1 is unsubstituted or contains one or more R a is the following atomic group substituted with

[0098] [ka]

[0099] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R bC replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with

[0100] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group.

[0101] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0102] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group.

[0103] Preferably, R a are each independently a halogen atom, a cyano group, optionally a halogen, C 1-6 Alkyl group, C 1-6 C substituted with at least one selected from an alkoxy group and a 3- to 6-membered cycloalkyl group 1-6 Alkyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and 5-6 membered heteroaryl groups substituted with at least one selected from alkoxy groups.

[0104] More preferably, R a are each independently fluorine, chlorine, or bromine; a cyano group; optionally a halogen, C 1-6 Alkyl group, C 1-6methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, or t-butyl group substituted with at least one selected from the group consisting of an alkoxy group and a 3- to 5-membered cycloalkyl group; optionally, a halogen, C 1-6 a cyclopropyl group, a cyclobutyl group, a cyclopentyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a phenyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 It is selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, and a thiazolyl group, each substituted with at least one alkyl group.

[0105] Embodiment 7. A compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0106] (However, C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (b-1) substituted with

[0107] [ka]

[0108] X1, X2, X3, and X9 are each independently selected from CH2, CH, N, and NH, and at least one of X1, X2, and X3 is N or NH.

[0109] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more Rb C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R bCy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0110] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group.

[0111] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0112] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group.

[0113] Preferably, R a each independently represents an optionally halogen-substituted C 1-6 Alkyl group, halogen atom, aminocarbonyl group, C optionally substituted with halogen 1-6alkylaminocarbonyl group, optionally substituted with halogen (C 1-6 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a 5-6 membered heteroarylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- to 10-membered heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0114] More preferably, R a each independently represents an aminocarbonyl group, an optionally halogen-substituted C 1-4 alkylaminocarbonyl group, optionally substituted with halogen (C 1-4 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3- to 5-membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- or 6-membered nitrogen-containing heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0115] Preferably, in formula (b-1), the L1 atomic group is bonded to the nitrogen atom in formula (b-1).

[0116] Preferably, in formula (b-1), R aWhen present, at least one of them is bonded to a carbon atom in formula (b-1).

[0117] Embodiment 8. A compound according to embodiment 7 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0118] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0119] R3 and R4 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0120] R5 and R6 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0121] L1 is a bond.

[0122] C y1 is unsubstituted or contains one or more R a is the following atomic group substituted with

[0123] [ka]

[0124] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0125] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, and a 5- to 10-membered heteroaryl group.

[0126] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0127] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group.

[0128] Preferably, R a each independently represents an optionally halogen-substituted C 1-6 Alkyl group, halogen atom, aminocarbonyl group, C optionally substituted with halogen 1-6 alkylaminocarbonyl group, optionally substituted with halogen (C 1-6 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6a 3-8 membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a 5-6 membered heteroarylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- to 10-membered heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0129] More preferably, R a are each independently an aminocarbonyl group; a methylaminocarbonyl group optionally substituted with a halogen, an ethylaminocarbonyl group optionally substituted with a halogen, a propylaminocarbonyl group optionally substituted with a halogen, an isopropylaminocarbonyl group optionally substituted with a halogen, an n-butylaminocarbonyl group optionally substituted with a halogen, an isobutylaminocarbonyl group optionally substituted with a halogen, an s-butylaminocarbonyl group optionally substituted with a halogen, or a t-butylaminocarbonyl group optionally substituted with a halogen; optionally a halogen, C 1-6 a cyclopropylaminocarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 a cyclobutylaminocarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 a cyclopentylaminocarbonyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a phenylaminocarbonyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a pyrrolidinylcarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 a piperidinylcarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6piperazinylcarbonyl groups substituted with at least one alkyl group.

[0130] Embodiment 9. A compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0131] (However, C y1 is one or more R a is an atomic group represented by the following general formula (c-1) substituted with

[0132] [ka]

[0133] X1, X2, and X3 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0134] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0135] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group.

[0136] Each R bare each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0137] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group.

[0138] Preferably, R a each independently represents an optionally halogen-substituted C 1-6 Alkyl group, halogen atom, aminocarbonyl group, C optionally substituted with halogen 1-6 alkylaminocarbonyl group, optionally substituted with halogen (C 1-6 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6a 5-6 membered heteroarylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- to 10-membered heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0139] More preferably, R a each independently represents an aminocarbonyl group, an optionally halogen-substituted C 1-4 alkylaminocarbonyl group, optionally substituted with halogen (C 1-4 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3- to 5-membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- or 6-membered nitrogen-containing heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0140] Preferably, in formula (c-1), at least one R a is bonded to the benzene ring moiety in formula (c-1).

[0141] Preferably, in formula (c-1), the L1 atomic group is bonded to X1, X2 or X3.

[0142] Preferably, in formula (c-1), the L1 atomic group is bonded to the nitrogen atom in formula (c-1).

[0143] Embodiment 10. A compound according to embodiment 9 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0144] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0145] R3 and R4 are each independently hydrogen, C 1-6 It is selected from alkyl groups.

[0146] R5 and R6 are each hydrogen, C 1-6 It is selected from alkyl groups.

[0147] L1 is a bond.

[0148] C y1 is one or more substituents R a is the following atomic group substituted with

[0149] [ka]

[0150] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R bC replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0151] Each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, and a 5- to 10-membered heteroaryl group.

[0152] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0153] Preferably, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group.

[0154] Preferably, R a each independently represents an optionally halogen-substituted C 1-6 Alkyl group, halogen atom, aminocarbonyl group, C optionally substituted with halogen 1-6 alkylaminocarbonyl group, optionally substituted with halogen (C 1-6 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a 5-6 membered heteroarylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6and a 5- to 10-membered heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0155] More preferably, R a are each independently an aminocarbonyl group; a methylaminocarbonyl group optionally substituted with a halogen, an ethylaminocarbonyl group optionally substituted with a halogen, a propylaminocarbonyl group optionally substituted with a halogen, an isopropylaminocarbonyl group optionally substituted with a halogen, an n-butylaminocarbonyl group optionally substituted with a halogen, an isobutylaminocarbonyl group optionally substituted with a halogen, an s-butylaminocarbonyl group optionally substituted with a halogen, or a t-butylaminocarbonyl group optionally substituted with a halogen; optionally a halogen, C 1-6 Alkyl group, C 1-6 a cyclopropylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a cyclobutylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a cyclopentylaminocarbonyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 an azetidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen, C 1-6 Alkyl group, C 1-6 a pyrrolidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a piperidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6a piperazinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a morpholinylcarbonyl group substituted with at least one group selected from alkoxy groups.

[0156] Embodiment 11. A compound according to embodiment 1, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein said compound is selected from:

[0157] [Table 1-1]

[0158] [Table 1-2]

[0159] [Table 1-3]

[0160] [Table 1-4]

[0161] [Table 1-5]

[0162] [Table 1-6]

[0163] [Table 1-7]

[0164] Embodiment 12. A pharmaceutical composition comprising a compound of any one of Embodiments 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, optionally including one or more pharmaceutical carriers.

[0165] Embodiment 13. Use of a compound described in any one of Embodiments 1 to 11 or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, or a pharmaceutical composition described in Embodiment 12, in the manufacture of a medicament for preventing and / or treating a disease associated with or induced by SSAO / VAP-1 protein. [Effects of the Invention]

[0166] The present invention provides novel halogenated allylamine compounds that are effective in treating and / or preventing diseases associated with or induced by SSAO / VAP-1 protein. Specifically, the compound represented by Formula I of the present invention, its pharmaceutically acceptable salts, esters, or stereoisomers and tautomers thereof exhibit excellent inhibitory activity against SSAO / VAP-1 protein, and are therefore applicable to the prevention and / or treatment of diseases associated with or induced by SSAO / VAP-1 protein.

[0167] Furthermore, since the compounds of the present invention exhibit a more selective inhibitory effect on SSAO / VAP-1 protein than on rhAOC1 protein or MAO protein, they can prevent and / or treat diseases associated with or induced by SSAO / VAP-1 protein without causing any unwanted side effects.

[0168] Furthermore, the compounds of the present invention are less likely to pass through the blood-brain barrier than existing pharmaceuticals, and therefore have an extremely low risk of toxicity to the nervous system, demonstrating excellent pharmaceutical safety.

[0169] Thereby, the present invention can provide a compound, a pharmaceutically acceptable salt, ester or stereoisomer, or tautomer thereof for preventing and / or treating diseases related to or induced by SSAO / VAP-1 protein with high safety. Details of the invention

[0170] The following will describe the embodiments of the present invention in more detail with specific embodiments. Those skilled in the art will understand that the embodiments described hereinafter are merely for explaining the present invention and are not limitations on the protection scope of the present invention. On the contrary, the present invention includes all alternatives, modifications and equivalent forms within the scope of the present invention defined by the claims. Unless otherwise specified, each embodiment of the present invention can be arbitrarily combined, and the resulting transformation, modification and variation of the technical idea are also included in the scope of the present invention. Definitions

[0171] In the present invention, the description of "C a-b atomic group" (a and b are integers greater than or equal to 1, and a < b) indicates that there are a - b carbon atoms in the "atomic group". For example, C 1-6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and C 1-6 alkoxy group refers to an alkoxy group having 1 to 6 carbon atoms, and C 3-8 cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, and C 1-6 alkoxyC 1-6 alkyl group refers to a group formed by bonding an alkoxy group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms. Also, in the present invention, the description of "atomic group" also indicates an atomic group containing two or more sub-atomic groups. In this case, the description of "C a-b " limits the total number of carbon atoms in the atomic group containing two or more sub-atomic groups. For example, the description of "C 7-12 alkylaryl group" indicates that the total number of carbon atoms in the alkylaryl atomic group containing an alkyl group portion and an aryl group portion is 7 - 10, that is, it may be decomposed into C 1-6 alkylphenyl group or C 1-2 alkylnaphthyl group, but is not limited thereto.

[0172] In the present invention, the terms "group" and "atomic group" refer to a monovalent atomic group or, if necessary, a divalent or higher atomic group that matches the chemical valence. For example, a "cycloalkyl group (also referred to as a cycloalkyl atomic group)" includes a monovalent atomic group obtained by removing one hydrogen atom from a cycloalkane, as well as a divalent or higher atomic group derived by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms of a cycloalkane. For example, when a "cycloalkyl group" is used as a terminal atomic group, an unsubstituted group is bonded to other parts of the compound structural formula in the form of a monovalent atomic group, while a substituted group has a corresponding number of valence electrons (number of substituents + 1) depending on the number of substituents. Those skilled in the art can easily determine the number of valence electrons indicated by the "group" and "atomic group." Furthermore, in the present invention, when an "atomic group" refers to an atomic group with a chemical valence of two or more, it is preferably bonded to a different atom (such as, but not limited to, a carbon atom or a nitrogen atom) in the atomic group.

[0173] The term "halogen" or "halogen atom" used in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom.

[0174] "C" according to the present invention 1-6 "Alkyl group" refers to a straight or branched chain alkyl group derived by removing one hydrogen atom from an alkane moiety containing 1-6 carbon atoms, and includes straight chain C 1-6 Alkyl groups and branched chain C 1-6 In fact, those skilled in the art will recognize that C 1-6 The alkyl group is branched (branched chain C 1-6 alkyl group) and have at least three carbon atoms. 1-6Examples of the "alkyl group" include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an isohexyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group, and a 1-methyl-2-methylpropyl group. 1-4 "Alkyl groups" are examples of the above having 1-4 carbon atoms.

[0175] "C" according to the present invention 2-6 The term "alkenyl group" refers to a straight-chain or branched-chain alkenyl group obtained by removing one hydrogen atom from an alkene moiety of 2 to 6 carbon atoms having at least one carbon-carbon double bond, and examples thereof include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 1,3-butadien-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, and 1,4-hexadien-1-yl. Preferably, "C 2-6 An "alkenyl group" contains one carbon-carbon double bond.

[0176] "C" according to the present invention 2-6 The term "alkynyl group" refers to a straight-chain or branched-chain alkynyl group derived by removing one hydrogen atom from an alkyne moiety of 2 to 6 carbon atoms having at least one carbon-carbon triple bond, and examples thereof include ethynyl group, propynyl group, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-1-yl, 3-hexyn-2-yl, 3-hexyn-1-yl, and 3-hexyn-2-yl. Preferably, "C 2-6An "alkynyl group" contains one carbon-carbon triple bond.

[0177] "C" according to the present invention 1-6 The "alkoxy group" is defined as "C 1-6 An "alkyl group" is an atomic group that is connected to the rest of the chemical formula by an oxygen atom, i.e., "C 1-6 alkyl-O-" atomic group, for example, 1-6 Examples of the alkyl group include an atomic group obtained by bonding an atomic group listed in the "alkyl group" with -O-, and include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, a t-butoxy group, an n-pentyloxy group, a neopentyloxy group, an n-hexyloxy group, and the like. 1-4 An "alkoxy group" is an example of the above having 1-4 carbon atoms, i.e., "C 1-4 It is an alkyl-O- group.

[0178] Said “C 1-6 Alkoxy C 1-6 "Alkoxy group" means C 1-6 Alkoxy group C 1-6 It is an atomic group formed by replacing one or more hydrogen atoms in an alkoxy group.

[0179] "C" according to the present invention 1-6 alkylamino group," "(C 1-6 alkyl)2amino group, C 1-6 alkylcarbonylamino group," "C 1-6 alkylaminocarbonyl group," "C 1-6 alkylcarbonyl group, C 1-6 alkylaminosulfonyl group," "C 1-6 alkylsulfonylamino group," "C 1-6 alkylsulfonyl group," "C 1-6 Alkylthio group (C 1-6 "Alkylthio group" and the like are C 1-6These are atomic groups formed by bonding an alkyl group to a corresponding atomic group such as -NH2, -CO-NH2-, -NH2-CO-, -CO-, -NH2SO2-, -SO2NH2-, -SO2-, or -S-.

[0180] "C" according to the present invention 1-6 Alkoxy C 1-6 alkyl group," "C 1-6 Alkylthio C 1-6 alkyl group," "C 1-6 Alkylamino C 1-6 alkyl group," "C 1-6 Alkylaminocarbonyl C 1-6 alkyl group," "C 1-6 Alkylcarbonylamino C 1-6 alkyl group," "C 1-6 Alkyl carbonyl C 1-6 alkyl group," "C 1-6 Alkylaminosulfonyl C 1-6 alkyl group," "C 1-6 Alkyl sulfonyl amino C 1-6 alkyl group," "C 1-6 Alkyl Sulfonyl C 1-6 "Alkyl group" etc. are C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylsulfonyl group is C 1-6 It is an atomic group formed by replacing one or more hydrogen atoms in an alkyl group.

[0181] The term "fused ring" as used herein refers to a polycyclic structure formed by two or more ring structures bonded together by a bond, spiro ring, or bridge. The bonded ring is a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms (i.e., sharing one bond). The bridged ring is a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms. The spiro ring is a fused ring structure formed by two or more ring structures sharing one ring atom.

[0182] A "cycloalkyl group" according to the present invention refers to a monovalent or (optionally) divalent group derived from a cycloalkane, including single-ring or fused-ring cycloalkanes, and may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Unless otherwise specified, a cycloalkyl group includes all possible single and fused rings (including fused rings in the form of bonds, spiro rings, or bridges). A cycloalkyl group may be a 3-12-membered monovalent or (optionally) divalent or more than divalent group, a 3-10-membered monovalent or (optionally) divalent or more than divalent group, a 3-8-membered monovalent or (optionally) divalent or more than divalent group, a 3-6-membered monovalent or (optionally) divalent or more than divalent group, a 4-6-membered monovalent or (optionally) divalent or more than divalent group, or a 5-7-membered monovalent or (optionally) divalent or more than divalent group.

[0183] The (monovalent or more than divalent) monocyclic cycloalkyl group can be a 3-12 membered cycloalkyl group, a 3-10 membered cycloalkyl group, a 3-8 membered cycloalkyl group, a 3-6 membered cycloalkyl group, a 4-6 membered cycloalkyl group, a 5-7 membered cycloalkyl group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, and the like.

[0184] Fused-ring (monovalent or more than divalent) cycloalkyl groups include fused-ring cycloalkyl groups, bridged cycloalkyl groups, and spirocycloalkyl groups.

[0185] The (monovalent or more) linked-ring cycloalkyl group may be a 6- to 12-membered linked-ring cycloalkyl group, a 7- to 10-membered linked-ring cycloalkyl group, examples of which include, but are not limited to, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl groups.

[0186] The "cycloalkenyl group" according to the present invention is an atomic group obtained by having at least one carbon-carbon double bond in the above-mentioned cycloalkyl group, and preferably has one carbon-carbon double bond.

[0187] The "cycloalkyl group" and "cycloalkenyl group" may also be a monovalent group obtained by removing one hydrogen atom from a 6- to 12-membered spiro ring or a 7- to 11-membered spiro ring, or a divalent group obtained by removing one hydrogen atom from each of two different carbon atoms, if desired. Illustrative examples of spiro rings are:

[0188] [ka]

[0189] This includes, but is not limited to:

[0190] The "cycloalkyl group" and "cycloalkenyl group" may also be a monovalent atomic group obtained by removing one hydrogen atom from a 6- to 12-membered bridged ring, a 7- to 11-membered bridged ring, or a divalent atomic group obtained by removing one hydrogen atom from each of two different carbon atoms, as appropriate. Specific examples of such bridged rings include:

[0191] [ka]

[0192] This includes, but is not limited to:

[0193] Therefore, unless otherwise specified, the "3- to 12-membered cycloalkenyl group" according to the present invention includes any possible monocyclic or fused ring (including fused in the form of a bond, spiro, or bridge) and is an atomic group having at least one carbon-carbon double bond in the above-mentioned 3- to 12-membered monovalent atomic group or (if necessary) divalent or higher atomic group cycloalkyl group. For example, it may be a monovalent or divalent atomic group derived from a 3- to 8-membered cycloalkene, a 7- to 11-membered spirocyclic cycloalkene, a 7- to 11-membered bonded cyclic cycloalkene, a 6- to 11-membered bridged cyclic cycloalkene, etc. Examples include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a 1,4-cyclohexadienyl group, a cycloheptenyl group, a 1,4-cycloheptadienyl group, a cyclooctenyl group, and a 1,5-cyclooctadienyl group.

[0194] The "heterocyclic group" according to the present invention is a non-aromatic monovalent or divalent cyclic atomic group in which at least one ring-constituting carbon atom of the above-mentioned cycloalkyl group is substituted with a heteroatom selected from O, S, and N. Preferably, it has no carbon-carbon double bond or one carbon-carbon double bond. Preferably, it is a heterocyclic group obtained by substituting the ring-constituting carbon atoms of the above-mentioned ring-constituting alkyl group with 1 to 3 heteroatoms selected from O, S, and N. Furthermore, the heterocyclic group according to the present invention also includes a case in which the ring-constituting carbon atom or sulfur atom is further substituted with an oxygen atom or nitrogen atom, for example, a ring-constituting carbon atom is substituted with C(=O), S(=O), S(=O)2, or S(=O)(=NH).

[0195] Specifically, the "heterocyclic group" according to the present invention may be an atomic group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, or may be a 3- to 14-membered heterocyclic group, a 3- to 12-membered heterocyclic group, a 3- to 10-membered heterocyclic group, a 4- to 10-membered heterocyclic group, a 3- to 8-membered heterocyclic group, a 4- to 12-membered heterocyclic group, a 4- to 8-membered heterocyclic group, a 4- to 6-membered heterocyclic group, or a 5- to 10-membered heterocyclic group.

[0196] The term "heterocyclic group" also includes mono- or (optionally) di- or more-valent monocyclic heterocyclic group systems, or mono- or (optionally) di- or more-valent polycyclic heterocyclic group systems (also called fused ring systems), including saturated and unsaturated heterocyclic groups, but not having aromatic character overall. Unless otherwise specified, this includes all possible monocyclic and fused ring systems (including fused rings in the form of bonds, spiro rings, and bridges), saturated and unsaturated, but not having aromatic character overall.

[0197] The monovalent or (optionally) divalent or more monocyclic heterocyclic group may be a 3-14 membered heterocyclic group, a 3-12 membered heterocyclic group, a 3-10 membered heterocyclic group, a 4-10 membered heterocyclic group, a 3-8 membered heterocyclic group, a 4-12 membered heterocyclic group, a 4-8 membered heterocyclic group, a 4-6 membered heterocyclic group, a 5-10 membered heterocyclic group, a 3-8 membered saturated heterocyclic group, a 3-6 membered heterocyclic group, a 4-12 membered heterocyclic group, a 4-7 membered heterocyclic group, a 4-6 membered heterocyclic group, a 5-10 membered heterocyclic group, a 5-7 membered heterocyclic group, a 5-6 membered heterocyclic group, a 5-6 membered oxygen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered saturated heterocyclic group, a 5-7 membered saturated heterocyclic group, or the like, and may be saturated, partially saturated, or unsaturated, but is not aromatic. Illustrative examples include aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, 4,5-glyoxalidinyl, pyrazolidinyl, 4,5-pyrazolinyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-thiazolinyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, hexahydropyridazinyl, 4,5-dihydrooxazolinyl, and the like. Examples of the aryl group include, but are not limited to, a 4,5-dihydroisoxazolyl group, a 2,3-dihydroisoxazolyl group, a 2H-1,2-oxazinyl group, a 6H-1,3-oxazinyl group, a 4H-1,3-thiazinyl group, a 6H-1,3-thiazinyl group, a 2H-pyranyl group, a 2H-pyranyl-2-ketonyl group, a 3,4-dihydro-2H-pyranyl group, a 1,1-dioxotetrahydrothiopyranyl group, a 1,1-dioxotetrahydrothiophenyl group, a 1-imino-1-oxo-tetrahydrothietanyl group, a 1-imino-1-oxo-tetrahydrothiophenyl group, a 1-imino-1-oxo-hexahydrothiopyranyl group, and the like.

[0198] The monovalent or (optionally) divalent or more fused heterocycles include fused heterocyclic groups, spiro heterocyclic groups, bridged heterocyclic groups, and may be saturated, partially saturated or unsaturated, but not aromatic.

[0199] The bonded heterocyclic group may be a 6- to 12-membered bonded heterocyclic group, a 7- to 10-membered bonded heterocyclic group, a 6- to 10-membered bonded ring group, a 6- to 12-membered saturated bonded heterocyclic group, a 7- to 8-membered saturated bonded heterocyclic group, or an 8-membered saturated bonded heterocyclic group, and examples thereof include a 3-azabicyclo[3.1.0]hexyl group, a 3,6-diazabicyclo[3.2.0]heptyl group, a 3,8-diazabicyclo[4.2.0]octyl group, a 3,7-diazabicyclo[4.2.0]octyl group, an octahydropyrrolo[3,4-c]pyrrolyl group, an octahydropyrrolo[3,4-b]pyrrolyl group, an octahydropyrrolo[3,4-b][1,4]oxazinyl group, an octahydro-1H- Examples of such groups include, but are not limited to, pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl, octahydrocyclopenta[c]pyrrolyl, hexahydrocyclopenta[c]furanyl, 2,2-dioxohexahydrocyclopenta[c]thiophenyl, and 2-imino-2-oxo-octahydrocyclopenta[c]thiophenyl.

[0200] The spiroheterocyclic group may be a monovalent atom group obtained by removing one hydrogen atom from a 6- to 12-membered spiroheterocycle, a 7- to 11-membered spiroheterocycle, a 6- to 12-membered saturated spiroheterocycle, or a 7-membered saturated spiroheterocycle, or a divalent atom group obtained by removing one hydrogen atom from each of two different carbon atoms as needed. Specific examples of spiroheterocycles include:

[0201] [ka]

[0202] This includes, but is not limited to:

[0203] The bridged heterocyclic group may be a monovalent atomic group obtained by removing one hydrogen atom from a 6- to 12-membered bridged heterocycle, a 7- to 11-membered bridged heterocycle, a 6- to 12-membered saturated bridged heterocycle, or a 7- to 8-membered saturated bridged heterocycle, or a divalent atomic group obtained by removing one hydrogen atom from each of two different carbon atoms as needed. Specific examples of the bridged heterocycle include:

[0204] [ka]

[0205] This includes, but is not limited to:

[0206] The term "aryl group" as used herein refers to a monovalent atomic group, or optionally a divalent or higher atomic group, derived from an aromatic cyclic hydrocarbon, and the aromatic cyclic hydrocarbon includes 6- to 8-membered monocyclic aromatic hydrocarbons and 8- to 14-membered fused-ring aromatic hydrocarbons. An example of a 6- to 8-membered monocyclic aryl group is a phenyl group. An example of an 8- to 14-membered fused-ring aryl group is a naphthyl group, a phenanthryl group, or an anthryl group. In the case of a divalent atomic group, examples include a phenylene group and a naphthylene group.

[0207] The "heteroaryl group" according to the present invention may be a 5-14-membered heteroaryl group, a 5-10-membered heteroaryl group, or a 5-6-membered heteroaryl group. It may also be an aromatic monovalent or divalent cyclic atomic group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms and at least one heteroatom selected from O, S, and N. Preferably, it has 1 to 3 ring-membering heteroatoms. Heteroaryl groups also include those in which ring-membering carbon and sulfur atoms are replaced with oxygen or nitrogen atoms, such as carbon atoms replaced with C(=O), S(=O), S(=O)2, or S(=O)(=NH). The aromatic heterocycle according to the present invention may be a monocyclic ring system or a fused ring system (fused via a bond, spiro, or bridge). Heteroaryl groups include monocyclic and fused-ring heteroaryl groups, and unless otherwise specified, a certain-membered heteroaryl group includes all possible monocyclic, fused-ring, fully aromatic, and partially aromatic heteroaryl groups. Monocyclic heteroaryl groups may be, for example, 5- to 7-membered heteroaryl groups or 5- to 6-membered heteroaryl groups, and examples thereof include, but are not limited to, furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, and triazinyl groups. The fused ring heteroaryl group may be an 8- to 12-membered heteroaryl group or a 9- to 10-membered heteroaryl group, examples of which include, but are not limited to, benzimidazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzothiophenyl, benzoxadiazolyl, benzothiazolyl, cinnolinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, quinoxalinyl, and quinazolinyl. The heteroaryl group may be a divalent atomic group derived from the above atomic groups.

[0208] In the present invention, the term "heteroatom" refers to an atom selected from S, O, and N. It also includes cases where S or O is replaced with an oxygen atom or a nitrogen atom.

[0209] The terms "3- to 6-membered ring," "3- to 8-membered ring," "4- to 6-membered ring," and "4- to 7-membered ring" used in the present invention refer to cyclic structures having 3-6 ring atoms, 3- to 8 ring atoms, 4- to 6 ring atoms, or 4- to 7 ring atoms, each of which may be a chemical structure, and the ring atoms are optionally selected from C, N, O, S, C(═O), S(═O), S(═O)2, and S(═O)(═NH), and the cyclic structure formed may be a monocyclic ring, a condensed polycyclic ring, a saturated ring, a partially saturated ring, or an aromatic ring. Specific examples of the atomic groups listed for the cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl group, and heteroaryl group include those listed above.

[0210] Among the "amino group" or atomic group containing the "amino group" according to the present invention, the atomic group / sub-atomic group that terminates in an amino group is -N(R e )2 (where R e are each independently hydrogen, the above C optionally substituted with a substituent A according to the present invention. 1-6 alkyl group, the above C optionally substituted with the substituent A according to the present invention 2-6 Alkenyl groups, optionally substituted with the substituent A according to the present invention, 2-6 The term "amino group" refers to an atomic group / sub-atomic group having an amino group at its terminal, which is selected from an alkynyl group, the cycloalkyl group optionally substituted with a substituent A according to the present invention, the cycloalkenyl group optionally substituted with a substituent A according to the present invention, the aryl group optionally substituted with a substituent A according to the present invention, the heteroaryl group optionally substituted with a substituent A according to the present invention, the heterocyclic group optionally substituted with a substituent A according to the present invention, the Cy2 according to the present invention optionally substituted with a substituent A according to the present invention, and other atomic groups (including, but not limited to, carbonyl groups, sulfonyl groups, etc.) bonded to the amino group in the atomic group containing an "amino group" according to the present invention. In the present invention, the term "amino group" refers to an atomic group / sub-atomic group having an amino group at its terminal, which is selected from an atomic group having an amino group bonded to two R eand further bonded to other atomic groups. For example, "(C 1-6 In the case of "C alkyl)2 amino group", it is the atomic group that ends in the amino group among the atomic groups that contain the "amino group"; 1-6 In the case of an "alkylamino group," it is an atomic group containing an "amino group" and having an amino group at the end. e "C 1-6 The other R e represents the group listed above; 1-6 Alkyl)2amino C 1-6 In the case of "alkyl group", the "(C 1-6 The term "amino group" refers to a subatomic group that has an amino group at the end of it, i.e., an amino group having two C alkyl groups. 1-6 Alkyl group (R e (corresponding to C) 1-6 bonded to an alkyl group; 1-6 In the case of "(C alkyl)2 aminocarbonyl group", 1-6 The term "amino group" refers to a subatomic group that has an amino group at the end of it, i.e., an amino group having two C alkyl groups. 1-6 Alkyl group (R e (corresponding to "C") and further bonded to a carbonyl group; 1-6 In the case of "alkylaminocarbonyl group", the "C 1-6 An "alkylamino group" is a subatomic group that has an amino group at the end of it, among the atomic groups that contain an "amino group." In other words, an amino group is one C 1-6 Alkyl group (R e and further bonded to a carbonyl group, but in this atomic group, one of the R e "C 1-6 The other R e represents the above-listed atomic group; "amino C 1-6 In the case of an "alkyl group," the "amino group" is a subatomic group that has an amino group at the end of the atomic group that includes the "amino group."e )2, that is, the atomic group is "N(R e )2-C 1-6 From the above, in the amino group according to the present invention, the chemical valence of N is trivalent.

[0211] [ka]

[0212] However, the two are R e In addition, in the present invention, "-N(R e )2" with two R e can form a nitrogen-containing heterocyclic group together with the nitrogen atom, and the heterocyclic group complies with the above definition of the present invention.

[0213] In the present invention, the term "optionally substituted" or "optionally substituted with" means that any part of the substitutable moiety known to those skilled in the art is unsubstituted or substituted with a substituent according to the present invention, and when there is one or more substituents, each substituent is independently selectable. When substituted, the number of substituents is determined by the number of substitutable positions of the substituted atomic group, and may be 1, 2, 3, 4, 5, 6, 7, 8, or more, as long as it does not exceed the number of substitutable positions of the substituted atomic group. When there are substituents, "one or more" substituents means one or more substituents, and the actual number of substituents varies depending on the substituted atomic group, and may be 1, 2, 3, 4, 5, 6, 7, 8, or more, as long as it does not exceed the number of substitutable positions of the substituted atomic group.

[0214] In the present invention, the term "optionally substituted" or "optionally substituted with" preceding an atomic group means that all subatomic groups contained in the atomic group may be optionally substituted. For example, "C optionally substituted with halogen" 7-12 The "alkylaryl group" means that the alkyl group portion may be substituted with a halogen, the aryl group portion may be substituted with a halogen, or both the alkyl group portion and the aryl group portion may be substituted with a halogen.

[0215] In the present invention,

[0216] [ka]

[0217] indicates a double bond optionally present in the ring, and the number of double bonds may be one, two, or three, but is limited to the maximum number possible in the ring. For example, a five-membered ring may have one or two double bonds, but a six-membered ring may have one, two, or three double bonds.

[0218] In the present invention,

[0219] [ka]

[0220] represents a single or double bond.

[0221] In the present invention, the term "absence" of a certain atomic group may mean that the atomic group itself is not present, but may also mean, for example, that "R d Regarding the definition of "absence of" in the formula (1), when a nitrogen atom constituting a ring is bonded to an adjacent atom in the ring by a single bond and a double bond, respectively, "NR d In the definition of "R d Furthermore, "absence of" a certain atomic group may mean that the atomic group is a bond, but for example, with respect to the definition of "absence of L1" of the present invention, this means that L1 is a bond and the Cy1 atomic group is directly bonded to the carbon atom bonded to the R6 atomic group.

[0222] In the present invention, the substituent in "optionally substituted with a substituent" may be the "substituent A" according to the present invention. The number of the substituents is determined by the number of substitutable positions of the substituted atomic group, and may be 1, 2, 3, 4, 5, 6, 7, 8 or more.

[0223] In the present invention, all atomic groups, substituents, chemical bond positions, and chemical valencies of atoms, etc., are consistent with common knowledge in the field of chemistry. For example, carbon atoms are tetravalent, nitrogen atoms are trivalent, oxygen atoms are divalent, and hydrogen atoms are monovalent.

[0224] Specifically, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

[0225] [ka]

[0226] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0227] R3 and R4 are each independently hydrogen, C optionally substituted with a substituent A 1-6 or forms, together with the nitrogen atom bonded thereto, a nitrogen-containing 5- to 10-membered heterocyclic group optionally substituted with a substituent A.

[0228] R5 and R6 are each independently hydrogen, C optionally substituted with a substituent A; 1-6 It is selected from alkyl groups.

[0229] L1 is a bond, -CR'R''-, -NR'-, -S-, -SO2-, -S(O)-, -SONR'-, -SON2NR'-, or -NR'CONR'-, and R' and R'' are each independently hydrogen, C optionally substituted with a substituent A; 1-6 It is selected from alkyl groups.

[0230] C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (A), (a), (b) or (c) substituted with

[0231] [ka]

[0232] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0233] Y1, Y2, Y3, and Y4 are each independently CR c R c , N.R. d , O, and S.

[0234] X1, X2, X3, X4, X9, X 10 are each independently CR c R c , N.R. d , O, S, and X5, X6, X7, and X8 are each independently selected from CR c R c , N.R. d and at least one of X1, X2, and X3 is NR d is.

[0235] Each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 2-6 alkenyl group, optionally one or more R b C replaced with 2-6 an alkynyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 an alkylthio group, optionally one or more R b C replaced with 1-6 Alkylthio C 1-6 alkyl group, optionally one or more R bC replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminosulfonyl group, optionally one or more R b (C 1-6 alkyl)2aminosulfonyl group, optionally one or more R b C replaced with 1-6 Alkylaminosulfonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2aminosulfonyl C1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylsulfonylamino group, optionally one or more R b C replaced with 1-6 Alkyl sulfonyl amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylsulfonyl group, optionally one or more R b C replaced with 1-6 Alkyl Sulfonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0236] Each Cy2 is independently selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 14-membered heteroaryl group.

[0237] Each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl group, (C 1-6 alkyl)2 aminosulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 alkylsulfonyl groups.

[0238] The substituents A each independently represent a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl group, (C 1-6 Alkyl)2 aminosulfonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, C 1-6 Alkylsulfonyl group, C 1-6It is selected from an alkylthio group, a 3- to 12-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 12-membered heterocyclic group, a 5- to 14-membered heteroaryl group, and an oxo group.

[0239] R c is absent, or each occurrence is independently selected from a hydrogen atom, or two R c forms an oxo group.

[0240] R d is absent, or each occurrence is independently selected from a hydrogen atom.

[0241] [ka]

[0242] represents a single or double bond.

[0243] [ka]

[0244] indicates an optional double bond moiety in the ring structure.

[0245] As a condition, C y1 is formula (c), then formula (c) is one or more R a is replaced by

[0246] As a condition, C y1 is formula (b), X1, X2, X3, X9, X 10 is not C=O.)

[0247] In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen and halogen, and are not simultaneously hydrogen. In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, and iodine, and are not simultaneously hydrogen. In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen, fluorine, and chlorine, and are not simultaneously hydrogen. In one embodiment of the present invention, R1 is hydrogen and R2 is fluorine. In one embodiment of the present invention, R1 and R2 together with the nitrogen atom to which they are bonded form a 5-8 membered nitrogen-containing heterocyclic group.

[0248] In one embodiment of the present invention, R3 and R4 are each independently hydrogen, C 1-6 In one embodiment of the present invention, R3 and R4 are each independently selected from hydrogen, C 1-4 In one embodiment of the present invention, R3 and R4 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, and t-butyl. In one embodiment of the present invention, R3 and R4 are hydrogen. In one embodiment of the present invention, R3 and R4 together with the nitrogen atom to which they are bonded form a nitrogen-containing 5- or 6-membered heterocyclic group. In one embodiment of the present invention, R3 and R4 together with the nitrogen atom to which they are bonded form a pyrrolinyl group, a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group.

[0249] In one embodiment of the present invention, R5 and R6 are each independently hydrogen, C 1-6 In one embodiment of the present invention, R5 and R6 are each independently selected from hydrogen, C 1-4 In one embodiment of the present invention, R5 and R6 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, and t-butyl. In one embodiment of the present invention, R5 and R6 are hydrogen.

[0250] In one embodiment of the present invention, L1 is a bond, -CR'R''-, -NR'-, or -S-, and R' and R'' are each independently hydrogen, C 1-6 In one embodiment of the present invention, L1 is a bond, -NR'-, or -S-, and R' and R'' are each independently selected from hydrogen, C 1-6 In one embodiment of the present invention, L1 is a bond, -NR'-, where R' is hydrogen, C 1-6 In one embodiment of the present invention, L1 is a bond.

[0251] In one embodiment of the present invention, for formula (A), R a When present, at least one of them is bonded to any one of Y1, Y2, Y3, and Y4. In one embodiment of the present invention, for formula (a), R a When present, at least one of them is bonded to any one of Y1, Y2, and Y3. In one embodiment of the present invention, for formula (c), R a At least one of X5, X6, X7, and X8 is present, and at least one of X5, X6, X7, and X8 is combined with any one of X5, X6, X7, and X8.

[0252] In one embodiment of the present invention, for formula (A), the L1 atomic group is bonded to X1, X2 or X3 in formula (A). In one embodiment of the present invention, for formula (a), the L1 atomic group is bonded to X1, X2 or X3 in formula (a). In one embodiment of the present invention, for formula (c), the L1 atomic group is bonded to X1, X2, X3 or X4 in formula (c).

[0253] In one embodiment of the invention, the L1 group is attached to the nitrogen atom.

[0254] In one embodiment of the present invention, C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (A-1), (A-2), (A-3), (a), (b) or (c), which is substituted with

[0255] [ka]

[0256] In one embodiment of the present invention, C y1 is unsubstituted or contains one or more R a is an atomic group substituted with the following general formula (A-11), (a-1), (a-2), (b-1), (c-1) or (c-2):

[0257] [ka]

[0258] In one embodiment of the present invention, C y1 is the formula (c-1) or (c-2), the formula (c-1) or (c-2) is one or more R a is replaced by

[0259] In one embodiment of the present invention, C y1 is the formula (b-1), X1, X2, X3, and X9 are not C=O.

[0260] In one embodiment of the present invention, for formula (A-11), R a When present, at least one of them is bonded to Y2. In one embodiment of the present invention, for formula (a-1), R a When present, at least one of them is bonded to Y2. In one embodiment of the present invention, for formula (a-2), R a When present, at least one of them is bonded to Y1. In one embodiment of the present invention, for formula (b-1), R a When present, at least one of them is bonded to a ring-constituting carbon atom. a is present, and at least one of them is bonded to a benzene ring atom group.

[0261] In one embodiment of the invention, m is an integer from 0 to 3. In one embodiment of the invention, m is 1 or 2. In one embodiment of the invention, n is an integer from 0 to 2. In one embodiment of the invention, n is 1 or 2.

[0262] In one embodiment of the present invention, R c is absent, or each occurrence is independently selected from a hydrogen atom, or two R c forms an oxo group.

[0263] In one embodiment of the present invention, R d is absent, or each occurrence is independently selected from a hydrogen atom.

[0264] In one embodiment of the present invention, Y1, Y2, Y3, and Y4 are each independently CR c R c , N.R. d In one embodiment of the present invention, at least one of Y1, Y2, Y3, and Y4 is C=O. In one embodiment of the present invention, Y1, Y2, and Y3 are each independently selected from CH2, NH, CH, and N.

[0265] In one embodiment of the present invention, X1, X2, X3, X4, X9, X 10 are each independently CR c R c , N.R. d and at least one of X1, X2, and X3 is N or NR d In one embodiment of the present invention, X1, X2, X3, X4, and X9 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0266] In one embodiment of the present invention, X5, X6, X7, and X8 are each independently CR c R c , N.R. d Selected from.

[0267] In one embodiment of the present invention, Cy1 is unsubstituted or contains one or more R a is an atomic group substituted with the following general formula (A-11) or (a-1).

[0268] [ka]

[0269] In one embodiment of the present invention, in formulas (A-11) and (a-1), Y2 and Y3 are each independently selected from CH2, NH, CH, and N. In one embodiment of the present invention, in formulas (A-11) and (a-1), X1, X2, and X3 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0270] In one embodiment of the present invention, in formula (A-11), X1 and X2 are each independently selected from CH2, CH, N, and NH. In one embodiment of the present invention, in formula (a-1), X1 and X2 are each independently selected from CH2, CH, N, and NH. In one embodiment of the present invention, in formula (A-11) and formula (a-1), Y2 is NH. In one embodiment of the present invention, in formula (A-11) and formula (a-1), Y3 is CH2 or CH. In one embodiment of the present invention, in formula (A-11) and formula (a-1), R a If there is at least one R a is bonded to the Y2 position. In one embodiment of the present invention, in formula (A-11) and formula (a-1), the L1 atomic group is bonded to X1, X2 or X3. In one embodiment of the present invention, in formula (A-11) and formula (a-1), the L1 atomic group is bonded to a nitrogen atom.

[0271] In one embodiment of the present invention, C y1 is unsubstituted or contains one or more R a is the following atomic group substituted with

[0272] [ka]

[0273] In one embodiment of the present invention, C y1 is unsubstituted or contains one or more R a is an atomic group represented by the following general formula (b-1) substituted with

[0274] [ka]

[0275] In one embodiment of the present invention, in formula (b-1), X1, X2, X3, and X9 are each independently selected from CH2, CH, N, and NH, and at least one of X1, X2, and X3 is N or NH.

[0276] In one embodiment of the present invention, in formula (b-1), the L1 atomic group is bonded to the nitrogen atom in formula (b-1). a When present, at least one of them is bonded to a carbon atom of formula (b-1).

[0277] In one embodiment of the present invention, C y1 is unsubstituted or contains one or more R a is the following atomic group substituted with

[0278] [ka]

[0279] In one embodiment of the present invention, C y1 is one or more R a is an atomic group represented by the following general formula (c-1) substituted with

[0280] [ka]

[0281] In one embodiment of the present invention, in formula (c-1), X1, X2, and X3 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0282] In one embodiment of the present invention, in formula (c-1), at least one R a is bonded to the benzene ring moiety in formula (c-1). In one embodiment of the present invention, in formula (c-1), the L1 atomic group is bonded to X1, X2 or X3. In one embodiment of the present invention, in formula (c-1), the L1 atomic group is bonded to the nitrogen atom in formula (c-1).

[0283] In one embodiment of the present invention, C y1 is one or more substituents R a is the following atomic group substituted with

[0284] [ka]

[0285] In one embodiment of the present invention, each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 an alkylthio group, optionally one or more R b C replaced with 1-6 Alkylthio C 1-6 alkyl group, optionally one or more R b C replaced with1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R bCy2-carbonylamino group substituted with

[0286] In one embodiment of the present invention, each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0287] In one embodiment of the present invention, each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b (C 1-6 alkyl)2 amino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b (C 1-6Alkyl)2amino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b (C 1-6 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b (C 1-6 Alkyl)2 Aminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with

[0288] In one embodiment of the present invention, each R a each independently represents a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with 1-6 alkyl group, optionally one or more R b C replaced with 1-6an alkoxy group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 Alkoxy C 1-6 an alkoxy group, optionally one or more R b C replaced with 1-6 alkylamino group, optionally one or more R b C replaced with 1-6 Alkylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylaminocarbonyl group, optionally one or more R b C replaced with 1-6 Alkylaminocarbonyl C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonylamino group, optionally one or more R b C replaced with 1-6 Alkylcarbonylamino C 1-6 alkyl group, optionally one or more R b C replaced with 1-6 alkylcarbonyl group, optionally one or more R b C replaced with 1-6 Alkyl carbonyl C 1-6 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-6 alkyl group, optionally one or more R b Cy2-C substituted with 1-6 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with

[0289] In one embodiment of the present invention, each R a are each independently a halogen atom, a cyano group, optionally a halogen, C 1-6 Alkyl group, C 1-6C substituted with at least one selected from an alkoxy group and a 3- to 6-membered cycloalkyl group 1-6 Alkyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and 5-6 membered heteroaryl groups substituted with at least one selected from alkoxy groups.

[0290] In one embodiment of the present invention, R a each independently represents an optionally halogen-substituted C 1-6 Alkyl group, halogen atom, aminocarbonyl group, C optionally substituted with halogen 1-6 alkylaminocarbonyl group, optionally substituted with halogen (C 1-6 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3-8 membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a 5-6 membered heteroarylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- to 10-membered heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0291] In one embodiment of the present invention, each R a are each independently a hydroxyl group, an amino group, a cyano group, a halogen atom, an aminocarbonyl group, or optionally one or more R b C replaced with1-4 alkyl group, optionally one or more R b C replaced with 1-4 an alkoxy group, optionally one or more R b C replaced with 1-4 Alkoxy C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 Alkoxy C 1-4 an alkoxy group, optionally one or more R b C replaced with 1-4 an alkylthio group, optionally one or more R b C replaced with 1-4 Alkylthio C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylamino group, optionally one or more R b (C 1-4 alkyl)2 amino group, optionally one or more R b C replaced with 1-4 Alkylamino C 1-4 alkyl group, optionally one or more R b (C 1-4 Alkyl)2amino C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylaminocarbonyl group, optionally one or more R b (C 1-4 alkyl)2 aminocarbonyl group, optionally one or more R b C replaced with 1-4 Alkylaminocarbonyl C 1-4 alkyl group, optionally one or more R b (C 1-4 Alkyl)2 Aminocarbonyl C 1-4 alkyl group, optionally one or more R b C replaced with 1-4 alkylcarbonylamino group, optionally one or more R b C replaced with 1-4 Alkylcarbonylamino C 1-4 alkyl group, optionally one or more R b C replaced with 1-4alkylcarbonyl group, optionally one or more R b C replaced with 1-4 Alkyl carbonyl C 1-4 alkyl group, optionally one or more R b Cy2- substituted with, optionally one or more R b Cy2-C substituted with 1-4 alkyl group, optionally one or more R b Cy2-C substituted with 1-4 an alkoxy group, optionally one or more R b Cy2-carbonyl group substituted with, optionally one or more R b Cy2-aminocarbonyl group substituted with, optionally one or more R b Cy2-carbonylamino group substituted with

[0292] In one embodiment of the present invention, R a are each independently a halogen atom, a cyano group, optionally a halogen, C 1-6 Alkyl group, C 1-6 C substituted with at least one selected from an alkoxy group and a 3- to 5-membered cycloalkyl group 1-4 alkyl group; optionally halogen, C 1-6 Alkyl group, C 1-6 a 3- to 5-membered cycloalkyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a phenyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 In one embodiment of the present invention, R a are each independently fluorine, chlorine, or bromine; a cyano group; optionally a halogen, C 1-6 Alkyl group, C 1-6 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl groups substituted with at least one selected from alkoxy groups and 3- to 5-membered cycloalkyl groups; optionally halogen, C 1-6a cyclopropyl group, a cyclobutyl group, a cyclopentyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a phenyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 It is selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, and a thiazolyl group, each substituted with at least one alkyl group.

[0293] In one embodiment of the present invention, R a each independently represents an aminocarbonyl group, an optionally halogen-substituted C 1-4 alkylaminocarbonyl group, optionally substituted with halogen (C 1-4 alkyl)2 aminocarbonyl group, optionally halogen, C 1-6 Alkyl group, C 1-6 a 3- to 5-membered cycloalkylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally with a halogen atom, C 1-6 Alkyl group, C 1-6 a phenylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 and a 5- or 6-membered nitrogen-containing heterocyclic carbonyl group substituted with at least one group selected from alkoxy groups.

[0294] In one embodiment of the present invention, R a are each independently an aminocarbonyl group; a methylaminocarbonyl group optionally substituted with a halogen, an ethylaminocarbonyl group optionally substituted with a halogen, a propylaminocarbonyl group optionally substituted with a halogen, an isopropylaminocarbonyl group optionally substituted with a halogen, an n-butylaminocarbonyl group optionally substituted with a halogen, an isobutylaminocarbonyl group optionally substituted with a halogen, an s-butylaminocarbonyl group optionally substituted with a halogen, or a t-butylaminocarbonyl group optionally substituted with a halogen; optionally a halogen, C 1-6 a cyclopropylaminocarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C1-6 a cyclobutylaminocarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 a cyclopentylaminocarbonyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a phenylaminocarbonyl group substituted with at least one alkyl group; optionally a halogen atom, C 1-6 a pyrrolidinylcarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 a piperidinylcarbonyl group substituted with at least one alkyl group, optionally with a halogen atom, C 1-6 piperazinylcarbonyl groups substituted with at least one alkyl group.

[0295] In one embodiment of the present invention, R a are each independently an aminocarbonyl group; a methylaminocarbonyl group optionally substituted with a halogen, an ethylaminocarbonyl group optionally substituted with a halogen, a propylaminocarbonyl group optionally substituted with a halogen, an isopropylaminocarbonyl group optionally substituted with a halogen, an n-butylaminocarbonyl group optionally substituted with a halogen, an isobutylaminocarbonyl group optionally substituted with a halogen, an s-butylaminocarbonyl group optionally substituted with a halogen, or a t-butylaminocarbonyl group optionally substituted with a halogen; optionally a halogen, C 1-6 Alkyl group, C 1-6 a cyclopropylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a cyclobutylaminocarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a cyclopentylaminocarbonyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6a phenylaminocarbonyl group substituted with at least one selected from the group consisting of an alkoxy group; optionally a halogen atom, C 1-6 Alkyl group, C 1-6 an azetidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen, C 1-6 Alkyl group, C 1-6 a pyrrolidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a piperidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a piperazinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 A morpholinylcarbonyl group substituted with at least one alkoxy group is selected from the group consisting of morpholinylcarbonyl groups.

[0296] In one embodiment of the present invention, R a are each independently optionally halogen, C 1-6 Alkyl group, C 1-6 an azetidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen, C 1-6 Alkyl group, C 1-6 a pyrrolidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a piperidinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 a piperazinylcarbonyl group substituted with at least one selected from an alkoxy group, optionally a halogen atom, C 1-6 Alkyl group, C 1-6 When the morpholinyl group is selected from morpholinylcarbonyl groups substituted with at least one alkoxy group, the nitrogen atom of the ring is bonded to a carbonyl group (C═O).

[0297] In one embodiment of the present invention, each Cy2 is independently selected from a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group. In one embodiment of the present invention, each Cy2 is independently selected from a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 6-membered heteroaryl group.

[0298] In one embodiment of the present invention, each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 In one embodiment of the present invention, each R b are each independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, an aminocarbonyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0299] In one embodiment of the present invention, each R b are each independently a hydroxyl group, an amino group, a cyano group, a halogen atom, an aminocarbonyl group, or C 1-4 Alkyl group, C 1-4 Alkoxy group, amino C 1-4 Alkyl groups, halogenated C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkoxy group, amino C 1-4 Alkoxy group, halogenated C 1-4 Alkoxy group, C 1-4 Alkylthio group, C 1-4 Alkylamino group, (C 1-4 alkyl)2 amino group, C 1-4 alkylaminocarbonyl group, (C 1-4 alkyl)2 aminocarbonyl group, C 1-4 Alkylcarbonylamino group, C 1-4 It is selected from alkylcarbonyl groups.

[0300] In one embodiment of the present invention, each substituent A is independently selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group, amino C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, amino C 1-6 Alkoxy group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 alkylaminocarbonyl group, (C1-6 alkyl)2 aminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, C 1-6 It is selected from an alkylthio group, a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, a 5- to 10-membered heteroaryl group, and an oxo group.

[0301] In one embodiment of the present invention, each substituent A is independently selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-4 Alkyl group, C 1-4 Alkoxy group, amino C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkyl group, C 1-4 Alkoxy C 1-4 Alkoxy group, amino C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 alkyl)2 amino group, C 1-4 alkylaminocarbonyl group, (C 1-4 alkyl)2 aminocarbonyl group, C 1-4 Alkylcarbonylamino group, C 1-4 Alkylcarbonyl group, halogenated C 1-4 Alkyl groups, halogenated C 1-4 Alkoxy group, C 1-4 It is selected from an alkylthio group, a 3- to 6-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, a naphthyl group, a 5- to 10-membered heteroaryl group, and an oxo group.

[0302] In one embodiment of the present invention, in the formula (b) and the formula (b-1), an aminocarbonyl group (

[0303] [ka]

[0304] However, the nitrogen atom is bonded to the above atomic group according to the present invention, or the nitrogen atom is contained in a nitrogen-containing heterocycle. In one embodiment of the present invention, in the formula (b) and the formula (b-1), an aminocarbonyl group atomic group (

[0305] [ka]

[0306] However, the nitrogen atom is bonded to the above atomic group according to the present invention, or the nitrogen atom (contained in a nitrogen-containing heterocycle) is bonded to a ring-constituting carbon atom.

[0307] In one embodiment of the present invention, in formula (c), X5, X6, X7 or X8 may be an aminocarbonyl group (

[0308] [ka]

[0309] In one embodiment of the present invention, in formula (c-1) and formula (c-2), an aminocarbonyl group (

[0310] [ka]

[0311] However, the nitrogen atom is bonded to the above atomic group according to the present invention, or the nitrogen atom (contained in a nitrogen-containing heterocycle) is bonded to a benzene ring structure. In one embodiment of the present invention, in formula (c), X5, X6, X7, and X8 each independently represent CH.

[0312] In one embodiment of the present invention, in formula (c), X5, X6, X7 and X8 are not C=O.

[0313] In one embodiment of the present invention, in formula (A-1) and formula (A-2), Y1 is C=O and Y2 is NR d Shows.

[0314] In one embodiment of the invention, a nitrogen ring atom in the ring is bonded to a carbonyl group (C=O) to form an aminocarbonyl group.

[0315] In one embodiment of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, wherein the compound is selected from:

[0316] [Table 2-1]

[0317] [Table 2-2]

[0318] [Table 2-3]

[0319] [Table 2-4]

[0320] [Table 2-5]

[0321] [Table 2-6]

[0322] [Table 2-7]

[0323] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, and optionally further comprising one or more drug carriers.

[0324] In one embodiment of the present invention, there is provided a pharmaceutical composition of the above compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, or the use of the above pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention and / or treatment of a disease associated with or induced by SSAO / VAP-1 protein.

[0325] In one embodiment of the present invention, there is provided a method for preventing and / or treating a disease associated with or induced by SSAO / VAP-1 protein, said method comprising administering to a subject in need of treatment an effective amount of a pharmaceutical composition of the compound according to the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, or said pharmaceutical composition according to the present invention.

[0326] In one embodiment of the present invention, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0327] [ka]

[0328] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0329] R3 and R4 are each independently hydrogen or C 1-6 It is selected from alkyl groups, or forms a nitrogen-containing 5- to 10-membered heterocyclic ring optionally substituted with a substituent together with the nitrogen atom bonded thereto.

[0330] R5 and R6 are each independently hydrogen or C1-6 It is selected from alkyl groups.

[0331] L1 is absent or -CR'R''-, -N-, -O-, -S-, -SO2-, S(O), -SONR'-, -SON2NR'-, -NR'CONR'-, and R' and R'' are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0332] C y1 is unsubstituted or one or more R a is an atomic group represented by the following general formula (A), (a), (b) or (c) substituted with

[0333] [ka]

[0334] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0335] Y1, Y2, Y3, and Y4 are each independently selected from CH2, CH, NH, N, O, S, and C=O.

[0336] X1, X2, X3, X4, X9, X 10 are each independently selected from CH, CH, N, O, S, NH, and C=O; X, X, X, and X are each independently selected from CH or N; and at least one of X, X, and X is N or NH.

[0337] Each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C replaced with 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C1-6 Alkylthio group, C 1-6 Alkylthio C 1-6 Alkyl group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 Alkylamino C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonylamino C 1-6 Alkyl groups, (C 1-6 Alkyl)2amino C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl C 1-6 Alkyl group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylaminosulfonyl C 1-6 Alkyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkyl sulfonyl amino C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkyl Sulfonyl C 1-6 Alkyl group, Cy2-, Cy2-C 1-6 Alkyl group, Cy2-C 1-6 It is selected from an alkoxy group, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0338] Cy2 is a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 12-membered heterocyclic group, an aryl group, or a 5- to 14-membered heteroaryl group.

[0339] Each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 alkylsulfonyl groups.

[0340] As a condition, C y1 is formula (c), formula (c) may be one or more R a is replaced by

[0341] As a condition, C y1 is formula (b), X1, X2, X3, X9, X 10 is not C=O.

[0342] [ka]

[0343] represents a single or double bond.

[0344] [ka]

[0345] indicates an optional double bond moiety in the ring structure.

[0346] In one embodiment of the present invention, there is provided a compound represented by Formula I below, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof:

[0347] [ka]

[0348] (wherein R1 and R2 are each independently selected from hydrogen and halogen, and are not both hydrogen.

[0349] R3 and R4 are each independently hydrogen or C 1-6 It is selected from alkyl groups, or forms a nitrogen-containing 5- to 10-membered heterocyclic ring optionally substituted with a substituent together with the nitrogen atom bonded thereto.

[0350] R5 and R6 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0351] L1 is absent or -CR'R''-, -N-, -O-, -S-, -SO2-, S(O), -SONR'-, -SON2NR'-, -NR'CONR'-, and R' and R'' are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0352] C y1 is unsubstituted or one or more R a is an atomic group represented by the following general formula (A-1), (A-2), (A-3), (a), (b) or (c), which is substituted with

[0353] [ka]

[0354] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0355] Y1, Y2, Y3, and Y4 are each independently selected from CH2, CH, NH, N, O, S, and C=O.

[0356] X1, X2, X3, X4, X9, X 10are each independently selected from CH, CH, N, O, S, NH, and C=O; X, X, X, and X are each independently selected from CH or N; and at least one of X, X, and X is N or NH.

[0357] Each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C replaced with 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylthio C 1-6 Alkyl group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 Alkylamino C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonylamino C 1-6 Alkyl groups, (C 1-6 Alkyl)2amino C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl C 1-6 Alkyl group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylaminosulfonyl C 1-6 Alkyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkyl sulfonyl amino C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkyl Sulfonyl C1-6 Alkyl group, Cy2-, Cy2-C 1-6 Alkyl group, Cy2-C 1-6 It is selected from an alkoxy group, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0358] Cy2 is a 3- to 12-membered cycloalkyl group, a 3- to 12-membered cycloalkenyl group, a 3- to 12-membered heterocyclic group, an aryl group, or a 5- to 14-membered heteroaryl group.

[0359] Each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 alkylsulfonyl groups.

[0360] As a condition, C y1 is formula (c), formula (c) may be one or more R a is replaced by

[0361] As a condition, C y1 is formula (b), X1, X2, X3, X9, X 10 is not C=O.

[0362] [ka]

[0363] represents a single or double bond.

[0364] [ka]

[0365] indicates an optional double bond moiety in the ring structure.

[0366] In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen, halogen, and are not simultaneously hydrogen.

[0367] R3 and R4 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0368] R5 and R6 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0369] L1 is absent or is -CR'R''-, -N-, -O-, or -S-, and R' and R'' are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0370] C y1 is unsubstituted or one or more R a is an atomic group represented by the following general formula (A-1), (A-2), (A-3), (a), (b) or (c), which is substituted with

[0371] [ka]

[0372] m is an integer from 0 to 3, and n is an integer from 0 to 2.

[0373] Y1, Y2, Y3, and Y4 are each independently selected from CH2, CH, NH, N, and C=O.

[0374] X1, X2, X3, X4, X9, X 10 are each independently selected from CH2, CH, N, NH, and C=O; X5, X6, X7, and X8 are each independently selected from CH or N; and at least one of X1, X2, and X3 is N or NH.

[0375] Each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylthio C 1-6 Alkyl group, C 1-6 Alkylamino group, C 1-6 Alkylamino C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonylamino C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl C 1-6 Alkyl group, Cy2, Cy2-C 1-6 Alkyl group, Cy2-C 1-6 It is selected from an alkoxy group, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0376] Cy2 is a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 10-membered heteroaryl group.

[0377] Each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0378] As a condition, C y1 is formula (c), formula (c) may be one or more R a is replaced by

[0379] As a condition, C y1 is formula (b), X1, X2, X3, X9, X 10 is not C=O.

[0380] [ka]

[0381] indicates an optional double bond moiety in the ring structure.

[0382] In one embodiment of the present invention, C y1 is unsubstituted or one or more R a is an atomic group substituted with the following general formula (A-11), (a-1), (a-2), (b-1), (c-1) or (c-2):

[0383] [ka]

[0384] m is an integer between 1 and 2.

[0385] Y1, Y2, and Y3 are each independently selected from CH2, CH, NH, and N.

[0386] X1, X2, X3, X4, and X9 are each independently selected from CH2, CH, N, NH, and C=O, and at least one of X1, X2, and X3 is N or NH.

[0387] As a condition, C y1 is represented by formula (c-1) or (c-2), the formula (c-1) or (c-2) may be one or more R a is replaced by

[0388] As a condition, C y1 is the formula (b-1), X1, X2, X3, and X9 are not C=O.

[0389] [ka]

[0390] indicates an optional double bond moiety in the ring structure.

[0391] In one embodiment of the present invention, C y1 is unsubstituted or one or more R a is an atomic group substituted with the following general formula (A-11) or (a-1).

[0392] [ka]

[0393] m is an integer between 1 and 2.

[0394] Y2 and Y3 are each independently selected from CH2, CH, NH, and N.

[0395] X1, X2, and X3 are each independently selected from CH2, CH, N, and NH, and at least one of X1, X2, and X3 is N or NH.

[0396] [ka]

[0397] indicates an optional double bond moiety in the ring structure.

[0398] In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen, halogen, and are not simultaneously hydrogen.

[0399] R3 and R4 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0400] R5 and R6 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0401] L1 does not exist.

[0402] C y1 is unsubstituted or one or more R a is the following atomic group substituted with

[0403] [ka]

[0404] Each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 1-6 Alkylamino C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl group, C 1-6 Alkylcarbonylamino group, C1-6 Alkylcarbonylamino C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl C 1-6 Alkyl group, Cy2, Cy2-C 1-6 Alkyl group, Cy2-C 1-6 It is selected from an alkoxy group, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0405] Cy2 is a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 10-membered heteroaryl group.

[0406] Each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6 It is selected from alkylcarbonyl groups.

[0407] [ka]

[0408] indicates an optional double bond moiety in the ring structure.

[0409] Preferably, Cy2 is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0410] In one embodiment of the present invention, C y1 is unsubstituted or one or more R ais an atomic group represented by the following general formula (b-1) substituted with

[0411] [ka]

[0412] X1, X2, X3, and X9 are each independently selected from CH2, CH, N, and NH, and at least one of X1, X2, and X3 is N or NH.

[0413] [ka]

[0414] indicates an optional double bond moiety in the ring structure.

[0415] The condition is that in general formula (b-1), X1, X2, X3, and X9 are not C=O.

[0416] In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen, halogen, and are not simultaneously hydrogen.

[0417] R3 and R4 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0418] R5 and R6 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0419] L1 does not exist.

[0420] C y1 is unsubstituted or one or more R a is the following atomic group substituted with

[0421] [ka]

[0422] Each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 1-6 Alkylamino C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonylamino C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl C 1-6 Alkyl group, Cy2, Cy2-C 1-6 Alkyl group, Cy2-C 1-6 It is selected from an alkoxy group, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0423] Cy2 is a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 10-membered heteroaryl group.

[0424] Each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Alkylaminocarbonyl group, C 1-6 Alkylcarbonylamino group, C 1-6It is selected from alkylcarbonyl groups.

[0425] In one embodiment of the present invention, C y1 is unsubstituted or one or more R a is the following atomic group substituted with

[0426] [ka]

[0427] In one embodiment of the present invention, R1 and R2 are each independently selected from hydrogen and fluorine, and are not simultaneously hydrogen.

[0428] In one embodiment of the present invention, C y1 is one or more substituents R a is the following atomic group substituted with

[0429] [ka]

[0430] In one embodiment of the present invention, each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 It is selected from an alkylaminocarbonyl group, Cy2, a Cy2-carbonyl group, and a Cy2-aminocarbonyl group.

[0431] Cy2 is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0432] In one embodiment of the present invention, each R b are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, C 1-6 Alkyl group, C 1-6The alkoxy group is selected from the group consisting of alkoxy groups.

[0433] In one embodiment of the present invention, C y1 is one or more substituents R a is the following atomic group substituted with

[0434] [ka]

[0435] In one embodiment of the present invention, each R a are independently a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an unsubstituted or one or more R b C substituted with a substituent 1-6 It is selected from alkyl groups and 3- to 6-membered cycloalkyl groups.

[0436] In one embodiment of the present invention, each R b are independently selected from a hydroxyl group, an amino group, a cyano group, a nitro group, and a halogen atom.

[0437] The "pharmaceutically acceptable salts" of the present invention refer to medicament-acceptable acid and base addition salts or solvate addition salts of compounds of Formula I. When the compound has an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), the salts may be formed with suitable inorganic or organic cations (bases), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and nitrogen-containing organic bases. When the compound has a basic functional group (e.g., -NH2, etc.), the salts may be formed with suitable inorganic or organic anions (acids), including salts formed with inorganic and organic acids. These "pharmaceutically acceptable salts" include, but are not limited to, acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, benzenesulfonate, benzoate, p-toluenesulfonate, 2,3-dihydroxybutanedioate, camphorsulfonate, citrate, methanesulfonate, ethanesulfonate, propanesulfonate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, succinate, and tartrate. Particularly preferred are salts of benzoate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, tartrate, and alkanoic acid (HOOC-(CH)). n-COOH (where n is 0 to 4)) salts (e.g., formate, acetate, propionate). Pharmaceutically acceptable salts include, but are not limited to, salts formed with bases such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. Pharmaceutically acceptable salts may also include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, barium salts, aluminum salts, iron salts, copper salts, ferrous salts, manganese salts, and divalent manganese salts.

[0438] A "pharmaceutically acceptable ester" of a compound of the present invention is an ester that is hydrolyzed in vivo by the compound of the present invention, including esters that are readily decomposed in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, ester groups derived from pharmaceutically acceptable aliphatic carboxylic acids (particularly alkanoic acids, alkenoic acids, cycloalkanoic acids, and alkanedioic acids), preferably having 6 or fewer carbon atoms in each alkyl or alkenyl moiety. Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

[0439] In the present invention, the nitrogen atom of an amino group may be optionally protected with an amino-protecting group during the reaction. The term "amino-protecting group" refers to an atomic group that is bonded to an amino group and is easily released under certain conditions. Examples of such groups include, but are not limited to, alkoxycarbonyl groups, acyl groups, and alkyl groups. Examples include t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, and trityl groups. Those skilled in the art will readily understand the details of such groups in the textbook Greene's Protective Groups in Organic Synthesis (4 th Appropriate selection and handling can be carried out by referring to the relevant edition.

[0440] The phrase "pharmaceutically acceptable" means that the substance or composition is pharmaceutically and / or toxicologically compatible with other ingredients contained in the formulation and / or pharmaceutical composition.

[0441] The term "isomer" as used herein includes stereoisomers and tautomers.

[0442] Stereoisomers are enantiomers that occur when a compound has an asymmetric carbon, but cis-trans isomers that occur when a compound has a carbon-carbon double bond or a cyclic structure.

[0443] A "tautomer" is a functional isomer that occurs when an atom in a molecule moves rapidly between two positions, but it is a special functional isomer. For example, in the case of a tautomer of a carbonyl group compound having α-H,

[0444] [ka]

[0445] where T, T1, and T2 are each independently any atomic group that complies with the compound bond-forming rules.

[0446] "Tautomers" may be, for example, other prototropic tautomers, specifically, but not limited to, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. Those skilled in the art can easily determine whether tautomers of a compound exist or their specific form.

[0447] Thus, all enantiomers, non-enantiomers, racemic isomers, cis-trans isomers, geometric isomers, epi isomers, tautomers, and mixtures thereof of any Formula I compounds are included within the scope of the present invention.

[0448] The pharmaceutical compositions of the present invention comprise at least one compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, and optionally one or more pharmaceutical carriers.

[0449] The pharmaceutical compositions of the present invention may be administered to a patient or subject in need of prophylaxis and / or treatment by any suitable route known in the art, such as oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration.

[0450] The pharmaceutical compositions of the present invention can be formulated into conventional solid preparations, such as tablets, capsules, pills, and granules; or into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. When formulating oral preparations, one or more suitable excipients, diluents, sweeteners, solubilizers, lubricants, adhesives, tablet disintegrants, stabilizers, preservatives, or encapsulating materials can be added. For parenteral administration, the pharmaceutical compositions can be formulated into injections, including injection solutions, sterile powders for injections, and concentrated solutions for injections. Injections can be produced using conventional methods currently used in the pharmaceutical industry. Injections can be prepared without additives or by adding appropriate additives according to the properties of the pharmaceutical. For rectal administration, the pharmaceutical compositions can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical compositions can be formulated into inhalants or sprays, etc. In the present invention, suitable solid carriers include, but are not limited to, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, trout gum, acacia, sodium alginate, paraben, methylcellulose, carboxymethylcellulose, low melting wax, cocoa butter, etc. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerides, and mixtures thereof.

[0451] The pharmaceutical compositions of the present invention are generally prepared by known methods. Known methods for preparing the pharmaceutical compositions of the present invention are conventional mixing, granulating, tableting, coating, dissolving or lyophilizing methods.

[0452] The pharmaceutical preparations are preferably in unit dose form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dose forms can be packaged in the form of a preparation containing discrete amounts, for example, packaged tablets, capsules, or powders in vials or ampoules.

[0453] The dosage of a pharmaceutical depends on various factors, such as the age, weight, condition, and route of administration of the patient. The exact dosage to be administered is determined by the judgment of the treating physician. Typical dosages for administering an active compound may be, for example, about 0.01 to about 100 mg daily, about 0.05 to about 75 mg / day, about 0.1 to about 50 mg / day, or about 5 to about 10 mg / day. The desired dosage also depends on the particular compound employed, the severity of the disease, the route of administration, the patient's weight and health, and the judgment of the treating physician.

[0454] The compounds of the present invention further include compounds in which one or more hydrogen, fluorine, carbon, nitrogen, oxygen, or sulfur atoms are substituted with radioactive or stable isotopes. These labeled compounds are used in metabolic or pharmacokinetic studies, and in biological analyses as receptor ligands.

[0455] The compounds of the present invention can be applied to the treatment and / or prevention of diseases associated with or induced by SSAO / VAP-1 protein, which comprises administering a compound of the present invention to a subject.

[0456] Pharmaceutical compositions containing the compounds of the present invention can be applied to the treatment and / or prevention of diseases associated with or induced by SSAO / VAP-1 protein, which comprises administering the compounds of the present invention to a subject.

[0457] Process for preparing the compounds of general formula (I) of the present invention

[0458] The compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Unless otherwise specified, previously defined variables retain their previously defined meanings. Exemplary conventional synthetic methods are described in the following embodiments, but they can be readily modified to prepare other compounds of the present invention. Those skilled in the art will readily appreciate that conventional methods known in the art (e.g., Organic Synthesis 2002) can be readily modified to prepare other compounds of the present invention. ndThe following reactions can be carried out by the method of the present invention (Michael B. Smith et al., edition). In the Examples section, the compounds of the present invention are specifically prepared.

[0459] In one embodiment of the present invention, the compound of general formula (I) is obtained by the reaction of formula (SM1) with formula (SM2).

[0460] [ka]

[0461] (wherein Cy1, R1, R2, R3, R4, R5, R6, and L1 are as defined above. X1 is a leaving group, including, but not limited to, a halogen or a sulfonate.)

[0462] Furthermore, when R3 and R4 are hydrogen,

[0463] [ka]

[0464] Protect the hydrogen atom bonded to N in the structure,

[0465] [ka]

[0466] where G1 and G2 are each amino protecting groups.

[0467] The "amino-protecting group" is a protecting group commonly used by those skilled in the art, such as t-butyloxycarbonyl, benzyloxycarbonyl, t-butyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl, chloroacetyl, triphenylmethyl, tetrahydropyranyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzenesulfonyl, and phthaloyl. The methods for protecting and deprotecting the amino group may be any known method by those skilled in the art, and may be, for example, those described in "Protective Groups in Organic Synthesis, 3 rd You may refer to the steps described in the edition.

[0468] In one embodiment of the present invention, a compound represented by general formula (I')

[0469] [ka]

[0470] (wherein Cy1, G1, G2, and X1 are defined as above) (1) Formula (SM1) is dissolved in an organic solvent 1 a step of dissolving the compound in a suitable base and reacting it with compound (SM2-a) to obtain compound (II-a); (2) Formula (II-a) in an organic solvent 2 and a step of dissolving the compound in a suitable deprotecting reagent and then deprotecting the compound to obtain the compound of formula (I').

[0471] In one embodiment of the present invention, a compound represented by general formula (I')

[0472] [ka]

[0473] (However, the definitions of Cy1 and X1 are as described above.

[0474] G2 is selected from a t-butyloxycarbonyl group, a benzyloxycarbonyl group, a t-butyl group, a 9-fluorenylmethyloxycarbonyl group, an allyloxycarbonyl group, a trifluoroacetyl group, a chloroacetyl group, a triphenylmethyl group, a tetrahydropyranyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, and an o-nitrobenzenesulfonyl group; (1) Formula (SM1) is dissolved in an organic solvent 1 and adding (SM2-c) and a base to obtain formula (II-c); (2) Formula (II-c) in an organic solvent 2 and a step of dissolving the compound in a solvent, adding a deprotecting agent, and carrying out deprotection to obtain the compound of formula (I').

[0475] In one embodiment of the present invention, a compound represented by general formula (I')

[0476] [ka]

[0477] (wherein Cy1 and X1 are defined as above) (1) Formula (SM1) is dissolved in an organic solvent 1 a step of dissolving the compound in a suitable base and reacting it with compound (SM2-b) to obtain compound (II-b); (2) Formula (II-b) in an organic solvent 2 and a step of dissolving the compound in toluene, adding hydrazine hydrate, and carrying out a hydrazine decomposition reaction to obtain the compound of formula (I').

[0478] In one embodiment of the present invention, the organic solvent 1 are DMF, DMA, ACN, methanol, ethanol, isopropanol, and THF.

[0479] In one embodiment of the present invention, the organic solvent 2 are methanol, ethanol, and isopropanol.

[0480] In one embodiment of the present invention, the base is sodium hydride, cesium carbonate, or potassium carbonate.

[0481] In one embodiment of the present invention, the deprotecting agent is hydrochloric acid, trifluoroacetic acid, hydrobromic acid, iodotrimethylsilane, or the like.

[0482] In one embodiment of the present invention, a phase transfer catalyst may be added during the reaction to obtain the target compound. The phase transfer catalyst may be a catalyst commonly used in the art, including, but not limited to, copper acetate, copper chloride, palladium on carbon, iron chloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, etc.

[0483] The "appropriate deprotecting agent" is a reagent that a person skilled in the art can select an appropriate acid, base, or oxidizing agent depending on the amino-protecting groups G1 and G2 in the chemical structure to carry out the deprotection reaction. Protective Groups in Organic Synthesis, 3 rd You may use the one described in the edition.

[0484] In the present invention, the "acid" may be any acid commonly used in this field, including organic and inorganic acids. Examples of organic acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and hydroiodic acid. Hydrochloric acid is preferred.

[0485] In the present invention, the "base" may be any base commonly used in this field, including organic and inorganic bases. Examples of organic bases include methylamine, ethylamine, propylamine, N,N-diisopropylethylamine, trimethylamine, triethylamine, N-methylmorpholine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, and quinoline. Examples of inorganic bases include hydrides, carbonates, and bicarbonates of alkali metals (e.g., lithium, sodium, potassium, and cesium); hydrides, carbonates, and bicarbonates of alkaline earth metals (magnesium, calcium, strontium, and barium); sodium t-butoxide, potassium t-butoxide, and sodium ethoxide.

[0486] In the present invention, the "oxidizing agent" may be an oxidizing agent commonly used in the art, including, but not limited to, cerium ammonium nitrate, 2,3-dichloro-5,6-dicyan-p-benzoquinone, copper chloride, manganese dioxide, permanganate, dichromate, peracetic acid, perbenzoic acid, etc.

[0487] In the present invention, the "organic solvent 1" refers to a single or mixed organic solvent commonly used in this field, including, but not limited to, ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, and alcohols. Specific examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, ethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), water, and mixed solvents thereof.

[0488] In the present invention, the "organic solvent 2 " refers to a single or mixed organic solvent commonly used in this field, including, but not limited to, ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, and alcohols. Specific examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, ethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), water, and mixed solvents thereof.

[0489] In the present invention, the reaction temperature may be adjusted as needed during the reaction, for example, to a high temperature, room temperature, low temperature, or the like. A high temperature is usually a temperature higher than 30°C, and a heat treatment may be performed as needed. Room temperature is usually 15 to 30°C. A low temperature is usually a temperature lower than 15°C, and a cooling treatment may be performed as needed. [Example]

[0490] In the examples, unless specific reaction conditions are specified, the reaction is carried out under standard conditions or under conditions recommended by the manufacturer. Reagents or instruments for which the manufacturer is not specified are all commercially available standard products.

[0491] In the present invention, unless otherwise specified, (i) temperatures are expressed in degrees Celsius (°C) and operations are performed in a room temperature environment; (ii) reaction progress is followed up by thin layer chromatography (TLC) or LC-MS; (iii) the final product has a clear proton nuclear magnetic resonance ( 1 H-NMR data and mass spectrometry (MS) data are available.

[0492] The abbreviations and English descriptions used in this invention have the following meanings: DCM: dichloromethane DIPEA: N,N-diisopropylethylamine -Boc: t-butoxycarbonyl group (Boc)2O: di-t-butylmethyl dicarbonate TEA: Triethylamine DMSO: dimethyl sulfoxide DMA or DMAc: Dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: ethanol EtONa: Sodium ethoxide aq.HCl: Dilute hydrochloric acid NaH: sodium hydride N2H4:Hydrazine AcONa: Sodium acetate Ac2O: acetic anhydride ACN: acetonitrile THF: tetrahydrofuran CuI: Cuprous iodide Cs2Co3: Cesium carbonate K2CO3: Potassium carbonate EA: Ethyl acetate MeOH: Methanol MTBE: Methyl t-butyl ether PE: Petroleum ether HATU: 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate TBAB: Tetrabutylammonium bromide (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindole-1,3-dione It can be prepared by the synthetic method of the intermediate reported by Ian A. McDonald et al. (Ian A. McDonald, Philippe Bey. A general preparation of fluoroallylamine enzyme inhibitors incorporating a β-substituted heteroatom. Tetrahedron Letters, Vol. 1, 26, No. 32, pp. 3807-3810, 1985).

[0493] Example 1: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A1)

[0494] [ka]

[0495] Step 1: Synthesis of (E)-1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0496] [ka]

[0497] The starting material, cyclopropylpiperidine-2,4-dione (5 g, 32.6 mmol, 1.0 eq), was slowly added to DMF-DMA (5 g, 41.8 mmol, 1.28 eq) and allowed to react at 25°C for 2 hours. The reaction was complete as determined by TLC. The reaction was concentrated to give the crude product (theoretical yield 6.789 g), which was used directly in the next reaction.

[0498] Step 2: Synthesis of 5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0499] [ka]

[0500] The crude (E)-1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione (calculated 6.789 g, 32.6 mmol) obtained in the previous step was dissolved in MeOH (50 mL) and 85% hydrazine hydrate (2.1 g, 35.9 mmol, 1.1 eq) was added. The mixture was refluxed for 0.5 h, and the reaction was complete by TLC. The reaction mixture was concentrated and allowed to stand to precipitate a large amount of white solid. A small amount of MTBE was added, and the cake was filtered under suction. The cake was recrystallized with 2 volumes of 95% EtOH, filtered under suction, and dried at 50 °C to give the product (3.7 g, 64% yield for two steps).

[0501] Step 3: Synthesis of (E)-2-(2-((5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione

[0502] [ka]

[0503] The intermediate 5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.0 g, 5.643 mmol, 1 eq) was dissolved in DMF (2.5 mL), cooled to 0 °C, and under nitrogen gas protection, 60% NaH (248 mg, 6.207 mmol, 1.1 eq) was added. Stir under nitrogen gas protection for 30 min, and then a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindole-1,3-dione (2.019 g, 6.722 mmol, 1.2 eq) in DMF (2.5 mL) was added dropwise. The reaction was allowed to proceed at 18 °C for 1 hour, and the reaction was determined to be complete by TLC. Extract with water (10 mL) and DCM:MeOH = 10:1 (15 mL × 3), wash the organic phase with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by silica gel column chromatography (eluent DCM:MeOH = 200:1) to obtain the product (583 mg, yield: 26.2%).

[0504] Step 4: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0505] [ka]

[0506] The intermediate (E)-2-(2-((5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione (583 mg, 1.478 mmol, 1 eq) was dissolved in EtOH (15 mL) and 85% hydrazine hydrate (305 mg, 5.174 mmol, 3.5 eq) was added and the mixture was refluxed for 2 hours. Upon completion of the reaction by TLC, the mixture was filtered with suction, concentrated, and the crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to give the product (70 mg, 17.9% yield).

[0507] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.12 (s, 1H), 6.79-7.00 (d, 1H), 4.70-4.71 (d, 2H), 3.48-3.51 (t, 2H), 3.04-3.05 (d, 2H), 2.75-2.78 (t, 2H), 2.59-2.65 (m, 1H), 0.71-0.76(m, 2H), 0.59-0.61 (m, 2H).

[0508] Molecular formula:C 13 H 17 FN4O, molecular weight: 264.30, LC-MS (Pos, m / z)=265.25 [M+H] + .

[0509] Example 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A2) hydrochloride

[0510] [ka]

[0511] Step 1: Synthesis of (E)-1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0512] [ka]

[0513] The starting material, cyclopropylpiperidine-2,4-dione (20 g, 0.130 mol, 1.0 eq) was slowly added to DMF-DMA (19.9 g, 0.167 mol, 1.28 eq) and stirred at 25°C for 2 hours. The reaction was complete as determined by TLC. The reaction was concentrated at 50°C to obtain the crude product, which was used directly in the next reaction.

[0514] Step 2: Synthesis of 5-cyclopropyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0515] [ka]

[0516] The intermediate (E)-1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione (calculated at 27.073 g, 0.130 mol) was dissolved in MeOH (100 mL) and 85% hydrazine hydrate (8.4 g, 0.143 mol, 1.1 eq) was added. The mixture was refluxed for 1 hour, and the reaction was complete by TLC. The reaction mixture was concentrated to give the crude product, which was recrystallized from 95% EtOH, filtered with suction, and the cake was dried at 50 °C to give the product (16 g, yield: 69.6%).

[0517] Step 3: Synthesis of (E)-2-(2-((5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione

[0518] [ka]

[0519] The intermediate 5-cyclopropyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (2000 mg, 11.286 mmol, 1 eq) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% NaH (496 mg, 12.414 mmol, 1.1 eq) was added under nitrogen protection. Stirred for 30 min under nitrogen protection, and then a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindole-1,3-dione (4037 mg, 13.543 mmol, 1.2 eq) in DMF (5 mL) was added dropwise. The reaction was allowed to proceed at 19 °C overnight at room temperature, and the reaction was determined to be complete by TLC. The reaction mixture was extracted with water (20 mL) and DCM:MeOH=10:1 (30 mL×3). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH=200:1) to give the product (100 mg, yield: 2.2%).

[0520] Step 4: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0521] [ka]

[0522] The intermediate (E)-2-(2-((5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione (70 mg, 0.177 mmol, 1 eq) was dissolved in EtOH (1.75 mL) and 85% hydrazine hydrate (36 mg, 0.621 mmol, 3.5 eq) was added. The mixture was refluxed for 2 hours. When the reaction was complete by TLC, the mixture was filtered under suction, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain the crude product. The crude product was dissolved in a small amount of ethanol, and hydrogen chloride in ethanol (0.1 mL) was added and stirred for 1 h to precipitate a solid. MTBE and PE were added to precipitate a white solid. The mixture was filtered under suction, and the cake was dried to obtain the product (40 mg, yield 74.9%).

[0523] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.46 (s, 3H), 7.72 (s, 1H), 7.06-7.26 (d, 1H), 4.89 (d, 2H), 3.54-3.57 (t, 2H), 3.43-3.44 (d, 2H), 2.98-3.02 (t, 2H), 2.57-2.62 (m, 1H), 0.71-0.76 (t, 2H), 0.56-0.60 (m, 2H).

[0524] Molecular formula:C 13 H 18 ClFN4O Molecular weight: 300.76 LC-MS(Pos, m / z)=264.8 [M+H] + .

[0525] Example 3: Synthesis of compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (compound A6) hydrochloride salt

[0526] [ka]

[0527] Step 1: Synthesis of intermediate (E)-(3-fluoro-2-((5-ethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)carbamate t-butyl

[0528] [ka]

[0529] The intermediate (E)-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (1.0 g, 3.08 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), sodium hydride (160 mg, 4.0 mmol, 1.3 eq, 60%) was added, and the mixture was incubated at room temperature for 30 min. Iodoethane (576 mg, 3.7 mmol, 1.2 eq) was added, and the mixture was heated to 60 °C and incubated for 4 h. The reaction was determined to be complete by LC-MS. The reaction flask was charged with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was dried and concentrated, and the crude product was purified by thin layer chromatography (MeOH:DCM = 1:20) to give the product (180 mg, yield: 16%).

[0530] Step 2: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0531] [ka]

[0532] The intermediate (E)-(3-fluoro-2-((5-ethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (180 mg, 0.51 mmol, 1.0 eq) was dissolved in ethanol (2 mL) and hydrogen chloride ethanol solution (2 mL) was added. The reaction was allowed to proceed for 12 h, and the reaction was complete as determined by LC-MS. The mixture was concentrated under reduced pressure, dissolved in water, and lyophilized to give the product (120 mg, 83% yield).

[0533] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.47 (s, 3H), 8.27 (s, 1H), 7.37 (s, 0.5H), 7.16 (s, 0.5H), 4.93 (s, 2H), 3.52-3.56 (m, 2H), 3.39-3.42 (m, 2H), 3.32-3.33 (d, 2H), 2.81-2.84(m, 2H), 1.04-1.07 (m, 3H).

[0534] Molecular formula:C 12 H 17 FN4O molecular weight:252.29 LC-MS(Pos, m / z)=253.22[M+H] + .

[0535] Example 4: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-t-butyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A7) hydrochloride

[0536] [ka]

[0537] Step 1: Synthesis of ethyl 3-(t-butylamino)propionate

[0538] [ka]

[0539] Dissolve t-butylamine (87.66 g, 1.20 mol, 1.2 eq) in ethanol (400 mL), add ethyl acrylate (100.00 g, 1.00 mol, 1.0 eq) dropwise in an ice bath, and react overnight at room temperature. GC shows no remaining starting material. Concentrate under reduced pressure to obtain the product (173 g, 99% yield).

[0540] Step 2: Synthesis of ethyl 3-(t-butyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate

[0541] [ka]

[0542] The intermediate ethyl 3-(t-butylamino)propionate (70.00 g, 0.404 mol, 1.0 eq), monoethyl malonate (53.37 g, 0.404 mol, 1.0 eq), 4-dimethylaminopyridine (9.88 g, 0.0808 mmol, 0.2 eq), and triethylamine (102.30 g, 1.010 mol, 2.5 eq) were dissolved in dichloromethane (490 mL) and stirred in an ice bath for 15 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93.02 g, 0.485 mol, 1.2 eq) was added in several portions, allowed to warm to room temperature, and allowed to react overnight. The reaction was complete as determined by TLC. Add water and concentrated hydrochloric acid (3:1, 360 mL) to a reaction flask in an ice bath, stir for 15 min, separate the layers, extract the aqueous phase with dichloromethane (300 mL), combine the organic phases, wash with saturated aqueous sodium bicarbonate (800 mL) and saturated aqueous sodium chloride (800 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the product (114 g, yield: 98.2%).

[0543] Step 3: Synthesis of 1-t-butylpiperidine-2,4-dione

[0544] [ka]

[0545] Ethyl 3-(t-butyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate (114.00 g, 0.397 mol, 1.0 eq) and sodium ethoxide (53.99 g, 0.793 mol, 2.0 eq) were dissolved in ethanol (456 mL) and reacted at 80 °C for 4 h, at which point the reaction was determined complete by TLC. The mixture was concentrated under reduced pressure to give the intermediate 1-t-butyl-2,4-dioxopiperidine-3-carboxylate sodium salt. The mixture was added with water, adjusted to pH 2 with concentrated hydrochloric acid, and reacted at 85 °C for 5 h and then at 95 °C for 1.5 h, at which point the reaction was determined complete by LC-MS. The reaction mixture was cooled to room temperature, and sodium chloride was added until the reaction mixture was saturated. The mixture was then extracted with dichloromethane (400 mL x 3). The organic phase was dried and concentrated to give an oily crude product. After cooling, a solid precipitated. MTBE was added and the mixture was stirred to precipitate a large amount of solid. The cake was filtered with suction, washed with a small amount of MTBE, and dried to give the product (45.3 g, yield: 67.48%).

[0546] Step 4: Synthesis of 5-t-butyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0547] [ka]

[0548] The intermediate 1-t-butylpiperidine-2,4-dione (40 g, 0.207 mol, 1.0 eq) was dissolved in N,N-dimethylformamide dimethyl acetal (35.04 g, 0.265 mol, 1.28 eq) and reacted at room temperature for 3 h. The reaction was complete as determined by TLC. Concentration under reduced pressure gave the intermediate (E)-1-t-butyl-3-((dimethylamino)methylene)piperidine-2,4-dione. Methanol (200 mL) and hydrazine hydrate (15.3 g, 0.228 mol, 1.1 eq) were added and the mixture was refluxed for 1 h. When the reaction is complete as indicated by LC-MS, concentrate under reduced pressure, add MTBE (300 mL), and stir overnight. A large amount of solid precipitates, which is filtered off with suction, washed with MTBE, and dried to give the product (40.00 g, yield: 87.7%).

[0549] Step 5: (E)-2-(2-((5-t-butyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0550] [ka]

[0551] 5-t-Butyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.08 g, 5.59 mmol, 1.0 eq) was dissolved in DMF (10 mL), cooled to 0 °C, and NaH (60% by mass, 246 mg, 6.147 mmol, 1.1 eq) was added. Stirred for 30 min, and then a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (2.00 g, 6.706 mmol, 1.2 eq) in DMF (5 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h, and the reaction was determined to be complete by LC-MS. Add water (12 mL), extract with a mixture of dichloromethane and methanol (10:1, 25 mL × 3), separate, combine the organic phases, backwash with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 3:1 to 2:1, with 0.5% triethylamine) to obtain the product (E)-2-(2-((5-t-butyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (1.3 g, Yield: 56.7%) and the regioisomeric (E)-2-(2-((5-(t-butyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (350 mg, yield: 15.3%).

[0552] Step 6: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-t-butyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0553] [ka]

[0554] (E)-2-(2-((5-t-butyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (1000 mg, 2.438 mmol, 1.0 eq) was dissolved in EtOH (30 mL), and hydrazine hydrate (502.4 mg, 8.531 mmol, 3.5 eq, 85%) was added. The mixture was refluxed for 2 h. When the reaction is complete as determined by LC-MS, the mixture is filtered with suction, the filtrate is concentrated under reduced pressure, EA (30 mL) is added, the mixture is refluxed, and the mixture is filtered while hot. The filtrate is concentrated under reduced pressure, diluted with a small amount of ethanol, hydrogen chloride ethanol solution is added, and the mixture is stirred at room temperature for 30 minutes. Acetonitrile is added, and the mixture is concentrated under reduced pressure to give the product (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-t-butyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride (747.9 mg, yield: 98%).

[0555] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 8.51 (brs, 3H), 8.22 (s, 1H), 7.16-7.36 (d, J=82 Hz, 1H), 4.93 (s, 2H), 3.52-3.56 (t, 2H), 3.31-3.32(d, 2H), 2.73-2.76 (t, 2H), 2.08 (s, 1H), 1.42 (s, 9H).

[0556] Molecular formula:C 14 H 21 FN4O molecular weight:280.35 LC-MS(Pos, m / z)=281.23[M+H] + .

[0557] Example 5: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclobutyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A9) hydrochloride

[0558] [ka]

[0559] Step 1: Synthesis of ethyl 3-(cyclobutylamino)propionate

[0560] [ka]

[0561] The starting material, cyclobutylamine (4.26 g, 59.93 mmol, 1.2 eq), was dissolved in ethanol (50 mL), and ethyl acrylate (5.0 g, 49.94 mmol, 1.0 eq) was slowly added dropwise in an ice bath. The reaction mixture was allowed to react for 12 hours, and TLC showed no remaining starting material. The mixture was concentrated under reduced pressure at 80 °C to give the product (8.55 g, 100% yield).

[0562] Step 2: Synthesis of ethyl 3-(cyclobutyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate

[0563] [ka]

[0564] The intermediate, ethyl 3-(cyclobutylamino)propionate (8.55 g, 49.94 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL), cooled to 0 °C in an ice-water bath, and monoethyl malonate (6.6 g, 49.94 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. Triethylamine (12.6 g, 124.85 mmol, 2.5 eq), 4-dimethylaminopyridine (609.6 mg, 4.99 mmol, 0.1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.5 g, 59.93 mmol, 1.2 eq) were then added in that order. The reaction was allowed to proceed for 12 hours, and the reaction was confirmed to be complete by TLC. Add 2.5 mol / L hydrochloric acid (100 mL), stir for 10 minutes, separate the layers, extract the aqueous phase with dichloromethane (50 mL), combine the organic phases, wash the organic phase with saturated aqueous sodium carbonate (50 mL) and water (50 mL) successively, separate the layers, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to give the product (10.1 g, yield: 71.1%).

[0565] Step 3: Synthesis of ethyl 1-cyclobutyl-2,4-dioxopiperidine-3-carboxylate

[0566] [ka]

[0567] The intermediate, ethyl 3-(cyclobutyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate (10.1 g, 35.40 mmol, 1.0 eq) was dissolved in ethanol (50 mL), sodium ethoxide (6.0 g, 88.49 mmol, 2.5 eq) was added, and the reaction was heated at 80 °C for 1 h. The reaction was complete by TLC. Concentration under reduced pressure gave the product (8.47 g, 100% yield).

[0568] Step 4: Synthesis of 1-cyclobutylpiperidine-2,4-dione

[0569] [ka]

[0570] The intermediate ethyl 1-cyclobutyl-2,4-dioxopiperidine-3-carboxylate (8.47 g, 35.40 mmol, 1.0 eq) was dissolved in water (20 mL) and concentrated hydrochloric acid (30 mL) and reacted at 120 °C for 2 h. The reaction was complete by TLC. The mixture was cooled to room temperature and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the product (3 g, yield: 50.8%).

[0571] Step 5: Synthesis of 1-cyclobutyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0572] [ka]

[0573] The intermediate 1-cyclobutylpiperidine-2,4-dione (3 g, 17.94 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and N,N-dimethylformamide dimethyl acetal (2.35 g, 19.74 mmol, 1.1 eq) was added. The reaction was allowed to proceed at room temperature for 1 h. The reaction was complete as determined by TLC. Concentration under reduced pressure gave the product (3.98 g, 100% yield).

[0574] Step 6: Synthesis of 5-cyclobutyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0575] [ka]

[0576] The intermediate (E)-1-cyclobutyl-3-((dimethylamino)methylene)piperidine-2,4-dione (3.98 g, 17.94 mmol, 1.0 eq) and hydrazine hydrate (1.16 g, 19.73 mmol, 1.1 eq) were dissolved in methanol (4 mL) and heated to reflux for 1 h until the reaction was complete as determined by TLC. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (2.1 g, 61.2% yield).

[0577] Step 7: Synthesis of (E)-2-(2-((5-cyclobutyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0578] [ka]

[0579] The intermediate 5-cyclobutyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.0 g, 5.23 mmol, 1.0 eq) was dissolved in DMF (5 mL), cooled in an ice-water bath, and NaH (60% by mass, 230 mg, 5.75 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 30 minutes, and then a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (2.0 g, 6.29 mmol, 1.2 eq) in DMF (5 mL) was added dropwise. After the addition was complete, the mixture was allowed to react for 1 hour, and the reaction was confirmed to be complete by TLC. Add water (50 mL) and extract with ethyl acetate (50 mL × 3). Wash the organic phase with water (50 mL × 2), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by thin layer chromatography (PE:EA = 1:2) to obtain the product (572 mg, yield: 27.2%).

[0580] Step 8: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclobutyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0581] [ka]

[0582] The intermediate (E)-2-(2-((5-cyclobutyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (572 mg, 1.40 mmol, 1.0 eq) was dissolved in EtOH (10 mL), and hydrazine hydrate (245 mg, 4.90 mmol, 3.5 eq) was added and the mixture was reacted at 80 °C for 3 h. When the reaction was confirmed to be complete by LC-MS, the mixture was cooled to room temperature, filtered under suction, and the filtrate was concentrated. The crude product was added to dichloromethane (10 mL) and pulped. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to give an oily liquid (296 mg). The mixture was dissolved in dichloromethane (2 mL), and hydrogen chloride ethanol solution (129 mg) was added dropwise. The mixture was stirred for 10 minutes and concentrated under reduced pressure to give the product (256 mg, yield: 58%).

[0583] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.43 (s, 3H), 8.26 (s, 1H), 7.36 (s, 0.5H), 7.15 (s, 0.5H), 4.93-4.92 (m, 3H), 3.57-3.54 (m, 2H), 3.34-3.33 (m, 2H), 2.83-2.80 (m, 2H), 2.20-2.13(m, 2H), 2.06-1.99 (m, 2H), 1.67-1.66 (m, 2H).

[0584] Molecular formula:C 14 H 19FN4O molecular weight:278.33 LC-MS(Pos, m / z)=279.19[M+H] + .

[0585] Example 6: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopentyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A10) hydrochloride

[0586] [ka]

[0587] Step 1: Synthesis of the intermediate ethyl 3-(cyclopentylamino)propionate

[0588] [ka]

[0589] The starting material, cyclopentylamine (5.1 g, 60 mmol, 1.0 eq), was dissolved in ethanol (10 mL), and ethyl acrylate (5.0 g, 50 mmol, 1.0 eq) was slowly added dropwise in an ice bath. The reaction mixture was allowed to react for 12 hours, and TLC showed no remaining starting material. The mixture was concentrated under reduced pressure to give the product (9.2 g, 99% yield).

[0590] Step 2: Synthesis of intermediate ethyl 3-(cyclopentyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate

[0591] [ka]

[0592] The intermediate ethyl 3-(cyclopentylamino)propionate (8.2 g, 44.26 mmol, 1.0 eq), monoethyl malonate (5.85 g, 44.26 mmol, 1.0 eq), 4-dimethylaminopyridine (1.08 g, 8.85 mmol, 0.2 eq), and triethylamine (10.3 g, 101.8 mmol, 2.3 eq) were dissolved in dichloromethane (100 mL) and stirred for 5 min. After stirring, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.49 g, 53.11 mmol, 1.2 eq) was added in several portions and the reaction was allowed to proceed for 12 h. The reaction was complete as determined by TLC. A reaction flask was charged with water and concentrated hydrochloric acid (3:1, 100 mL), stirred for 10 min, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate (100 mL) and water (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (11.5 g, 87% yield).

[0593] Step 3: Synthesis of intermediate ethyl 1-cyclopentyl-2,4-dioxopiperidine-3-carboxylate

[0594] [ka]

[0595] The intermediate ethyl 3-(cyclopentyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate (11.5 g, 38.4 mmol, 1.0 eq) and sodium ethoxide (5.23 g, 76.8 mmol, 2.0 eq) were dissolved in ethanol (100 mL) and reacted at 80 °C for 2 h. The reaction was complete as determined by LC-MS. Concentration under reduced pressure gave the product (9.73 g, 100% yield).

[0596] Step 4: Synthesis of intermediate 1-cyclopentylpiperidine-2,4-dione

[0597] [ka]

[0598] The intermediate, ethyl 1-cyclopentyl-2,4-dioxopiperidine-3-carboxylate (9.72 g, 38.4 mmol, 1.0 eq) was dissolved in water (50 mL) and concentrated hydrochloric acid (20 mL) and reacted at 120 °C for 1.5 h. The reaction was complete by LC-MS. The mixture was cooled to room temperature, saturated with solid sodium chloride, extracted with dichloromethane (100 mL x 3), dried, and concentrated to give the product (6.95 g, 100% yield).

[0599] Step 5: Synthesis of intermediate 1-cyclopentyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0600] [ka]

[0601] The intermediate 1-cyclopentylpiperidine-2,4-dione (6.95 g, 38.4 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide dimethyl acetal (5.04 g, 42.24 mmol, 1.1 eq) and reacted for 1 h. The reaction was complete as determined by LC-MS. Concentration under reduced pressure gave the product (9.07 g, 100% yield).

[0602] Step 6: Synthesis of intermediate 5-cyclopentyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0603] [ka]

[0604] The intermediate 1-cyclopentyl-3-((dimethylamino)methylene)piperidine-2,4-dione (9.07 g, 38.4 mmol, 1.0 eq) and hydrazine hydrate (2.114 g, 42.24 mmol, 1.1 eq) were dissolved in methanol (50 mL) and reacted at 60 °C for 40 min. The reaction was complete as determined by LC-MS. After cooling to room temperature and concentrating under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1), followed by pulping with methyl t-butyl ether (50 mL) and suction filtration to give the product (3.1 g, 39% yield).

[0605] Step 7: Synthesis of intermediate (E)-2-(2-((5-cyclopentyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0606] [ka]

[0607] The intermediate 5-cyclopentyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.0 g, 4.87 mmol, 1.0 eq) was dissolved in DMF (5 mL) and sodium hydride (214 mg, 5.36 mmol, 1.12 eq, 60%) was added. After stirring for 30 min, a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (1.74 g, 5.84 mmol, 1.2 eq) in DMF (5 mL) was added dropwise. The reaction was allowed to proceed for 1 h, and the reaction was determined to be complete by LC-MS. Add water (10 mL), extract with ethyl acetate (50 mL × 2), separate the layers, wash the organic phase with water (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain the product (700 mg, yield: 34%).

[0608] Step 8: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopentyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0609] [ka]

[0610] The intermediate (E)-2-(2-((5-cyclopentyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (700 mg, 1.65 mmol, 1.0 eq) was dissolved in EtOH (10 mL) and hydrazine hydrate (290 mg, 5.77 mmol, 3.5 eq) was added. The mixture was reacted at 80 °C for 30 min. Upon completion of the reaction as determined by LC-MS, the mixture was filtered under suction, and the filtrate was concentrated. The crude product was purified by thin-layer chromatography (TLC) (DCM:MeOH=10:1). The resulting oil was dissolved in methanol (2 mL), and hydrogen chloride in ethanol (0.25 mL) was added dropwise. The mixture was stirred for 30 min and concentrated under reduced pressure to give the product (230 mg, 42% yield).

[0611] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.37 (s, 3H), 8.24 (s, 1H), 7.36 (s, 0.5H), 7.16 (s, 0.5H), 4.91 (s, 3H), 3.42-3.45 (m, 2H), 3.34-3.35 (d, 2H), 2.78-2.81 (m, 2H), 1.69 (s, 4H), 1.54 (s, 4H).

[0612] Molecular formula:C 15 H 21 FN4O molecular weight:292.36 LC-MS(Pos, m / z)=293.20[M+H] + .

[0613] Example 7: Synthesis of compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (compound A13)

[0614] [ka]

[0615] Step 1: Synthesis of intermediate t-butylglycine ethyl ester

[0616] [ka]

[0617] Ethyl bromoacetate (10.0 g, 59.88 mmol, 1.0 eq) was added dropwise to a solution of t-butylamine (21.9 g, 299.40 mmol, 5.0 eq) in methyl t-butyl ether (200 mL). After the addition, the mixture was stirred at room temperature for 40 h. The reaction mixture was filtered, and the filtrate was concentrated. Methyl t-butyl ether (100 mL) was added to the concentrate, which was washed with water (30 mL) and saturated brine (50 mL) in that order. The mixture was then dried, filtered, and the filtrate was concentrated to give the product (8.5 g, 89.2% yield).

[0618] Step 2: Synthesis of intermediate ethyl 3-(t-butyl(2-ethoxy-2-oxoethyl)amino)-3-oxopropionate

[0619] [ka]

[0620] t-Butylglycine ethyl ester (6.0 g, 37.68 mmol, 1.0 eq), monoethyl malonate (5.48 g, 41.15 mmol, 1.1 eq), triethylamine (8.77 g, 86.67 mmol, 2.3 eq), and DMAP (921 mg, 7.54 mmol, 0.2 eq) were added in that order to DCM (150 mL). EDCI (8.62 g, 45.22 mmol, 1.2 eq) was added in portions to DCM and stirred overnight at room temperature until the reaction was complete by TLC. The reaction mixture was poured into 1 mol / L hydrochloric acid (300 mL), separated, and the organic phase was washed sequentially with water (50 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (10.0 g, 97.1% yield).

[0621] Step 3: Synthesis of intermediate ethyl 1-(t-butyl)-2,4-dioxopyrrolidine-3-carboxylate

[0622] [ka]

[0623] Sodium ethoxide (4.98 g, 73.17 mmol, 2.0 eq) was added to ethanol (100 mL) and stirred at room temperature. Ethyl 3-(t-butyl(2-ethoxy-2-oxoethyl)amino)-3-oxopropionate (10.0 g, 36.59 mmol, 1.0 eq) was added to the above ethanolic solution of sodium ethoxide and stirred at room temperature for 5 h until the reaction was complete as indicated by TLC. The reaction mixture was concentrated to give the crude product (calculated from the theoretical yield), which was used directly in the next reaction.

[0624] Step 4: Synthesis of intermediate 1-(t-butyl)pyrrolidine-2,4-dione

[0625] [ka]

[0626] Ethyl 1-(tert-butyl)-2,4-dioxopyrrolidine-3-carboxylate (8.31 g, 36.57 mmol, 1.0 eq) was added in portions to 1 mol / L hydrochloric acid (150 mL). After the dropwise addition, the mixture was heated to 85 °C and stirred for 4 h until the reaction was complete by TLC. After cooling to room temperature, DCM (200 mL) was added and the layers were separated. The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product (4.2 g, 74.0% yield for two steps).

[0627] Step 5: Synthesis of intermediate 1-(t-butyl)-3-((dimethylamino)methylene)pyrrolidine-2,4-dione

[0628] [ka]

[0629] 1-(t-Butyl)pyrrolidine-2,4-dione (2.20 g, 14.18 mmol, 1.0 eq) was added to 1,1-dimethoxy-N,N-dimethylmethylamine (1.69 g, 14.18 mmol, 1.0 eq) and stirred at room temperature for 0.5 h. TLC indicated the reaction was complete. The methanol was removed under reduced pressure to give the crude product (calculated from theoretical yield), which was used directly in the next reaction.

[0630] Step 6: Synthesis of intermediate 1-benzyl-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one

[0631] [ka]

[0632] Benzylhydrazine dihydrochloride (2.76 g, 14.17 mmol, 1.0 eq) and 1-(tert-butyl)-3-((dimethylamino)methylene)pyrrolidine-2,4-dione (2.98 g, 14.17 mmol, 1.0 eq) were added in that order to ethanol (30 mL) and stirred at 20 °C for 1 h, then heated to 90 °C for 3 h, at which point the reaction was complete as indicated by TLC. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium bicarbonate (50 mL), extracted with DCM (25 mL x 3), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the product (3.0 g, 78.6% yield for two steps).

[0633] Step 7: Synthesis of intermediate 5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one

[0634] [ka]

[0635] The intermediate 1-benzyl-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one (3.0 g, 11.14 mmol, 1.0 eq) was dissolved in methanol (45 mL), concentrated hydrochloric acid (1.0 mL) and wet palladium on carbon (1.0 g) were added, and the mixture was reacted under hydrogen gas for 40 h. TLC indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give the product (1.8 g, 90.2% yield).

[0636] Step 8: Synthesis of intermediate (E)-2-(2-((5-(t-butyl)-4-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0637] [ka]

[0638] 5-(tert-Butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (359 mg, 2.01 mmol, 1.2 eq), cesium carbonate (1.20 g, 3.69 mmol, 2.2 eq), and (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (500 mg, 1.68 mmol, 1.0 eq) in DMAc (10 mL) were stirred at 55 °C for 16 h, when the reaction was complete by TLC. The cake was filtered, the cake was washed with ethyl acetate (30 mL), the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (ethyl acetate) to give the product (320 mg, 0.81 mmol, yield: 48.0%) and the regioisomeric (E)-2-(2-((5-(t-butyl)-4-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione (100 mg, yield: 15.0%).

[0639] Step 9: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one

[0640] [ka]

[0641] The intermediate (E)-2-(2-((5-(tert-butyl)-4-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (320 mg, 0.81 mmol, 1.0 eq) and 85% hydrazine hydrate (190 mg, 3.23 mmol, 4.0 eq) were added in that order to ethanol (8.0 mL) and stirred at 40 °C for 15 h, at which point TLC indicated the reaction was complete. The mixture was cooled to room temperature, filtered, the cake washed with a small amount of ethanol, and the filtrate was concentrated. Anhydrous ethanol (4 mL) was added, filtered, and the filtrate was concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol, 5:1, v / v) to give the product (85 mg, yield: 39.54%).

[0642] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.05 (s, 1H), 6.87-7.08 (d, 1H), 4.83 (d, 2H), 4.43 (s, 2H), 3.16 (s, 2H), 3.10 (d, 2H), 1.43 (s, 9H).

[0643] Molecular formula:C 13 H 19 FN4O Molecular weight: 266.32 LC-MS(m / z)=267.24 [M+H] + .

[0644] Example 8: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridine (Compound A14) hydrochloride

[0645] [ka]

[0646] Step 1: Synthesis of intermediate (E)-(3-fluoro-2-((5-(4-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)carbamate t-butyl

[0647] [ka]

[0648] The intermediate (E)-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (200 mg, 0.62 mol, 1.0 eq) was dissolved in N,N-dimethylacetamide (2 mL), 1-fluoro-4-iodobenzene (412.9 mg, 1.86 mmol, 3.0 eq), anhydrous potassium carbonate (171.1 mg, 1.24 mmol, 2.0 eq), and cuprous iodide (11.8 mg, 0.06 mmol, 0.1 eq) were added, and the mixture was heated to 130 °C under nitrogen gas protection for 16 h. The reaction was complete as determined by TLC. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (MeOH:DCM = 1:20) to give the product (97 mg, yield: 40.5%).

[0649] Step 2: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-(4-fluorophenyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridine hydrochloride

[0650] [ka]

[0651] The intermediate (E)-(3-fluoro-2-((5-(4-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (97 mg, 0.23 mmol, 1.0 eq) was dissolved in 30% hydrogen chloride in ethanol (2 mL) and stirred at room temperature for 3 h. The reaction was complete as determined by LC-MS. After concentration under reduced pressure, the crude product was purified by reverse-phase column chromatography (eluted with 0.5% aqueous trifluoroacetic acid) and lyophilized to give the product (25 mg, 30.6% yield).

[0652] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.37-8.35 (s, 4H), 7.39-7.34 (m, 2.5H), 7.25-7.19 (m, 2.5H), 4.94 (m, 2H), 3.96-3.93 (m, 2H), 3.39-3.38 (m, 2H), 3.00-2.97 (m, 2H).

[0653] Molecular formula:C 16 H 16 F2N4O molecular weight:318.33 LC-MS(Pos, m / z)=319.13 [M+H] + .

[0654] Example 9: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione (Compound A19)

[0655] [ka]

[0656] Step 1: Synthesis of 5-cyclopropyl-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione

[0657] [ka]

[0658] 1-Cyclopropyl-5-(ethoxycarbonyl)-6-oxo-1,2,3,6-tetrahydropyridine-4-sodium alkoxide (1.0 g, 4.05 mmol) and m-fluorophenylhydrazine hydrochloride (656.3 mg, 4.05 mmol) were added to ethanol (10 mL) and heated at 80 °C overnight. The reaction was confirmed complete by TLC. Aqueous citric acid was added to the reaction mixture and the pH was adjusted to 6-7. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 40:1 to 20:1) to give the product (440.0 mg, yield: 37.8%).

[0659] Step 2: Synthesis of (E)-5-cyclopropyl-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione

[0660] [ka]

[0661] 5-Cyclopropyl-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione (440.0 mg, 1.54 mmol), (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (551.0 mg, 1.85 mmol), and potassium carbonate (425.6 mg, 3.08 mmol) were added to DMA (8 mL), stirred at room temperature for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. ethyl acetate (50 mL) was added, washed with water (10 mL × 4), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 200:1 to 40:1) to give the product (450.0 mg, yield: 58.0%).

[0662] Step 3: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione

[0663] [ka]

[0664] (E)-5-Cyclopropyl-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-2-(3-fluorophenyl)-1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-dione (450.0 mg, 0.893 mmol) in ethanol (5 mL) and hydrazine hydrate (49% wt, 446.8 mg, 8.93 mmol) was stirred at room temperature overnight and the reaction was complete by TLC. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to give the product (100.0 mg, 29.9% yield).

[0665] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.95 (s, 2H), 7.57-7.47 (m, 3H), 7.38 (s, 0.5H), 7.29-7.24 (m, 1H), 7.18 (s, 0.5H), 5.19-5.18 (d, 2H), 3.61-3.58 (t, 2H), 3.57-3.51 (d, 2H), 2.85-2.81 (t, 2H), 2.73-2.69 (m, 1H), 0.79-0.76 (m, 2H), 0.69-0.66 (m, 2H).

[0666] Molecular formula:C 19 H 20 F2N4O2 molecular weight: 375.24 LC-MS(Pos, m / z)=375.22[M+H] + .

[0667] Example 10: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A21)

[0668] [ka]

[0669] Step 1: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0670] [ka]

[0671] (E)-2-(2-((5-(t-butyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (350 mg, 0.853 mmol, 1.0 eq) prepared in Example 4 was dissolved in EtOH (15 mL), and hydrazine hydrate (175.8 mg, 2.984 mmol, 3.5 eq) was added and the mixture was refluxed for 2 h. When the reaction was determined to be complete by LC-MS, the mixture was filtered under reduced pressure, the filtrate was concentrated under reduced pressure, EA (20 mL) was added, the mixture was refluxed, and the mixture was filtered while still hot. The filtrate was cooled, and then filtered under reduced pressure again to give the product (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (192.2 mg, yield: 80.0%).

[0672] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.63 (s, 1H), 6.78-6.99 (d, J=84 Hz, 1H), 4.70 (d, 2H), 3.56-3.59 (t, 2H), 3.04-3.05 (d, 2H), 2.90-2.94 (t, 2H), 1.43 (s, 9H).

[0673] Molecular formula:C 14 H 21 FN4O molecular weight:280.35 LC-MS(Pos, m / z)=281.22[M+H] + .

[0674] Example 11: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (Compound A22)

[0675] [ka]

[0676] Step 1: Synthesis of intermediate 1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0677] [ka]

[0678] 1-Cyclopropylpiperidine-2,4-dione (2.50 g, 16.33 mmol, 1.0 eq) was added to 1,1-dimethoxy-N,N-dimethylmethylamine (2.14 g, 17.95 mmol, 1.1 eq) and stirred at room temperature for 0.5 h until the reaction was complete as indicated by TLC. Excess 1,1-dimethoxy-N,N-dimethylmethylamine was removed under reduced pressure to give the crude product (calculated from the theoretical yield), which was used directly in the next reaction.

[0679] Step 2: Synthesis of the intermediate ((1-cyclopropyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine

[0680] [ka]

[0681] The crude 1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione (3.40 g, 16.33 mmol, 1.0 eq) from the previous step, glycine (1.23 g, 16.33 mmol, 1.0 eq), and sodium acetate (1.61 g, 19.59 mmol, 1.2 eq) were added to ethanol (50 mL), heated to 50 °C, stirred until the reaction was complete, and concentrated to give the crude product (calculated from the theoretical yield), which was used directly in the next reaction.

[0682] Step 3: Synthesis of intermediate 2-acetyl-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0683] [ka]

[0684] ((1-Cyclopropyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine (3.89 g, 16.33 mmol, 1.0 eq) in acetic anhydride (40 mL) was heated to 120 °C and stirred for 5 h, at which point the reaction was complete as indicated by LC-MS. The mixture was concentrated, poured into saturated aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (30 mL x 2), the organic phase washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product (calculated from the theoretical yield), which was used directly in the next reaction.

[0685] Step 4: Synthesis of intermediate 5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0686] [ka]

[0687] 2-Acetyl-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (3.55 g, 16.33 mmol, 1.0 eq) and potassium carbonate (4.51 g, 32.66 mmol, 2.0 eq) were added in order to a mixture of methanol (30 mL) and water (30 mL) and stirred at room temperature for 3 h. TLC indicated the reaction was complete. The reaction mixture was concentrated, added to ethyl acetate (100 mL), washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1, v / v) to give the product (950 mg, 33.1% yield for 4 steps).

[0688] Step 5: Synthesis of intermediate (Z)-2-(2-((5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione

[0689] [ka]

[0690] 5-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (900 mg, 5.11 mmol, 1.0 eq), cesium carbonate (2.50 g, 7.66 mmol, 1.5 eq), and (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (1.67 g, 5.62 mmol, 1.1 eq) in acetonitrile (30 mL) were stirred at 55 °C for 16 h, and TLC showed a small amount of starting material remaining. The reaction mixture was cooled to room temperature, filtered, and the cake was washed once with ethyl acetate (15 mL), concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1, v / v) to give the product (1.05 g, 2.67 mmol, yield: 52.3%).

[0691] Step 6: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0692] [ka]

[0693] (Z)-2-(2-((5-Cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (600 mg, 1.53 mmol, 1.0 eq) and 85% hydrazine hydrate (898 mg, 15.25 mmol, 10 eq) were added in that order to ethanol (15 mL) and stirred at 40 °C for 5 h until the reaction was complete by TLC. After cooling to room temperature, the mixture was filtered. The cake was washed with a small amount of ethanol and the filtrate was concentrated. Anhydrous ethanol (10 mL) was added, filtered, and the filtrate was concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol, 5:1, v / v) to give the product (105 mg, yield: 26.2%).

[0694] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.09 (brs, 2H), 7.30 (s, 1H), 7.31-7.10 (d, 1H), 6.66 (s, 1H), 4.70 (s, 2H), 3.37-3.41 (m, 2H), 3.20 (s, 2H), 2.60-2.63 (m, 3H), 0.69-0.74 (m, 2H), 0.55-0.56 (m, 2H).

[0695] Molecular formula:C 14 H 18 FN3O molecular weight:263.32 LC-MS(m / z)=264.20 [M+H] + .

[0696] Example 12: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A23) hydrochloride

[0697] [ka]

[0698] Step 1: Synthesis of intermediate (E)-2-(2-((5-(t-butyl)-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0699] [ka]

[0700] The intermediate 5-(t-butyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (5.0 g, 25.87 mmol, 1.0 eq) was dissolved in DMF (20 mL) and cooled to -10 °C under nitrogen gas protection. Sodium hydride (1.14 g, 28.46 mmol, 1.1 eq, 60%) was added and the reaction was allowed to proceed for 30 min. A solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (9.3 g, 31.04 mmol, 1.2 eq) in DMF (10 mL) was slowly added dropwise and the reaction was allowed to proceed for 2 h. The reaction was determined to be complete by LC-MS. Saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (5.9 g, yield: 59%).

[0701] Step 2: Synthesis of intermediate (E)-2-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)isoindoline-1,3-dione

[0702] [ka]

[0703] The intermediate (E)-2-(2-((5-(t-butyl)-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (6.3 g, 15.34 mmol, 1.0 eq) was dissolved in concentrated hydrochloric acid (30 mL) and ethanol (30 mL) and reacted at 60 °C for 12 h. The reaction was complete as determined by LC-MS. The mixture was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate (50 mL) and filtered with suction to give the product (5.4 g, 99% yield).

[0704] Step 3: Synthesis of intermediate (E)-2-(2-(aminomethyl)-3-fluoroallyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0705] [ka]

[0706] The intermediate (E)-2-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)isoindoline-1,3-dione (5.4 g, 15.24 mmol, 1.0 eq) and hydrazine hydrate (3.05 g, 60.96 mmol, 4.0 eq) were dissolved in ethanol (100 mL) and reacted at 80 °C for 1.5 h. The reaction was complete as determined by LC-MS. The mixture was cooled to room temperature, filtered, and the mother liquor was concentrated under reduced pressure to give the product (3.4 g, 100% yield).

[0707] Step 4: Synthesis of intermediate (E)-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)carbamate t-butyl

[0708] [ka]

[0709] The intermediate (E)-2-(2-(aminomethyl)-3-fluoroallyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (3.4 g, 15.24 mmol, 1.0 eq), di-tert-butyl dicarbonate (6.65 g, 30.48 mmol, 2.0 eq), 4-dimethylaminopyridine (171 mg, 1.52 mmol, 0.1 eq), and triethylamine (2.31 g, 22.86 mmol, 1.5 eq) were dissolved in dichloromethane (50 mL) and reacted for 2.5 h. The reaction was complete as determined by LC-MS. Saturated aqueous sodium carbonate (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 1:60) to give the product (2.57 g, yield: 51%).

[0710] Step 5: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0711] [ka]

[0712] The intermediate (E)-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (200 mg, 0.61 mmol, 1.0 eq) was dissolved in ethanol (2 mL) and hydrogen chloride ethanol solution (2 mL) was added. The reaction was allowed to proceed for 2.5 h, and the reaction was complete as determined by LC-MS. The mixture was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate (5 mL), filtered with suction, and the cake was dried to give the product (150 mg, yield: 93%).

[0713] 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.55 (s, 3H), 8.30 (s, 1H), 7.44 (s, 1H), 7.37 (s, 0.5H), 7.17 (s, 0.5H), 4.97 (s, 2H), 3.35-3.38 (m, 2H), 3.31-3.33 (d, 2H), 2.72-2.76 (m, 2H).

[0714] Molecular formula:C 10 H 13 FN4O molecular weight:224.24 LC-MS(Pos, m / z)=225.16[M+H] + .

[0715] Example 13: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A24) hydrochloride

[0716] [ka]

[0717] Step 1: Synthesis of intermediate (E)-(3-fluoro-2-((5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl)carbamate t-butyl

[0718] [ka]

[0719] The intermediate (E)-(3-fluoro-2-((4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (500 mg, 1.54 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (80 mg, 2.0 mmol, 1.3 eq, 60%) was added. The reaction was allowed to proceed at room temperature for 30 min. Iodomethane (263 mg, 1.85 mmol, 1.2 eq) was added and the reaction was allowed to proceed for 2 h. The reaction was judged complete by LC-MS. Water (5 mL) was added to the reaction flask, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:80) to give the product (100 mg, 19% yield).

[0720] Step 2: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0721] [ka]

[0722] The intermediate (E)-(3-fluoro-2-((5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)allyl) t-butyl carbamate (100 mg, 0.29 mmol, 1.0 eq) was dissolved in ethanol (1 mL) and hydrogen chloride in ethanol (1 mL) was added. The reaction was allowed to proceed for 12 h, and the reaction was complete as determined by LC-MS. Concentration under reduced pressure gave the product (55 mg, 69% yield).

[0723] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 8.41 (s, 3H), 8.25 (s, 1H), 7.37 (s, 0.5H), 7.16 (s, 0.5H), 4.91-4.92 (d, 2H), 3.52-3.56 (m, 2H), 3.33-3.35 (d, 2H), 2.92 (s, 3H), 2.83-2.85 (m, 2H).

[0724] Molecular formula:C 11 H 15 FN4O molecular weight:238.27 LC-MS(Pos, m / z)=239.19[M+H] + .

[0725] Example 14: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (Compound A25)

[0726] [ka]

[0727] Step 1: Synthesis of intermediate ethyl 3-(ethylamino)propionate

[0728] [ka]

[0729] A 65% aqueous solution of ethylamine (29.1 g, 419.51 mmol, 1.4 eq, 65%) was dissolved in ethanol (100 mL), and a solution of ethyl acrylate (30.00 g, 299.65 mmol, 1.0 eq) in ethanol (20 mL) was added dropwise to the above solution (1.5 h). After the addition, the mixture was stirred at room temperature for 1 h, and the reaction mixture was concentrated to give the product (42.0 g, yield: 96.5%).

[0730] Step 2: Synthesis of intermediate ethyl 3-((3-ethoxy-3-oxopropyl)(ethyl)amino)-3-oxopropionate

[0731] [ka]

[0732] The intermediate ethyl 3-(ethylamino)propionate (20.0 g, 137.74 mmol, 1.0 eq), monoethyl malonate (18.20 g, 137.74 mmol, 1.0 eq), triethylamine (32.06 g, 316.80 mmol, 2.3 eq), and DMAP (3.37 g, 27.55 mmol, 0.2 eq) were added in that order in DCM (500 mL), followed by EDCI (31.69 g, 165.29 mmol, 1.2 eq) in several portions. The reaction was stirred at room temperature overnight and was complete as indicated by TLC. The reaction mixture was poured into water (300 mL) and adjusted to a pH of 3-4 with 3 mol / L hydrochloric acid. The layers were separated, and the organic phase was washed with water (150 mL x 2), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product (29.0 g, yield: 81.2%).

[0733] Step 3: Synthesis of intermediate ethyl 1-ethyl-2,4-dioxopiperidine-3-carboxylate

[0734] [ka]

[0735] Sodium (5.14 g, 223.68 mmol, 2.0 eq) was added to ethanol (150 mL) and stirred until the reaction was complete. Ethyl 3-((3-ethoxy-3-oxopropyl)(ethyl)amino)-3-oxopropionate (29.0 g, 118.84 mmol, 1.0 eq) was added to the above ethanolic solution of sodium ethoxide and stirred at room temperature for 2 h until the reaction was complete as indicated by TLC. The reaction mixture was concentrated to give the crude product (calculated from the theoretical yield) which was used directly in the next reaction.

[0736] Step 4: Synthesis of intermediate 1-ethylpiperidine-2,4-dione

[0737] [ka]

[0738] Ethyl 1-ethyl-2,4-dioxopiperidine-3-carboxylate (23.85 g, 111.84 mmol, 1.0 eq) was added in portions to 2 mol / L hydrochloric acid (300 mL), heated to 100 °C, and reacted for 3 h until the reaction was complete by TLC. After cooling to room temperature, the mixture was extracted with DCM (150 mL x 3). The organic phase was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product (12.0 g, 76.0% yield for two steps).

[0739] Step 5: Synthesis of intermediate 1-ethyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0740] [ka]

[0741] The intermediate 1-ethylpiperidine-2,4-dione (6.00 g, 42.50 mmol, 1.0 eq) was added to 1,1-dimethoxy-N,N-dimethylmethylamine (5.32 g, 44.63 mmol, 1.05 eq) and stirred at room temperature for 0.5 h until the reaction was complete by TLC. The reaction was concentrated to give the crude product (calculated from theoretical yield) which was used directly in the next reaction.

[0742] Step 6: Synthesis of intermediate ((1-ethyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine

[0743] [ka]

[0744] The intermediate 1-ethyl-3-((dimethylamino)methylene)piperidine-2,4-dione (8.85 g, 42.49 mmol, 1.0 eq), glycine (3.19 g, 42.49 mmol, 1.0 eq), and sodium acetate (4.18 g, 50.99 mmol, 1.2 eq) in ethanol (100 mL) was heated at 50 °C and stirred until the reaction was complete. The mixture was concentrated to give the crude product (calculated from theoretical yield) which was used directly in the next reaction.

[0745] Step 7: Synthesis of intermediate 2-acetyl-5-ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0746] [ka]

[0747] The intermediate ((1-ethyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine (10.12 g, 42.49 mmol, 1.0 eq) was added to acetic anhydride (80 mL) and heated to 120 °C with stirring for 5 h. LC-MS showed the reaction was complete. After concentration, the residue was taken up in saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product (calculated from the theoretical yield), which was used directly in the next reaction.

[0748] Step 8: Synthesis of intermediate 5-ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0749] [ka]

[0750] The intermediate 2-acetyl-5-ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (8.76 g, 42.49 mmol, 1.0 eq) and potassium carbonate (11.74 g, 84.98 mmol, 2.0 eq) were added in order to a mixture of methanol (50 mL) and water (50 mL) and stirred at room temperature for 3 h. TLC indicated the reaction was complete. The reaction mixture was concentrated, added to ethyl acetate (200 mL), washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether, 1:1 to 1:0, v / v) to give the product (2.2 g, 31.53% yield for 4 steps).

[0751] Step 9: Synthesis of intermediate (Z)-2-(2-((5-ethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0752] [ka]

[0753] 5-Ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (1.5 g, 9.13 mmol, 1.0 eq), cesium carbonate (4.46 g, 13.70 mmol, 1.5 eq), and (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (3.00 g, 10.05 mmol, 1.1 eq) in DMA (20 mL) were reacted with stirring at 55 °C for 16 h, and TLC showed a small amount of starting material remaining. The reaction mixture was cooled to room temperature, filtered, and the cake was washed with ethyl acetate (40 mL). The organic phase was washed with water (20 mL × 2) and saturated brine (20 mL) in that order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate) to give the product (1.45 g, yield: 41.6%).

[0754] Step 10: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one

[0755] [ka]

[0756] (Z)-2-(2-((5-ethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (1.45 g, 3.80 mmol, 1.0 eq) and 85% hydrazine hydrate (1.12 g, 19.01 mmol, 5 eq) were added in that order to ethanol (20 mL) and reacted with stirring at 40 °C for 15 h, when the reaction was complete by TLC. The mixture was cooled to room temperature, filtered, and the cake was washed with a small amount of ethanol. The filtrate was concentrated, and then absolute ethanol (10 mL) was added. The filtrate was filtered and concentrated to give a crude product (750 mg), of which 375 mg was purified by thin-layer chromatography (dichloromethane:methanol, 5:1, v / v) to give the product (85 mg, yield 17.8%).

[0757] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.22 (s, 1H), 6.96-7.17 (d, 1H), 6.61 (s, 1H), 4.58 (d, 2H), 3.37-3.44 (m, 4H), 3.13 (d, 2H), 2.65-2.68(t, 2H), 1.02-1.06 (t, 3H).

[0758] Molecular formula:C 13 H 18 FN3O Molecular weight: 251.31 LC-MS(m / z)=252.28 [M+H] + .

[0759] Example 15: Synthesis of compound (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one (compound A26)

[0760] [ka]

[0761] Step 1: Synthesis of the compound (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-(t-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one

[0762] [ka]

[0763] (E)-2-(2-((5-(t-butyl)-4-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-3-fluoroallyl)isoindole-1,3-dione (100 mg, 0.25 mmol, 1.0 eq) prepared in Example 7 and 85% hydrazine hydrate (59 mg, 1.01 mmol, 4.0 eq) were added in that order to ethanol (5.0 mL) and reacted with stirring at 40 °C for 5 h, until the reaction was complete as indicated by TLC. The mixture was cooled to room temperature, filtered, the cake washed with a small amount of ethanol, and the filtrate was concentrated. Anhydrous ethanol (3.0 mL) was added, filtered, and the filtrate was concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol, 5:1, v / v) to give the product (35 mg, yield: 52.1%).

[0764] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.58 (s, 1H), 7.02-7.23 (d, 1H), 4.85 (d, 2H), 4.54 (s, 2H), 3.26 (d, 2H), 1.43 (m, 9H).

[0765] Molecular formula:C 13 H 19 FN4O Molecular weight: 266.32 LC-MS(m / z)=267.22 [M+H + ].

[0766] Example 16: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-isopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A27) hydrochloride

[0767] [ka]

[0768] Step 1: Synthesis of ethyl 3-(isopropylamino)propionate

[0769] [ka]

[0770] Dissolve the starting material, isopropylamine (7.09 g, 0.12 mol, 1.2 eq) in ethanol (20 mL), add ethyl acrylate (10 g, 0.1 mol, 1.0 eq) dropwise in an ice bath, and react for 12 hours. TLC indicates no remaining starting material. Concentrate under reduced pressure to give the product (15 g, 94% yield).

[0771] Step 2: Synthesis of ethyl 3-(isopropyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate

[0772] [ka]

[0773] The intermediate ethyl 3-(isopropylamino)propionate (15 g, 94.2 mmol, 1.0 eq), monoethyl malonate (12.44 g, 94.2 mmol, 1.0 eq), 4-dimethylaminopyridine (2.3 g, 18.84 mmol, 0.2 eq), and triethylamine (21.9 g, 220 mmol, 2.3 eq) were dissolved in dichloromethane (150 mL) and stirred for 10 minutes. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.66 g, 113 mmol, 1.2 eq) was added dropwise in several portions in an ice bath, and the mixture was allowed to warm to room temperature and react for 2 hours. When the reaction was complete as determined by TLC, water and concentrated hydrochloric acid (4:1, 150 mL) were added, stirred for 10 minutes, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated aqueous sodium carbonate (150 mL) and water (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (17.25 g, yield: 67%).

[0774] Step 3: Synthesis of ethyl 1-isopropyl-2,4-dioxopiperidine-3-carboxylate

[0775] [ka]

[0776] The intermediate ethyl 3-(isopropyl(3-ethoxy-3-oxopropyl)amino)-3-oxopropionate (17.25 g, 63.11 mmol, 1.0 eq) and sodium ethoxide (8.59 g, 126 mmol, 2.0 eq) were dissolved in ethanol (100 mL) and reacted at 80 °C for 1 h. The reaction was complete by TLC. Concentration under reduced pressure gave the product (14.34 g, 100% yield).

[0777] Step 4: Synthesis of 1-isopropylpiperidine-2,4-dione

[0778] [ka]

[0779] The intermediate, ethyl 1-isopropyl-2,4-dioxopiperidine-3-carboxylate (14.23 g, 63.11 mmol, 1.0 eq) was dissolved in water (80 mL) and concentrated hydrochloric acid (20 mL) and reacted at 110 °C for 1 h. The reaction was complete as determined by LC-MS. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (100 mL x 3). The organic phase was dried and concentrated to give the product (7.14 g, 72% yield).

[0780] Step 5: Synthesis of 1-isopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[0781] [ka]

[0782] The intermediate 1-isopropylpiperidine-2,4-dione (7.14 g, 46 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide dimethyl acetal (6.03 g, 50.6 mmol, 1.1 eq) and reacted for 0.5 h. The reaction was complete as determined by LC-MS. Concentration under reduced pressure gave the product (9.67 g, 100% yield).

[0783] Step 6: Synthesis of 5-isopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0784] [ka]

[0785] The intermediate 1-isopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione (9.67 g, 46 mmol, 1.0 eq) and hydrazine hydrate (2.506 g, 50.06 mmol, 1.1 eq) were dissolved in methanol (50 mL) and reacted at 60 °C for 30 min. The reaction was complete as determined by LC-MS. After cooling to room temperature and concentrating under reduced pressure, the crude product was recrystallized from ethyl acetate (80 mL), filtered with suction, and the cake was dried to give the product (4.5 g, 54% yield).

[0786] Step 7: Synthesis of (E)-2-(2-((5-isopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0787] [ka]

[0788] The intermediate 5-isopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (300 mg, 1.67 mmol, 1.0 eq) was dissolved in DMF (1.5 mL) and NaH (87 mg, 2.21 mmol, 1.3 eq) was added. The mixture was stirred for 30 min, and then a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (599 mg, 2.0 mmol, 1.2 eq) in DMF (1.5 mL) was added dropwise. The mixture was allowed to react for 30 min, and the reaction was determined to be complete by LC-MS. Add water (10 mL) and extract with ethyl acetate (20 mL × 2). Wash the organic phase with water (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by silica gel column chromatography (PE:EA = 1:2) to obtain the product (200 mg, yield: 30%).

[0789] Step 8: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-isopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0790] [ka]

[0791] The intermediate (E)-2-(2-((5-isopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (200 mg, 0.5 mmol, 1.0 eq) was dissolved in EtOH (2 mL), and hydrazine hydrate (88 mg, 1.75 mmol, 3.5 eq) was added. The mixture was incubated at 80 °C for 30 min. Upon completion of the reaction by TLC, the mixture was filtered under suction, and the filtrate was concentrated. The crude product was purified by thin layer chromatography (DCM:MeOH = 10:1) to give an oily liquid. Methanol (2 mL) and hydrogen chloride ethanol solution (0.15 mL) were added, and the mixture was stirred for 5 min. The mixture was concentrated under reduced pressure to give the product (60 mg, 39% yield).

[0792] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.24 (s, 3H), 8.20 (s, 1H), 7.36 (s, 0.5H), 7.16 (s, 0.5H), 4.86-4.87 (d, 2H), 4.73-4.80 (m, 1H), 3.40-3.44 (m, 2H), 3.34 (s, 2H), 2.77-2.79 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H).

[0793] Molecular formula:C 13 H 20 ClFN4O Molecular weight:302.78 LC-MS(Pos, m / z)=267.28[M+H] + .

[0794] Example 17: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-methyl-1H-pyrazole-4-formamide (Compound B1)

[0795] [ka]

[0796] Step 1: Synthesis of methyl 1H-pyrazole-4-carboxylate

[0797] [ka]

[0798] 1H-Pyrazole-4-carboxylic acid (10.0 g, 0.0892 mol, 1.0 eq) was dissolved in methanol (36.0 mL), sulfuric acid (10.0 mL) was added dropwise at 0 °C, the mixture was heated to 75 °C, and left overnight. LC-MS showed the reaction was complete. The reaction mixture was poured into cold water (50.0 mL), and saturated aqueous sodium carbonate was added dropwise to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (20.0 mL x 4). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (10.37 g, 92.2% yield).

[0799] Step 2: Synthesis of methyl (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate

[0800] [ka]

[0801] Methyl 1H-pyrazole-4-carboxylate (2.0 g, 15.86 mmol, 1.0 eq), (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (5.2 g, 17.44 mmol, 1.1 eq), and potassium carbonate (3.29 g, 23.79 mmol, 1.5 eq) were dissolved in acetonitrile (20 mL) and allowed to stand overnight at room temperature until complete by TLC. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product (6.0 g crude).

[0802] Step 3: Synthesis of methyl (E)-1-(2-(aminomethyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate

[0803] [ka]

[0804] Methyl (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate (6.0 g crude) was dissolved in ethanol (60.0 mL) and hydrazine hydrate (10.27 g, 174.44 mmol, 85%) was added. The mixture was allowed to react at room temperature overnight, and LC-MS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Toluene was added and the mixture was concentrated under reduced pressure to give the product (5.0 g crude).

[0805] Step 4: Synthesis of methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate

[0806] [ka]

[0807] Methyl (E)-1-(2-(aminomethyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate (5.0 g crude) and sodium carbonate (1.85 g, 17.44 mmol, 1.0 eq) were dissolved in tetrahydrofuran (20.0 mL) and water (10.0 mL) and reacted at 40 °C for 2.5 h until TLC indicated completion. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (40.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (3.2 g, 64.4% yield for 3 steps).

[0808] Step 5: Synthesis of (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid

[0809] [ka]

[0810] Methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylate (1.98 g, 6.32 mmol, 1.0 eq), NaOH (1.517 g, 37.915 mmol) were dissolved in methanol (9.0 mL) and water (9.0 mL) and reacted at 60 °C for 4 h. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, water (20.0 mL) was added, and the pH was adjusted to 5-6 with citric acid. Extraction was performed with dichloromethane (20.0 mL × 4). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was pulped with a small amount of ethyl acetate (2.5 mL), filtered with suction, and the cake was used as the product (690.0 mg, yield: 36.5%).

[0811] Step 6: Synthesis of t-butyl (E)-(3-fluoro-2-((4-(methylcarbamoyl)-1H-pyrazol-1-yl)methyl)allyl)carbamate

[0812] [ka]

[0813] (E)-1-(2-(((t-Butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid (150.0 mg, 0.501 mmol, 1.0 eq) and DIPEA (272.0 mg, 2.11 mmol, 4.2 eq) were dissolved in DMF (2.0 mL). Under nitrogen gas protection, HATU (286.0 mg, 0.752 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and methylamine hydrochloride (41.0 mg, 0.601 mmol, 1.2 eq) was added. The mixture was allowed to warm to room temperature and allowed to stand overnight. The reaction was complete by TLC. Ethyl acetate (40.0 mL) was added to the reaction mixture, which was then washed with saturated aqueous sodium carbonate (4.0 mL), saturated aqueous ammonium chloride (4.0 mL), and saturated aqueous sodium chloride (4.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 150:1 to 30:1) to obtain the product (133.0 mg, yield: 85%).

[0814] Step 7: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-methyl-1H-pyrazole-4-formamide

[0815] [ka]

[0816] (E)-(3-Fluoro-2-((4-(methylcarbamoyl)-1H-pyrazol-1-yl)methyl)allyl) t-Butyl carbamate (133.0 mg, 0.426 mmol, 1.0 eq) was dissolved in ethanol (1.0 mL), and hydrogen chloride in ethanol (1.0 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 2 h until completion was indicated by TLC. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography (DCM:MeOH=8:1) to give the product (80.0 mg, yield: 88.9%).

[0817] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (s, 1H), 8.03-8.01 (d, 1H), 7.82 (s, 1H), 7.03-6.82 (d, 1H), 4.76-4.75 (d, 2H), 3.06-3.05 (d, 2H), 2.71-2.69 (d, 3H), 1.71(s, 2H).

[0818] Molecular formula: C9H 13 FN4O molecular weight:212.23 LC-MS(Pos, m / z)=213.19[M+H] +

[0819] Example 18: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-ethyl-1H-pyrazole-4-formamide (Compound B2)

[0820] [ka]

[0821] Step 1: Synthesis of t-butyl (E)-(2-((4-(ethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0822] [ka]

[0823] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid (500.0 mg, 1.67 mmol, 1.0 eq.) in DMF (4.0 mL) was added to an ice bath with DIPEA (1.29 g, 10.02 mmol, 6.0 eq.) and HATU (952.5 g, 2.50 mmol, 1.5 eq.). The mixture was stirred for 2 h, and then ethylamine hydrochloride (340.4 mg, 4.17 mmol, 2.5 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was determined to be complete by TLC. EA (70 mL) and aqueous sodium carbonate (40 mL) were added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography (DCM:MeOH=20:1) to give the product (426.0 mg, yield: 78.1%).

[0824] Step 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-ethyl-1H-pyrazole-4-formamide

[0825] [ka]

[0826] (E)-(2-((4-(ethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (426.0 mg, 1.30 mmol, 1.0 eq.) was dissolved in EtOH (4 mL), and hydrogen chloride in ethanol (4 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and the pH was adjusted to 7-8 with saturated aqueous sodium carbonate. DCM (50 mL) was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=10:1) to give the product (157.0 mg, yield: 53.4%).

[0827] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (s, 1H), 8.04-8.06 (m, 1H), 7.83 (s, 1H), 7.03 (s, 0.5H), 6.82 (s, 0.5H), 4.75 (m, 2H), 3.18-3.22 (m, 2H), 3.04-3.05 (m, 2H), 1.55 (s, 2H), 1.06-1.10 (m, 3H).

[0828] Molecular formula:C 10 H 15 FN4O Molecular weight: 226.26 LC-MS(Pos, m / z)=227.21[M+H] + .

[0829] Example 19: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-4-formamide (Compound B3)

[0830] [ka]

[0831] Step 1: Synthesis of t-butyl (E)-(2-((4-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0832] [ka]

[0833] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid (440.0 mg, 1.47 mmol, 1.0 eq.) in DMF (4.5 mL) was added to an ice bath with DIPEA (285.0 mg, 2.20 mmol, 1.5 eq.) and HATU (1.67 g, 4.41 mmol, 3.0 eq.). The mixture was stirred in an ice bath for 2 hours, and then t-butylamine (150.5 mg, 2.05 mmol, 1.4 eq.) was added. The mixture was allowed to warm slowly to room temperature and stirred for 12 hours. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure, and EA (100 mL) and aqueous sodium carbonate (60 mL) were added. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=20:1) to give the product (400.0 mg, yield: 76.7%).

[0834] Step 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-4-formamide

[0835] [ka]

[0836] (E)-(2-((4-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate t-Butyl ester (300.0 mg, 0.84 mmol, 1.0 eq.) was dissolved in EtOH (4 mL). Hydrogen chloride in ethanol (4 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and the pH was adjusted to 7-8 with saturated aqueous sodium carbonate. DCM (30 mL) was added and the layers were separated. The aqueous phase was extracted with n-butanol (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 10:1) to give the product (92.0 mg, yield: 43%).

[0837] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.19 (s, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.03 (s, 0.5H), 6.82 (s, 0.5H), 4.73-4.74 (d, 2H), 3.05 (d, 2H), 1.53-1.70 (s, 2H), 1.34 (s, 9H).

[0838] Molecular formula:C 12 H 19 FN4O Molecular weight: 254.31 LC-MS(Pos, m / z)=255.24[M+H] + .

[0839] Example 20: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-cyclopropyl-1H-pyrazole-4-formamide (Compound B4) hydrochloride

[0840] [ka]

[0841] Step 1: Synthesis of t-butyl (E)-(2-((4-(cyclopropylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0842] [ka]

[0843] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid (133.0 mg, 0.44 mmol, 1.0 eq.) in DMF (3.0 mL) was added to an ice bath with DIPEA (170.4 mg, 1.32 mmol, 3.0 eq.) and HATU (253.4 mg, 0.667 mmol, 1.5 eq.). The mixture was stirred for 2 h, and then cyclopropylamine (32.6 mg, 0.57 mmol, 1.3 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure, and EA (50 mL), saturated aqueous ammonium chloride solution (30 mL), and saturated aqueous sodium chloride solution (30 mL) were added. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the product (97.6 mg, yield: 65.5%).

[0844] Step 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-cyclopropyl-1H-pyrazole-4-formamide hydrochloride

[0845] [ka]

[0846] (E)-2-((4-(cyclopropylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (97.6 mg, 0.28 mmol, 1.0 eq.) was dissolved in EtOH (3 mL), and hydrogen chloride in ethanol (3 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure to give the product (35.7 mg, 46.3% yield).

[0847] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 8.27 (s, 2H), 8.24 (s, 1H), 8.13-8.14 (d, 1H), 7.89 (s, 1H), 7.35 (s, 0.5H), 7.15 (s, 0.5H), 4.89-4.90 (d, 2H), 2.71-2.75 (m, 1H), 0.64-0.67 (m, 2H), 0.49-0.51 (m, 2H).

[0848] Molecular formula:C 11 H 15 FN4O Molecular weight: 238.27 LC-MS(Pos, m / z) =239.21[M+H] + .

[0849] Example 21: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-N-ethyl-1H-pyrrole-3-formamide (Compound B11) hydrochloride

[0850] [ka]

[0851] Step 1: Synthesis of methyl (Z)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrrole-3-formate

[0852] [ka]

[0853] Methyl 1H-pyrrole-3-formate (1.77 g, 14.19 mmol, 1.0 eq.), (E)-2-(2-bromomethyl-3-fluoroallyl)isoindoline-1,3-dione (5.50 g, 18.45 mmol, 1.3 eq.), and potassium carbonate (5.88 g, 42.57 mmol, 3.0 eq.) were added to DMF (100 mL) and stirred at room temperature for 2 h. Upon completion by TLC, the mixture was concentrated under reduced pressure, added to ethyl acetate (100 mL), washed with water (50 mL x 4), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (5.89 g crude).

[0854] Step 2: Synthesis of methyl (E)-1-(2-aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formate

[0855] [ka]

[0856] (Z)-1-(2-((1,3-Dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrrole-3-methyl formate (5.89 g crude) and hydrazine hydrate (85%, 10.16 g, 172.6 mmol, 10.0 eq) were added to ethanol (60 mL) and stirred overnight at room temperature. Upon completion of the reaction as determined by TLC, ethyl acetate (60 mL) was added and the mixture was washed with saturated aqueous NH4Cl (30 mL x 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (1.96 g crude).

[0857] Step 3: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-methylformate

[0858] [ka]

[0859] (E)-1-(2-Aminomethyl-3-fluoroallyl)-1H-pyrrole-3-methylformate (1.96 g crude) and triethylamine (1.40 g, 13.85 mmol, 1.5 eq) were added to tetrahydrofuran (20 mL), and (Boc)O (2.22 g, 10.16 mmol, 1.1 eq) was added dropwise. The mixture was stirred at room temperature for 2 h. Upon completion of the reaction by TLC, ethyl acetate (80 mL) was added and washed with saturated aqueous NH4Cl (40 mL x 2). The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the product (2.87 g, 65.0% yield for three steps).

[0860] Step 4: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formic acid

[0861] [ka]

[0862] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-methyl formate (2.87 g, 9.19 mmol, 1.0 eq.) was dissolved in methanol (15 mL), and NaOH (2.21 g, 55.13 mmol, 6.0 eq.) (15 mL) was added. The mixture was stirred at 60 °C for 4 h. Upon completion of the reaction by TLC, the mixture was concentrated under reduced pressure, and the pH was adjusted to 4 with 5% aqueous citric acid. The mixture was extracted with DCM (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (2.00 g, 73.0% yield).

[0863] Step 5: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-N-ethyl-1H-pyrrole-3-formamide

[0864] [ka]

[0865] (E)-1-(2-(t-Butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formic acid (200.0 mg, 0.67 mmol, 1.0 eq.) in DMF (2 mL) was added to the mixture in an ice bath. DIPEA (519.8 mg, 4.02 mmol, 6.0 eq.) and HATU (382.4 mg, 1.01 mmol, 1.5 eq.) were added, and the mixture was stirred for 1 hour. Ethylamine hydrochloride (164.0 mg, 2.01 mmol, 3.0 eq.) was added, and the mixture was allowed to warm slowly to room temperature and stirred overnight. When the reaction was complete by TLC, it was concentrated under reduced pressure, dissolved in EA (60 mL), washed successively with saturated aqueous NaHCO3 (50 mL), saturated aqueous NH4Cl (50 mL), and saturated brine (50 mL × 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (DCM:MeOH = 40:1) to give the product (133.0 mg, yield: 61.0%).

[0866] Step 6: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-N-ethyl-1H-pyrrole-3-formamide hydrochloride

[0867] [ka]

[0868] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-N-ethyl-1H-pyrrole-3-formamide (133.0 mg, 0.41 mmol) in EtOH (5.0 mL) was added dropwise with hydrogen chloride ethanol solution (5.0 mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and the crude product was purified with methyl t-butyl ether for 2 hours and filtered to give the product (93.0 mg, 86.9% yield).

[0869] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.55 (s, 3H), 7.84 (s, 1H), 7.37-7.36 (t, 1H), 7.32 (s, 0.5H), 7.11 (s, 0.5H), 6.88-6.87 (t, 1H), 6.49-6.47 (q, 1H), 4.74-4.73 (d, 2H), 3.24-3.16 (m, 4H), 1.06 (t, 3H).

[0870] Molecular formula:C 11 H 17 ClN3FO Molecular weight: 261.73 LC-MS(Pos, m / z)=226.18[M+H] + .

[0871] Example 22: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-Nt-butyl-1H-pyrrole-3-formamide (Compound B12)

[0872] [ka]

[0873] Step 1: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-Nt-butyl-1H-pyrrole-3-formamide

[0874] [ka]

[0875] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formic acid (200.0 mg, 0.67 mmol, 1.05 eq.) in DMF (2 mL) was added to the mixture in an ice bath. DIPEA (248.3 mg, 1.92 mmol, 3.0 eq.) and HATU (365.2 mg, 0.96 mmol, 1.5 eq.) were added, and the mixture was stirred in an ice bath for 1 hour. t-Butylamine (51.5 mg, 0.70 mmol, 1.1 eq.) was added, and the mixture was allowed to warm to room temperature and stirred overnight. When the reaction was complete by TLC, it was concentrated under reduced pressure, dissolved in EA (60 mL), washed successively with saturated aqueous NaHCO3 (50 mL), saturated aqueous NH4Cl (50 mL), and saturated brine (50 × 4 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (DCM:MeOH = 10:1) to give the product (165.0 mg, yield: 69.6%).

[0876] Step 2: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-Nt-butyl-1H-pyrrole-3-formamide

[0877] [ka]

[0878] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-Nt-butyl-1H-pyrrole-3-formamide (165.0 mg, 0.47 mmol) in EtOH (5.0 mL) was added dropwise to HCl (5.0 mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was then concentrated under reduced pressure, and DCM (40 mL) and 15% aqueous NaOH (40 mL) were added. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by thin-layer chromatography (DCM:MeOH = 10:1) to give (E)-1-(2-aminomethyl-3-fluoroallyl)-Nt-butyl-1H-pyrrole-3-formamide (77.0 mg, yield: 65.1%).

[0879] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.31 (s, 1H), 7.01 (s, 0.5H), 6.96 (s, 1H), 6.79 (s, 0.5H), 6.72-6.71 (t, 1H), 6.44-6.43 (d, 1H), 4.50-4.49 (d, 2H), 3.03-3.02 (d, 2H), 1.71 (s, 2H), 1.33 (s, 9H).

[0880] Molecular formula:C 13 H 20 FN3O Molecular weight: 253.32 LC-MS(Pos, m / z)= 254.24[M+H] + .

[0881] Example 23: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-ethyl-1H-pyrazole-3-formamide (Compound B20)

[0882] [ka]

[0883] Step 1: Synthesis of t-butyl (E)-(2-((3-(ethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0884] [ka]

[0885] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylic acid (233.5 mg, 0.78 mmol, 1.0 eq.) in DMF (3 mL) was added to an ice bath with DIPEA (604.5 mg, 4.68 mmol, 6.0 eq.) and HATU (444.8 mg, 1.17 mmol, 1.5 eq.). The mixture was stirred for 2 h, and then ethylamine hydrochloride (159.0 mg, 1.95 mmol, 2.5 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was determined to be complete by TLC. EA (40 mL) and saturated aqueous sodium carbonate (50 mL) were added, and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=20:1) to give the product (153.0 mg, yield: 60.2%).

[0886] Step 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-ethyl-1H-pyrazole-3-formamide

[0887] [ka]

[0888] (E)-(2-((3-(ethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (153.0 mg, 0.46 mmol, 1.0 eq.) was dissolved in EtOH (3.0 mL), and hydrogen chloride in ethanol (3.0 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and DCM (25 mL) and saturated aqueous sodium carbonate (25 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=10:1) to give the product (30.1 mg, 28.6% yield).

[0889] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.01-8.03 (m, 1H), 7.81 (m, 1H), 7.00 (s, 0.5H), 6.79 (s, 0.5H), 6.61-6.62 (m, 1H), 4.79 (m, 2H), 3.20-3.26 (m, 2H), 3.06-3.07 (m, 2H), 1.69 (s, 2H), 1.06-1.10 (m, 3H).

[0890] Molecular formula:C 10 H 15 FN4O Molecular weight: 226.26 LC-MS(Pos, m / z)=227.21[M+H] + .

[0891] Example 24: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-3-formamide (Compound B21)

[0892] [ka]

[0893] Step 1: Synthesis of methyl (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylate

[0894] [ka]

[0895] (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (3.0 g, 10.0 mmol, 1.0 eq.), potassium carbonate (2.0 g, 15.0 mmol, 1.5 eq.), and methyl 1H-pyrazole-3-carboxylate (1.5 g) in DMF (10 mL) were stirred at room temperature for 2 h. The reaction was complete as determined by TLC. The mixture was concentrated under reduced pressure to remove DMF, and EA (100 mL) and water (200 mL) were added. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 6:1 to 1:1) to give the product (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylate (2.25 g, yield: 66.1%) and the regioisomer (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylate (772.5 mg, yield: 22.7%).

[0896] Step 2: Synthesis of methyl (E)-1-(2-(aminomethyl)-3-chloroallyl)-1H-pyrazole-3-carboxylate

[0897] [ka]

[0898] Methyl (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylate (2.25 g, 6.55 mmol, 1.0 eq.) and hydrazine hydrate (984.2 mg, 19.6 mmol, 3.0 eq.) in ethanol (20 mL) was stirred at room temperature for 12 hours, filtered under suction, and the filtrate was concentrated. The mixture was pulverized with ethanol (20 mL), filtered, and the filtrate was concentrated under reduced pressure to give the product (1.79 g crude).

[0899] Step 3: Synthesis of methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylate

[0900] [ka]

[0901] Methyl (E)-1-(2-(aminomethyl)-3-chloroallyl)-1H-pyrazole-3-carboxylate (1.79 g crude), triethylamine (993.6 mg, 9.82 mmol, 1.5 eq.), and di-tert-butyl dicarbonate (1.85 g, 8.51 mmol, 1.3 eq.) were added to THF (40 mL) and stirred at room temperature for 2 h. The reaction was confirmed complete by TLC. EA (100 mL) and saturated aqueous ammonium chloride (150 mL) were added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 8:1 to 5:1) to give the product (545.1 mg, 27.2% yield for two steps).

[0902] Step 4: Synthesis of (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylic acid

[0903] [ka]

[0904] Methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylate (545.0 mg, 1.73 mmol, 1.0 eq.) was dissolved in methanol (5 mL), and aqueous NaOH solution (6 mol / L, 2.5 mL) was added. The mixture was stirred at 40 °C for 1 hour. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure, and the pH of the system was adjusted to 4 with 5% aqueous citric acid. The mixture was extracted with DCM (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (490.7 mg crude).

[0905] Step 5: Synthesis of t-butyl (E)-(2-((3-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0906] [ka]

[0907] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-3-carboxylic acid (296.0 mg, 0.98 mmol, 1.0 eq.) in DMF (5 mL) was added to an ice bath with DIPEA (382.8 mg, 2.96 mmol, 3.0 eq.) and HATU (563.5 mg, 1.48 mmol, 1.5 eq.). The mixture was stirred for 2 h, and t-butylamine (86.8 mg, 1.18 mmol, 1.2 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure, and EA (60 mL) and saturated aqueous sodium carbonate (50 mL) were added. The layers were separated, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=20:1) to give the product (200.0 mg, 32.6% yield for two steps).

[0908] Step 6: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-3-formamide

[0909] [ka]

[0910] (E)-(2-((3-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (200.0 mg, 0.56 mmol, 1.0 eq.) was dissolved in EtOH (3.0 mL), and hydrogen chloride in ethanol (3.0 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and DCM (40 mL) and saturated aqueous sodium carbonate (40 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=10:1) to give the product (118.0 mg, 82.5% yield).

[0911] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 7.81-7.82 (d, 1H), 7.04 (s, 1H), 7.02(s, 0.5H), 6.81 (s, 0.5H), 6.60-6.61 (d, 1H), 4.78-4.79 (d, 2H), 3.06-3.07 (d, 2H), 1.36 (s, 9H).

[0912] Molecular formula:C 12 H 19 FN4O Molecular weight: 254.31 LC-MS(Pos, m / z)=255.25[M+H] + .

[0913] Example 25: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-Np-chlorophenyl-1H-pyrazole-4-formamide (Compound B28)

[0914] [ka]

[0915] Step 1: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-Np-chlorophenyl-1H-pyrazole-4-formamide

[0916] [ka]

[0917] (E)-1-(2-(t-Butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrazole-4-formic acid (190.0 mg, 0.64 mmol, 1.0 eq.) in DMF (2 mL) was added to the mixture in an ice bath. DIPEA (246.1 mg, 1.90 mmol, 3.0 eq.) and HATU (362.1 mg, 0.95 mmol, 1.5 eq.) were added, and the mixture was stirred in an ice bath for 1 hour. p-Chloroaniline (89.1 mg, 0.70 mmol, 1.1 eq.) was then added, and the mixture was allowed to warm slowly to room temperature and stirred overnight. When the reaction was complete by TLC, it was concentrated under reduced pressure, dissolved in EA (60 mL), washed successively with saturated aqueous NaHCO3 (50 mL), saturated aqueous NH4Cl (50 mL), and saturated brine (50 mL × 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (DCM:MeOH = 10:1) to give the product (90.0 mg, yield: 34.7%).

[0918] Step 2: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-Np-chlorophenyl-1H-pyrazole-4-formamide

[0919] [ka]

[0920] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-Np-chlorophenyl-1H-pyrazole-4-formamide (90.0 mg, 0.22 mmol) in EtOH (5.0 mL) was added dropwise with hydrogen chloride in ethanol (5.0 mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and DCM (40 mL) and 15% aqueous NaOH (40 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH = 10:1) to give the product (48.0 mg, yield: 70.6%).

[0921] 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 9.96 (s, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.75-7.73 (d, 2H), 7.41-7.38 (d, 2H), 7.09 (s, 0.5H), 6.87 (s, 0.5H), 4.82 (s, 2H), 3.09 (s, 2H), 1.81 (s, 2H).

[0922] Molecular formula:C 14 H 14 N4ClFO Molecular weight: 308.74 LC-MS(Pos, m / z)= 309.09[M+H] + .

[0923] Example 26: (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N,N-dimethyl-1H-pyrazole-4-formamide (Compound B29)

[0924] [ka]

[0925] Step 1: Synthesis of t-butyl (E)-(2-((4-(dimethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0926] [ka]

[0927] (E)-1-(2-(((t-Butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-4-carboxylic acid (150.0 mg, 0.501 mmol, 1.0 eq) and DIPEA (272.0 mg, 2.105 mmol, 4.2 eq) were dissolved in DMF (2.0 mL). Under nitrogen gas protection, HATU (286.0 mg, 0.752 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred for 0.5 h, and then a solution of diethylamine in methanol (90.4 mg, 0.601 mmol, 1.2 eq, 30%) was added. The mixture was allowed to warm to room temperature and allowed to stand overnight. The reaction was complete by TLC. Ethyl acetate (40.0 mL) was added to the reaction mixture, which was then washed with saturated aqueous sodium carbonate (4.0 mL), saturated aqueous ammonium chloride (4.0 mL), and saturated aqueous sodium chloride (4.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 120:1 to 30:1) to give the product (132.0 mg, yield: 80.7%).

[0928] Step 2: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N,N-dimethyl-1H-pyrazole-4-formamide

[0929] [ka]

[0930] (E)-(2-((4-(dimethylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (132.0 mg, 0.404 mmol, 1.0 eq) was dissolved in ethanol (1.0 mL), and hydrogen chloride in ethanol (1.5 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 2 h until completion was indicated by TLC. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to give the product (37.0 mg, yield: 40.4%).

[0931] 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (s, 1H), 7.74 (s, 1H), 7.03-6.81 (d, 1H), 4.77 (s, 2H), 3.35-2.95(m, 8H), 1.75 (s, 2H).

[0932] Molecular formula:C 10 H 15 FN4O molecular weight:226.26 LC-MS(Pos, m / z)=227.19[M+H] +

[0933] Example 27: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-5-formamide (Compound B30)

[0934] [ka]

[0935] Step 1: Synthesis of methyl (E)-1-(2-(aminomethyl)-3-chloroallyl)-1H-pyrazole-5-carboxylate

[0936] [ka]

[0937] Methyl (E)-1-(2-((1,3-dioxoisoindolin-2-yl)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylate (772.5 mg, 2.25 mmol, 1.0 eq.) in ethanol (20 mL) and hydrazine hydrate (337.5 mg, 6.75 mmol, 3.0 eq.) were added and stirred at room temperature for 5 hours. The reaction was confirmed complete by TLC. DCM (150 mL) and water (80 mL) were added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (441.6 mg crude).

[0938] Step 2: Synthesis of methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylate

[0939] [ka]

[0940] Methyl (E)-1-(2-(aminomethyl)-3-chloroallyl)-1H-pyrazole-5-carboxylate (441.6 mg crude product) was dissolved in THF (7 mL), triethylamine (290.0 mg, 2.86 mmol) and di-tert-butyl dicarbonate (541.9 mg, 2.48 mmol) were added, and the mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. EA (50 mL) and saturated aqueous ammonium chloride (60 mL) were added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 6:1 to 1:1) to give the product (176.6 mg, 27.2% yield for two steps).

[0941] Step 3: Synthesis of (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylic acid

[0942] [ka]

[0943] Methyl (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylate (176.6 mg, 0.56 mmol, 1.0 eq.) was dissolved in methanol (2 mL), and aqueous NaOH (6 mol / L, 1 mL) was added. The mixture was stirred at 40 °C for 2 hours, and the reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure, and the pH of the system was adjusted to 4 with 5% aqueous citric acid. The mixture was extracted with DCM (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product (124.3 mg, yield: 74.1%).

[0944] Step 4: Synthesis of t-butyl (E)-(2-((5-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate

[0945] [ka]

[0946] (E)-1-(2-(((t-butoxycarbonyl)amino)methyl)-3-fluoroallyl)-1H-pyrazole-5-carboxylic acid (124.3 mg, 0.41 mmol, 1.0 eq.) in DMF (3 mL) was added to an ice bath with DIPEA (160.7 mg, 1.24 mmol, 3.0 eq.) and HATU (236.6 mg, 0.62 mmol, 1.5 eq.). The mixture was stirred for 2 h, and then t-butylamine (36.4 mg, 0.49 mmol, 1.2 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure, and EA (50 mL) and saturated aqueous sodium carbonate (50 mL) were added. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=20:1) to give the product (100.0 mg, yield: 68.0%).

[0947] Step 5: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-N-(t-butyl)-1H-pyrazole-5-formamide

[0948] [ka]

[0949] (E)-t-Butyl (2-((5-(t-butylcarbamoyl)-1H-pyrazol-1-yl)methyl)-3-fluoroallyl)carbamate (100.0 mg, 0.28 mmol, 1.0 eq.) was dissolved in EtOH (2.5 mL), and hydrogen chloride in ethanol (2.5 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, and DCM (30 mL) and saturated aqueous sodium carbonate (40 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM:MeOH=10:1) to give the product (23.0 mg, 32.3% yield).

[0950] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.0 (s, 1H), 7.48 (d, 1H), 6.92 (s, 0.5H), 6.80-6.81 (d, 1H), 6.70 (s, 0.5H), 5.07 (d, 2H), 3.05-3.06 (d, 2H), 1.36 (s, 9H).

[0951] Molecular formula:C 12 H 19 FN4O Molecular weight: 254.31 LC-MS(Pos, m / z)=255.22[M+H] + .

[0952] Example 28: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formamide (Compound B31) hydrochloride

[0953] [ka]

[0954] Step 1: Synthesis of (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formamide

[0955] [ka]

[0956] (E)-1-(2-(t-Butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formic acid (200.0 mg, 0.67 mmol, 1.0 eq.) was dissolved in DMF (2 mL). DIPEA (259.9 mg, 2.01 mmol, 3.0 eq.) and HATU (382.4 mg, 1.01 mmol, 1.5 eq.) were added in an ice bath and stirred for 1 h. An aminomethanol solution (5%, 685.1 mg, 2.01 mmol, 3.0 eq.) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. When the reaction was complete by TLC, it was concentrated under reduced pressure, dissolved in EA (60 mL), washed successively with saturated aqueous NaHCO3 (50 mL), saturated aqueous NH4Cl (50 mL), and saturated brine (50 mL × 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography (DCM:MeOH = 20:1) to give the product (155.0 mg, yield: 77.8%).

[0957] Step 2: Synthesis of (E)-1-(2-aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formamide hydrochloride

[0958] [ka]

[0959] (E)-1-(2-(t-butyloxycarbonyl)aminomethyl-3-fluoroallyl)-1H-pyrrole-3-formamide (155.0 mg, 0.52 mmol) in EtOH (5.0 mL) was added dropwise to hydrogen chloride in ethanol (5.0 mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was confirmed complete by TLC. The mixture was concentrated under reduced pressure, pulped with methyl t-butyl ether for 2 hours, filtered, and the cake was collected to give the product (94.0 mg, 77.2% yield).

[0960] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.54 (s, 3H), 7.64 (s, 2H), 7.41-7.40 (t, 1H), 7.31 (s, 0.5H), 7.11 (s, 0.5H), 6.88-6.87 (t, 1H), 6.50-6.49 (q, 1H), 4.74-4.73 (d, 2H), 3.25-3.23 (d, 2H).

[0961] Molecular formula: C9H 12 N3FO Molecular weight: 197.21 LC-MS(Pos, m / z)= 198.21[M+H] + .

[0962] Example 29: Preparation of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A28) hydrochloride and (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound A29) hydrochloride

[0963] [ka]

[0964] Step 1: Synthesis of 4-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridine

[0965] [ka]

[0966] The starting materials, 4-chloro-2H-pyrazolo[4,3-c]pyridine (5.0 g, 32.55 mmol, 1.0 eq), 4-methoxybenzyl chloride (5.58 g, 35.81 mmol, 1.1 eq), and potassium carbonate (8.98 g, 65.1 mmol, 2.0 eq) were dissolved in DMF (30 mL) and reacted at room temperature for 1.5 h. LC-MS showed no remaining starting material. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (80 mL x 2). The organic phase was washed with water (100 mL x 2), dried, and concentrated to give the product (8.9 g, 100% yield).

[0967] Step 2: Synthesis of intermediate 2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0968] [ka]

[0969] The intermediate 4-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridine (8.9 g, 32.51 mmol, 1.0 eq) was dissolved in acetic acid (80 mL) and water (20 mL) and reacted at 100 °C for 12 h. The reaction was complete as determined by LC-MS. The mixture was concentrated under reduced pressure, and the crude product was pulped with methyl t-butyl ether (100 mL) and filtered with suction to give the product (8.3 g, 100% yield).

[0970] Step 3: Synthesis of 5-ethyl-2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0971] [ka]

[0972] The intermediate 2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (8.3 g, 32.51 mmol, 1.0 eq) and sodium hydride (1.95 g, 48.76 mmol, 1.5 eq) were dissolved in DMF (80 mL) and stirred for 30 min. After stirring, iodoethane (7.6 g, 48.76 mmol, 1.5 eq) was added dropwise and the reaction mixture was stirred at 60 °C for 30 min. The reaction was confirmed complete by LC-MS. Water (80 mL) was slowly added to the flask, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic phase was washed with water (200 mL x 4), dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (5.0 g, 54% yield).

[0973] Step 4: Synthesis of intermediate 5-ethyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0974] [ka]

[0975] The intermediate 5-ethyl-2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (5.0 g, 17.64 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (50 mL) and reacted at 75 °C for 12 h. The reaction was complete as determined by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 1:1), pulped with methyl t-butyl ether (10 mL), and filtered under suction to give the product (1.1 g, 38% yield).

[0976] Step 5: Synthesis of (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione and (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[0977] [ka]

[0978] The intermediate 5-ethyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (500 mg, 3.06 mmol, 1.0 eq) was dissolved in DMF (3 mL) and NaH (159 mg, 3.98 mmol, 1.3 eq) was added. After stirring for 30 min, a solution of (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (1.004 g, 3.37 mmol, 1.1 eq) in DMF (2 mL) was added dropwise. The reaction was allowed to proceed for 30 min and was determined to be complete by LC-MS. Add water (10 mL), extract with ethyl acetate (20 mL × 2), separate the layers, wash the organic phase with water (20 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, pulp the crude product with methyl t-butyl ether (10 mL), and suction filter to obtain a mixture of (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione and (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (390 mg).

[0979] Step 6: (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride, and (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride

[0980] [ka]

[0981] (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione and (E)-2-(2-((5-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (390 mg, 1.02 mmol, 1.0 eq) were dissolved in EtOH (8 mL), and hydrazine hydrate (178 mg, 3.57 mmol, 3.5 eq) was added. The mixture was reacted at 80 °C for 30 min. When the reaction is completed by LC-MS, the mixture is cooled to room temperature, filtered by suction, and the filtrate is concentrated under reduced pressure. The crude product is first purified by thin layer chromatography (DCM:MeOH=10:1). Methanol (1 mL) is added to the obtained product to dissolve it, and then hydrogen chloride ethanol solution (0.015 mL) is added dropwise. The mixture is stirred for 5 minutes and concentrated under reduced pressure. The crude product is purified by thin layer chromatography (dichloromethane:isopropanol:ammonia water=10:1:0.5) to obtain (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride (18 mg, yield: 6.1%) with a small Rf value, which is used as the hydrochloride salt of compound A28.

[0982] 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.65 (s, 1H), 8.27 (s, 3H), 7.44 (s, 0.5H), 7.35-7.37 (d, 1H), 7.24 (s, 0.5H), 6.48-6.50 (m, 1H), 5.07-5.08 (d, 2H), 3.88-3.90 (m, 2H), 3.38-3.39 (m, 2H), 1.17-1.21 (m, 3H).

[0983] Molecular formula:C 12 H 16 ClFN4O Molecular weight:286.74 LC-MS(Pos, m / z)=251.21[M+H] + .

[0984] And (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride (13 mg, yield: 4.4%) with a high Rf value was obtained, which was converted into the hydrochloride salt of compound A29.

[0985] 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.38 (s, 3H), 8.10 (s, 1H), 7.62-7.64 (d, 1H), 7.36 (s, 0.5 H), 7.16 (s, 0.5H), 6.90-6.91 (d, 1H), 5.06-5.10 (d, 2H), 3.95-3.97 (m, 2H), 3.38-3.39 (m, 2H), 1.19-1.23 (m, 3H).

[0986] Molecular formula:C 12 H 16 ClFN4O Molecular weight:286.74 LC-MS(Pos, m / z)=251.19[M+H] + .

[0987] Example 30: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Compound A31) hydrochloride

[0988] [ka]

[0989] Step 1: Synthesis of ethyl (E)-2-(2-carbamoylhydrazono)propionate

[0990] [ka]

[0991] The starting materials, ethyl 2-oxopropionate (21 g, 0.18 mol, 1.0 eq) and semicarbazide hydrochloride (20 g, 0.18 mol, 1.0 eq), were dissolved in water (150 mL), sodium acetate (29 g, 0.35 mol, 1.9 eq) was added, and the mixture was stirred at room temperature for 12 h. The reaction was complete as determined by TLC. The cake was filtered under suction, washed with a small amount of water, and dried to obtain the product (29 g, 94% yield), which was used directly in the next reaction.

[0992] Step 2: Synthesis of ethyl 4-formyl-1H-pyrazole-5-carboxylate

[0993] [ka]

[0994] Phosphorus oxychloride (32.8 mL) was added dropwise to DMF (71.3 mL) in an ice bath. After the addition was complete, the ice bath was removed, the mixture was warmed to room temperature, and stirred for 30 min. The reaction mixture was then heated to 40 °C and ethyl (E)-2-(2-carbamoylhydrazono)propionate (26.6 g, 0.154 mol, 1.0 eq) was added. The mixture was then warmed to 80 °C and stirred for 3 h. The reaction was determined to be complete by TLC. The reaction mixture was poured into ice water and adjusted to pH 10 with 50% aqueous sodium hydroxide solution under stirring. The solution was heated to 50°C to completely dissolve the residue, and the pH was adjusted to 7 with concentrated hydrochloric acid in an ice bath. The mixture was extracted with ethyl acetate (2 x 200 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was pulped with DCM to obtain the product (14 g, yield: 66%).

[0995] Step 3: Synthesis of ethyl 4-formyl-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate

[0996] [ka]

[0997] The intermediate ethyl 4-formyl-1H-pyrazole-5-carboxylate (10.5 g, 0.06 mol, 1.0 eq) was dissolved in DMF (60 mL), potassium carbonate (25.9 g, 0.18 mol, 3.0 eq) and p-methoxybenzyl chloride (12.2 g, 0.078 mol, 1.3 eq) were added, and the mixture was stirred at room temperature for 3 h. The reaction was confirmed complete by TLC. Water (200 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 x 200 mL), washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA:PE = 0 to 1:2) to give the product (12.5 g, 69% yield).

[0998] Step 4: Synthesis of ethyl 4-((ethylamino)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate

[0999] [ka]

[1000] Ethylamine hydrochloride (4.0 g, 48.4 mmol, 4.0 eq) was dissolved in MeOH (20 mL), triethylamine (4.9 g, 48.4 mmol, 4.0 eq) was added, and the mixture was stirred for 10 min. Ethyl 4-formyl-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate (3.5 g, 12.1 mmol, 1.0 eq) and acetic acid (0.5 mL) were added, and the mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (2.3 g, 36.3 mmol, 3.0 eq) was added, and the mixture was stirred at room temperature for 12 h. The reaction was determined to be complete by LCMS. The solution is adjusted to pH 10 with saturated aqueous sodium bicarbonate, extracted with DCM (2 × 30 mL), washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give the product (4.3 g, calculated for 100% yield).

[1001] Step 5: Synthesis of 4-((ethylamino)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylic acid

[1002] [ka]

[1003] The intermediate, ethyl 4-((ethylamino)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate (4.3 g crude, 13.5 mmol, 1.0 eq) was dissolved in MeOH (20 mL) and water (20 mL), and lithium hydroxide monohydrate (1.7 g, 40.6 mmol, 3.0 eq) was added. The mixture was stirred at 50 °C for 3 h, and the reaction was complete as determined by LC-MS. The solution was adjusted to pH = 2 with 2 mol / L aqueous hydrochloric acid and lyophilized to give the product (5 g crude, calculated at 100% yield).

[1004] Step 6: Synthesis of 5-ethyl-1-(4-methoxybenzyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

[1005] [ka]

[1006] The intermediate 4-((ethylamino)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylic acid (5.0 g crude, 17.28 mmol, 1.0 eq) was dissolved in DMF (30 mL), HATU (8.5 g, 22.46 mmol, 1.9 eq) and DIPEA (6.7 g, 51.84 mmol, 3.0 eq) were added, and the mixture was stirred for 1.5 h. The reaction was complete by LC-MS. The reaction mixture was added to water (50 mL), extracted with ethyl acetate (2 × 50 mL), concentrated, and the crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to give the product (1.4 g, 30% yield for 3 steps).

[1007] Step 7: Synthesis of 5-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

[1008] [ka]

[1009] The intermediate 5-ethyl-1-(4-methoxybenzyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (1.4 g, 5.16 mmol, 1.0 eq) was dissolved in TFA (8 mL), anisole (0.15 mL) was added, and the mixture was stirred at 80 °C for 3 h. The reaction was complete by TLC. The reaction mixture was concentrated, and the crude product was purified by thin layer chromatography (DCM:MeOH = 20:1) to give the product (560 mg, 72% yield).

[1010] Step 8: Synthesis of (E)-2-(2-((5-ethyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione

[1011] [ka]

[1012] The intermediate 5-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (560 mg, 3.7 mmol, 1.0 eq) was dissolved in DMF (10 mL), potassium carbonate (1.5 g, 11.1 mmol, 3.0 eq) and (E)-2-(2-(bromomethyl)-3-fluoroallyl)isoindoline-1,3-dione (1.3 g, 4.4 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature for 12 h. The reaction was complete by TLC. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (2 × 30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to give the product (300 mg, 22% yield).

[1013] Step 9: Synthesis of (E)-1-(2-(aminomethyl)-3-fluoroallyl)-5-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one hydrochloride

[1014] [ka]

[1015] The intermediate (E)-2-(2-((5-ethyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-3-fluoroallyl)isoindoline-1,3-dione (300 mg, 0.814 mmol, 1.0 eq) was dissolved in EtOH (5 mL) and hydrazine hydrate (203.8 mg, 4.072 mmol, 5.0 eq) was added. The mixture was stirred at 45 °C for 3 h, and the reaction was complete by TLC. The reaction was cooled to room temperature, the solids were removed, and the filtrate was concentrated. The solids were removed again, and the filtrate was concentrated. The crude product was purified by thin-layer chromatography (DCM:MeOH = 5:1). The resulting oil was dissolved in DCM (3 mL) and hydrogen chloride in ethanol (1 mL) was added dropwise. The reaction was complete by TLC. The solution was concentrated to give the product (90 mg, yield: 40%).

[1016] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.35(s, 3H), 7.54 (s, 1H), 7.31 (s, 0.5H), 7.11 (s, 0.5H), 4.99 (d, 2H), 4.23-4.29 (d, 2H), 3.46-3.47 (d, 4H), 1.16 (m, 3H).

[1017] Molecular formula:C 11 H 16 ClFN4O Molecular weight:238.27 LC-MS(m / z)=239.21 [M+H] + .

[1018] Example 31: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-1-bromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (Compound A32) hydrochloride

[1019] [ka]

[1020] Step 1: Synthesis of intermediate 1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione

[1021] [ka]

[1022] 1-Cyclopropylpiperidine-2,4-dione (50 g, 326.6 mmol, 1 eq) was added to 1,1-dimethoxy-N,N-dimethylmethylamine (42.8 g, 359 mmol, 1.1 eq) and stirred at room temperature for 0.5 h. The reaction was complete as determined by TLC and used directly in the next reaction.

[1023] Step 2: Synthesis of the intermediate ((1-cyclopropyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine

[1024] [ka]

[1025] The 1-cyclopropyl-3-((dimethylamino)methylene)piperidine-2,4-dione solution obtained in the previous step was dissolved in ethanol (1000 mL), and glycine (24.5 g, 326.6 mmol, 1 eq) and sodium acetate (32.2 g, 391.8 mmol, 1.2 eq) were added. The mixture was heated to 50 °C and reacted for 6 h. After completion of the reaction, the mixture was concentrated to obtain the product, which was used directly in the next reaction.

[1026] Step 3: Synthesis of intermediate 2-acetyl-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one

[1027] [ka]

[1028] The crude ((1-cyclopropyl-2,4-dioxopiperidin-3-ylidene)methyl)glycine obtained in the previous step was added to acetic anhydride (1000 mL) and heated to 120 °C for 5 h. After completion of the reaction, the mixture was concentrated to remove acetic anhydride, and the concentrate was added to saturated aqueous sodium bicarbonate solution and adjusted to neutral pH. The mixture was extracted with ethyl acetate (300 mL × 4), and the organic phases were combined, dried, and concentrated to obtain the product, calculated as the theoretical yield, which was used directly in the next reaction.

[1029] Step 4: Synthesis of intermediate 5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one

[1030] [ka]

[1031] The crude 2-acetyl-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one was dissolved in methanol (300 mL) and added to an aqueous solution (300 mL) of potassium carbonate (33.9 g, 464.3 mmol, 1.5 eq). The mixture was stirred at room temperature for 20 min. The reaction was confirmed to be complete by TLC. The mixture was concentrated to remove methanol, the pH was adjusted to a slightly acidic state, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to give the crude product (37.8 g). This was purified by silica gel column chromatography (ethyl acetate:petroleum ether, 1:1 to 1:0, v / v) to give the product (13.05 g, 21.4% yield for 4 steps).

[1032] Step 5: Synthesis of intermediate 1-bromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one

[1033] [ka]

[1034] 5-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one (3 g, 17 mmol, 1 eq) was dissolved in DCM (50 mL) and NBS (3 g, 17 mmol, 1 eq) was added in portions in an ice-water bath at 0 °C for 30 min. The reaction was complete as determined by TLC. The reaction mixture was washed with water (50 mL) and saturated brine (50 mL) successively. The organic phase was dried and concentrated to give the crude product (4.47 g). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1, v / v) to give the product (2.82 g, yield: 65.6%).

[1035] Step 6: Synthesis of intermediate (E)-(2-((1-bromo-5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)carbamate t-butyl

[1036] [ka]

[1037] 1-Bromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one (2.14 g, 8.37 mmol, 1 eq) was dissolved in anhydrous THF (40 mL). NaH (670 mg, 16.74 mmol) was slowly added dropwise in several portions under ice-water bath conditions. After the dropwise addition, the mixture was stirred at 0 °C for 30 min. tert-Butyl (E)-(2-(bromomethyl)-3-fluoroallyl)carbamate (2.34 g, 8.74 mmol, 1.05 eq) was added and the mixture was allowed to react at room temperature for 40 h. The reaction was confirmed to be complete by TLC. After quenching with saturated aqueous ammonium chloride, the organic phase was washed with water and saturated brine, dried, and concentrated to give the crude product (3.89 g), which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 3:1, v / v) to give the product (1.77 g, yield: 47.8%).

[1038] Step 7: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-1-bromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride

[1039] [ka]

[1040] (E)-(2-((1-bromo-5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (350 mg, 0.791 mmol, 1 eq) was dissolved in hydrogen chloride in ethanol (12 mL), stirred until the reaction was complete, concentrated, and lyophilized to give the product (134 mg, yield: 49.6%).

[1041] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.41 (brs, 3H), 7.55 (s, 1H), 7.30-7.02 (d, 1H), 4.76 (d, 2H), 3.42-3.47 (m, 2H), 3.29-3.30 (m, 2H), 2.56-2.65 (m, 3H), 0.71-0.77 (m, 2H), 0.56-0.60 (m, 2H).

[1042] Molecular formula:C 14 H 17 BrFN3O molecular weight:342.21 LC-MS(m / z)=343.92[M+H] + .

[1043] Example 32: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-1,3-dibromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (Compound A33) hydrochloride

[1044] [ka]

[1045] Step 1: Synthesis of 1,3-dibromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one

[1046] [ka]

[1047] 5-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one (3 g, 17 mmol, 1 eq) was dissolved in DCM (50 mL). NBS (6 g, 34 mmol, 2 eq) was added in several portions under ice-water bath conditions. The reaction was allowed to proceed at room temperature for 20 min. The reaction was confirmed to be complete by TLC. The organic phase was washed with water (50 mL) and saturated brine (50 mL) successively, dried, and concentrated to give the crude product (6.03 g). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 4:1, v / v) to give the product (3.33 g, yield: 58.4%).

[1048] Step 2: Synthesis of t-butyl (E)-(2-((1,3-dibromo-5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)carbamate

[1049] [ka]

[1050] 1,3-Dibromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrole[3,4-c]pyridin-4-one (3.83 g, 11.4 mmol, 1.0 eq) was dissolved in anhydrous THF (60 mL). NaH (912 mg, 22.8 mmol, 2.0 eq) was slowly added dropwise under ice-water bath conditions. After the dropwise addition, the mixture was stirred at 0 °C for 30 min. Then, tert-butyl (E)-(2-(bromomethyl)-3-fluoroallyl)carbamate (3.06 g, 11.4 mmol, 1.0 eq) was added and the mixture was allowed to react at room temperature for 40 h. The reaction was confirmed to be complete by TLC. After quenching with saturated aqueous ammonium chloride, the organic phase was washed with water and saturated brine, dried, and concentrated to give the crude product (6.17 g), which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1, v / v) to give the product (3.98 g, yield: 67.5%).

[1051] Step 3: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-1,3-dibromo-5-cyclopropyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride

[1052] [ka]

[1053] (E)-(2-((1,3-Dibromo-5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (400 mg, 0.767 mmol, 1 eq) was dissolved in hydrogen chloride in ethanol (12 mL), stirred until the reaction was complete, concentrated, and lyophilized to give the product (103 mg, 31.9% yield).

[1054] 1 H-NMR (300 MHz, DMSO-d6) δ(ppm): 8.53 (brs, 3H), 6.58-6.85 (d, 1H), 4.81-4.82 (d, 2H), 3.43-3.45 (m, 4H), 2.60-2.62 (m, 3H), 0.71-0.78 (m, 2H), 0.56-0.61 (m, 2H).

[1055] Molecular formula:C 14 H 16 Br2FN3O Molecular weight:421.11 LC-MS(m / z)=421.94[M+H] + .

[1056] Example 33: Synthesis of compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1-methyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (compound A35) hydrochloride salt

[1057] [ka]

[1058] Step 1: Synthesis of intermediate (E)-(2-((5-cyclopropyl-1-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl)carbamate t-butyl

[1059] [ka]

[1060] (E)-(2-((1-bromo-5-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (500 mg, 1.13 mmol, 1 eq), potassium phosphate (720 mg, 3.39 mmol, 3 eq), methylboronic acid (271 mg, 4.52 mmol, 4 eq), and tricyclohexylphosphine (31.7 mg, 0.113 mmol, 0.1 eq) were placed in a microwave tube, toluene (30 mL) was added, and nitrogen gas was bubbled through the tube for 5 min. Pd2(dba)3 (52 mg, 0.0565 mmol, 0.05 eq) was then added and the mixture was heated in a microwave oven at 120 °C for 1 min. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by reverse phase column chromatography (CH3CN:H2O=1:4) and lyophilized to obtain the product (230 mg, yield: 53.9%).

[1061] Step 2: Synthesis of the compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1-methyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride

[1062] [ka]

[1063] (E)-(2-((5-cyclopropyl-1-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)-3-fluoroallyl) t-Butyl carbamate (230 mg, 0.609 mmol, 1 eq) was dissolved in hydrogen chloride in ethanol (10 mL), stirred until the reaction was complete, concentrated, and lyophilized to give the product (134.7 mg, yield: 79.7%).

[1064] 1 H-NMR (300 MHz, DMSO-d6) δ(ppm): 8.62 (brs, 3H), 7.33 (s, 1H), 6.87-7.14 (d, 1H), 4.74 (s, 2H), 3.37-3.41 (m, 2H), 3.24 (m, 2H), 2.52-2.63 (m, 3H), 2.07 (s, 3H), 0.68-0.72 (m, 2H), 0.55-0.58 (m, 2H).

[1065] Molecular formula:C 15 H 21 ClFN3O Molecular weight:277.34 LC-MS(m / z)=278.09[M+H] + .

[1066] Example 34: Synthesis of compound (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one (compound A36) hydrochloride

[1067] [ka]

[1068] Step 1: Synthesis of t-butyl (E)-(2-((5-cyclopropyl-1,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-one)methyl)-3-fluoroallyl)carbamate

[1069] [ka]

[1070] t-Butyl (E)-(2-((5-cyclopropyl-1,3-dibromo-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-one)methyl)-3-fluoroallyl)carbamate (500 mg, 0.96 mmol, 1 eq), methylboronic acid (230 mg, 3.84 mmol, 4 eq), and potassium phosphate (1.63 g, 7.68 mmol, 8 eq) were placed in a flask, charged with 1,4-dioxane (12 mL), purged with nitrogen, and added Pd(PPh3)4 (60 mg, 0.05 mmol, 0.05 eq). Stir under nitrogen protection for 5 h until the reaction was complete by TLC. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with water and saturated brine, dried, and concentrated to give the crude product (570 mg). The crude product was purified by reverse-phase column chromatography (CHCN:H0=1:3) to give the product (170 mg, yield: 45.2%).

[1071] Step 2: Synthesis of (E)-2-(2-(aminomethyl)-3-fluoroallyl)-5-cyclopropyl-1,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride

[1072] [ka]

[1073] (E)-(2-((5-cyclopropyl-1,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-2-one)methyl)-3-fluoroallyl) t-Butyl carbamate (170 mg, 0.434 mmol, 1 eq) was dissolved in hydrogen chloride in ethanol (10 mL), stirred until the rea...

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. 【Chemistry 1】 (However, R 1 and R 2 are each independently selected from hydrogen and halogen, and are not simultaneously hydrogen. R 3 and R 4 are each independently selected from hydrogen. R 5 and R 6 are each independently selected from hydrogen. L 1 does not exist. C y1 is unsubstituted or one or more R a is an atomic group represented by the following general formula (A-11), (a-1), or (b-1), which is substituted with 【Chemistry 2】 m is an integer from 1 to 2. Y 2 , Y 3 are each independently CH 2 , NH. X 1 , X 2 , X 3 , X 9 are each independently CH 2 , CH, N, NH, and X 1 , X 2 , X 3 At least one of is N. Each R a are independently a cyano group, or an unsubstituted or b C replaced with 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, Cy 2 -, Cy 2 -C 1-6 Alkyl group, Cy 2 -Carbonyl group, Cy 2 -aminocarbonyl group. Cy 2 is a 3- to 8-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 10-membered heteroaryl group. Each R b are independently a halogen atom, C 1-6 Alkyl group, C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups. 【Chemistry 3】 represents an optional double bond moiety in the ring structure.)

2. The compound according to claim 1 or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. Isomers. (However, C y1 is unsubstituted or one or more R a is an atomic group represented by the following general formula (A-11) or (a-1). 【Chemistry 4】 m is an integer from 1 to 2. Y 2 , Y 3 are each independently CH 2 , NH. X 1 , X 2 , X 3 are each independently CH 2 , CH, N, NH, and X 1 , X 2 , X 3 At least one of is N. 【Chemistry 5】 represents an optional double bond moiety in the ring structure.)

3. 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. C y1 is unsubstituted or one or more R a is the following atomic group substituted with 【Chemistry 6】 Each R a are independently a cyano group, or an unsubstituted or b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, Cy 2 , Cy 2 -C 1-6 Selected from alkyl groups 。 Cy 2 is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 10-membered heteroaryl group. It is. Each R b are independently a halogen atom, C 1-6 Alkyl group, C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

4. 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. C y1 is unsubstituted or one or more R a is the following atomic group substituted with 【Chemistry 7】 Each R a are independent, C 1-6 Alkylaminocarbonyl group, Cy 2 -Carbonyl group, Cy 2 -aminocarbonyl group. Cy 2 is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, or a phenyl group. Each R b are independently a halogen atom, C 1-6 Alkyl group, C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

5. 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (However, C y1 is unsubstituted or one or more R a is the following atomic group substituted with 【Chemistry 8】

6. 6. The compound according to claim 5, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. C y1 is unsubstituted or has one or more substituents R a is the following atomic group substituted with 【Chemistry 9】 Each R a are independently a cyano group, or an unsubstituted or one or more R b C substituted with a substituent 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 1-6 Alkylaminocarbonyl group, Cy 2 -Carbonyl group, Cy 2 -aminocarbonyl group. Cy 2 is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group. Each R b are independently selected from halogen atoms.

7. 7. The compound according to claim 6, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. C y1 is one or more substituents R a is the following atomic group substituted with 【Chemistry 10】

8. A compound or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, said compound being selected from: 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, optionally comprising one or more pharmaceutical carriers.

10. A compound according to any one of claims 1-8 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition according to claim 9, which is related to or inhibits the SSAO / VAP-1 protein. Manufacture of medicines for preventing and / or treating diseases induced by SSAO / VAP-1 protein Use in.

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