Novel compounds as LRRK2 protein kinase domain inhibitors

Abstract

The present invention relates to a pharmaceutical composition comprising a novel LRRK2 protein kinase domain inhibitor or a pharmaceutically acceptable salt thereof for preventing or treating diseases mediated by or associated with LRRK2, and a method for treating and preventing diseases using same.

Description

A novel compound as an inhibitor of the LRRK2 protein kinase domain

[0001] The present invention relates to a novel compound that inhibits the LRRK2 (Leucine-Rich Repeat Kinase 2) protein kinase domain. The novel compound of the present invention has excellent inhibitory activity against LRRK2 and exhibits excellent effects in the prevention or treatment of diseases mediated by or related to LRRK2.

[0002]

[0003] Various genetic mutations have been studied in relation to Parkinson's disease (PD), and among them, LRRK2 (Leucine-Rich Repeat Kinase 2) is known as a target for developing treatments for sporadic and familial Parkinson's disease.

[0004] The LRRK2 protein is a large protein composed of six domains, and the enzymatic part consists of two domains: a GTPase domain and a kinase domain. The GTPase domain is divided into subdomains such as the Ras-like GTPase (ROC) domain and the C-terminal domain of ROC (COR). Enzymatic activity is divided into two types: autophosphorylation and heterologous phosphorylation of the kinase domain, and GTPase activity of the ROC domain. In addition, the four domains that make up the LRRK2 protein are ARM, ANK, LRR, and the C-terminal WD40 domain, each of which is involved in various types of protein-protein binding.

[0005] The LRRK2 protein is the most common causative gene for autosomal dominant familial Parkinson's disease. The G2019S mutation is the most common mutation and is found in both sporadic and familial Parkinson's disease. In idiopathic Parkinson's disease (iPD), oxidative stress and endoplasmic reticulum dysfunction enhance substrate phosphorylation of the LRRK2 protein. For this reason, LRRK2 overexpression is closely associated with Parkinson's disease.

[0006] The LRRK2 protein is primarily considered a cytosolic protein, but it is also found in the membranes of organelles such as mitochondria and lysosomes. In cells, LRRK2 phosphorylates Rab GTPases, and phosphorylated Rab proteins are known to regulate endolysosomal membrane trafficking. LRRK2 also functions in vesicle trafficking and organelle homeostasis, including the Golgi apparatus, endosomes, and lysosomes. Mutations in the LRRK2 protein that cause Parkinson's disease enhance these functions. Overactivation of the LRRK2 protein leads to Parkinson's disease symptoms, including endolysosomal dysfunction, mitochondrial dysfunction, excessive inflammatory responses, and neuronal cell damage.

[0007] Currently, treatments for Parkinson's disease primarily focus on symptom relief. There is currently no disease-modifying therapy that can prevent or slow the progression of the disease. If diagnosed with Parkinson's, medications or surgery are administered to replace the dopamine deficiency in the brain.

[0008] Accordingly, the inventors of the present invention developed a novel compound that inhibits the kinase function of LRRK2, thereby completing the present invention for a novel compound capable of treating or preventing Parkinson's disease.

[0009]

[0010] (Prior art literature)

[0011] (Non-patent literature)

[0012] (Non-patent Document 1) Taymans et al. LRRK2 kinase inhibition as a therapeutic strategy for Parkinson's disease, where do we stand? Current Neuropharmacology 14(3):214-25, (2016)

[0013] (Non-patent Document 2) Taymans, J.-M. et al. Perspective on the current state of the LRRK2 field. npj Park.'s Dis. 9, 104 (2023)

[0014]

[0015] The present invention aims to provide novel compounds that exhibit inhibitory effects on the LRRK2 protein kinase domain. The compounds of the present invention can bind to the LRRK2 kinase domain and inhibit the enzymatic activity of the LRRK2 protein. The present invention also aims to provide a method for preventing or treating Parkinson's disease using compounds that inhibit the LRRK2 kinase domain.

[0016]

[0017] The present invention relates to a compound of the following chemical formula 1, or a pharmaceutically acceptable salt thereof.

[0018] [Chemical Formula 1]

[0019]

[0020] In the above formula,

[0021] are not independently present or are single bonds,

[0022] X1 to X4 are each independently C or N,

[0023] R1 and R2 are each independently hydrogen, alkyl, -O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocycloalkyl, -alkyl-aryl or -alkyl-heteroaryl, or

[0024] R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together,

[0025] R3 is absent, hydrogen, halo, cyano, alkyl, -alkyl-O-alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0026] R4 is hydrogen, halo, cyano, -NH2, -alkyl, -alkyl-O-alkyl, -O-alkyl, -N(R 4A )(R 4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0027] R 4A Inland R 4D are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl,

[0028] R5 is hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0029] R6 is absent, hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0030] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with one or more selected from the group consisting of halo, NH2, cyano, haloalkyl, alkyl, alkenyl, alkynyl, -alkynyl-alkyl, -O-alkyl, -alkyl-CN, -alkyl-OH, -alkyl-O-alkyl, -alkyl-NH2, -alkyl-N(alkyl)(alkyl), -alkyl-cycloalkyl, NH2, -N(alkyl)(alkyl), -C(=O)-NH2, -C(=O)-heteroaryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted or unsubstituted with alkyl or -OH, and wherein the alkyl may be substituted or unsubstituted with halo.

[0031] In one embodiment, in the compound of formula 1 of the present invention

[0032] X1 to X4 are each independently C or N,

[0033] R1 and R2 are each independently hydrogen, -C 1-6 Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-aryl or -C 1-6 Alkyl-heteroaryl, or

[0034] R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together,

[0035] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0036] R4 is hydrogen, halo, cyano, -NH2, -C1-6 alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -N(R 4A )(R4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0037] R 4A Inland R 4D are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl,

[0038] R5 is hydrogen, cyano, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0039] R6 is absent, hydrogen, cyano, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0040] The above cycloalkyl, heterocycloalkyl, aryl or heteroaryl is halo, NH2, cyano, cycloalkyl, haloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -O-C1-6 alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 which may be substituted with one or more selected from the group consisting of alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, and heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, wherein the -C 1-6 Alkyl may be substituted or unsubstituted with halo.

[0041] In one embodiment, in the compound of formula 1 of the present invention

[0042] X1 to X4 are each independently C or N,

[0043] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0044] R1 and R2 are 3- to 10-membered heteromonocycloalkyl or 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together,

[0045] A 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together is selected from the group consisting of halo, NH2, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 It may be substituted with one or more selected from the group consisting of alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, and heteroaryl, wherein the heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, wherein the -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0046] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C1-6 Alkyl-OC 1-6 Alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl is cyano, -C 1-6 It may be substituted with one or more selected from the group consisting of alkyl and heterocycloalkyl, wherein the -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0047] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0048] R 4A Inland R 4C are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0049] R5 is hydrogen, cyano, or -C1-6 alkyl,

[0050] R6 may be absent, hydrogen, aryl or heteroaryl.

[0051] In one embodiment, in the compound of formula 1 of the present invention

[0052] X1 and X4 are each independently C or N,

[0053] X2 and X3 are N,

[0054] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0055] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0056]

[0057] or And,

[0058] R 1A Inland R 1S are each independently hydrogen, halo, NH2, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, and the -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0059] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano,

[0060] R 3A Inland R 3F are each independently hydrogen, cyano, -C 1-6 Alkyl or heterocycloalkyl, where -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0061] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0062] R 4A Inland R 4C are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0063] R5 is hydrogen, cyano, or -C1-6 alkyl,

[0064] R6 may be absent, hydrogen, aryl or heteroaryl.

[0065] In one embodiment, in the compound of formula 1 of the present invention

[0066] X1 and X4 are each independently C or N,

[0067] X2 and X3 are N,

[0068] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0069] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0070]

[0071] or And,

[0072] R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH,

[0073] R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, heterocycloalkyl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0074] R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl,

[0075] R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl),

[0076] R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl

[0077] R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-heteroaryl, wherein said heteroaryl may be substituted or unsubstituted with -OH,

[0078] R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl,

[0079] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano,

[0080] R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl,

[0081] R 3D is hydrogen, -C 1-6 Alkyl or heterocycloalkyl, where -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0082] R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl,

[0083] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0084] R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0085] R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl or heteroaryl, wherein said heteroaryl may be substituted or unsubstituted with -C1-6 alkyl,

[0086] R5 is hydrogen, cyano, or -C1-6 alkyl,

[0087] R6 may be absent, hydrogen, aryl or heteroaryl.

[0088] In one embodiment, in the compound of formula 1 of the present invention

[0089] X1 and X4 are each independently C or N,

[0090] X2 and X3 are N,

[0091] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0092] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0093]

[0094] or And,

[0095] R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH,

[0096] R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0097] R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl,

[0098] R1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl),

[0099] R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl

[0100] R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH,

[0101] R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl,

[0102] R3 is absent, hydrogen, halo, cyano, -C1-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano,

[0103] R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl,

[0104] R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0105] R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl,

[0106] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0107] R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0108] R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl,

[0109] R5 is hydrogen or -C1-6 alkyl,

[0110] R6 may be absent, hydrogen, aryl or heteroaryl.

[0111] In one embodiment, in the compound of formula 1 of the present invention

[0112] X1 and X4 are each independently C or N,

[0113] X2 and X3 are N,

[0114] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0115] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0116]

[0117]

[0118] or And,

[0119] R3 is absent, hydrogen, halo, cyano, -C1-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano,

[0120] R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl,

[0121] R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0122] R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl,

[0123] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0124] R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0125] R 4Cis hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl,

[0126] R5 is hydrogen or -C1-6 alkyl,

[0127] R6 may be absent, hydrogen, aryl or heteroaryl.

[0128] In one embodiment, in the compound of formula 1 of the present invention

[0129] X1 and X4 are each independently C or N,

[0130] X2 and X3 are N,

[0131] R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0132] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0133]

[0134] or And,

[0135] R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH,

[0136] R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0137] R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl,

[0138] R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl),

[0139] R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl

[0140] R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH,

[0141] R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl,

[0142] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 alkyl,

[0143]

[0144] or And,

[0145]

[0146] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and,

[0147] R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH,

[0148] R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl,

[0149] R5 is hydrogen or -C1-6 alkyl,

[0150] R6 may be absent, hydrogen, aryl or heteroaryl.

[0151] In one embodiment, in the compound of formula 1 of the present invention

[0152] X1 and X4 are each independently C or N,

[0153] X2 and X3 are N,

[0154] R1 and R2 are each independently hydrogen or -C1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl,

[0155] R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together

[0156]

[0157] or And,

[0158] R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH,

[0159] R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0160] R 1E and R1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl,

[0161] R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl),

[0162] R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl

[0163] R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH,

[0164] R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl,

[0165] R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano,

[0166] R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl,

[0167] R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo,

[0168] R 3E and R 3Fare each independently hydrogen or -C 1-6 It is alkyl,

[0169] R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 alkyl,

[0170]

[0171] or And,

[0172] R5 is hydrogen or -C1-6 alkyl,

[0173] R6 may be absent, hydrogen, aryl or heteroaryl.

[0174] In one embodiment, the compound of the present invention may be a compound selected from the group consisting of compounds of Table 1 below or a pharmaceutically acceptable salt thereof.

[0175]

[0176] [Table 1]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] In one embodiment, the compound of the present invention may be a compound selected from the group consisting of compounds of Table 2 below or a pharmaceutically acceptable salt thereof.

[0218]

[0219] [Table 2]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] In one embodiment, the present invention relates to the following compound (NRX02067) or a pharmaceutically acceptable salt thereof.

[0231]

[0232] The above compound (NRX02067) (4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1,5,7-triaza-1H-indene-3-carbonitrile)

[0233] 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d] pyrimidine-5-carbonitrile,

[0234] 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1,5,7-triaza-1H-indene-3-carbonitrile,

[0235] 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile, or

[0236] It is known as 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile.

[0237] The present invention relates to a method for preparing a compound of the present invention or a pharmaceutically acceptable salt thereof, comprising a step of reacting a compound of the following chemical formula 2 and a compound of the following chemical formula 3.

[0238] [Chemical Formula 2]

[0239]

[0240]

[0241] [Chemical Formula 3]

[0242]

[0243] In the above formula,

[0244] are not independently present or are single bonds,

[0245] X1 to X4 are each independently C or N,

[0246] Y is a halogen,

[0247] R1 and R2 are each independently hydrogen, alkyl, -O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocycloalkyl, -alkyl-aryl or -alkyl-heteroaryl, or

[0248] R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together,

[0249] R3 is absent, hydrogen, halo, cyano, alkyl, -alkyl-O-alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0250] R4 is hydrogen, halo, cyano, -NH2, -alkyl, -alkyl-O-alkyl, -O-alkyl, -N(R 4A )(R 4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0251] R 4A Inland R 4D are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl,

[0252] R5 is hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0253] R6 is absent, hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0254] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with one or more selected from the group consisting of halo, NH2, cyano, haloalkyl, alkyl, alkenyl, alkynyl, -alkynyl-alkyl, -O-alkyl, -alkyl-CN, -alkyl-OH, -alkyl-O-alkyl, -alkyl-NH2, -alkyl-N(alkyl)(alkyl), -alkyl-cycloalkyl, NH2, -N(alkyl)(alkyl), -C(=O)-NH2, -C(=O)-heteroaryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted or unsubstituted with alkyl or -OH, and wherein the alkyl may be substituted or unsubstituted with halo.

[0255] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by or related to LRRK2, comprising the compound or a pharmaceutically acceptable salt thereof.

[0256] In one embodiment, the disease mediated by or associated with LRRK2 may be Parkinson's disease.

[0257] The present invention provides a method for preventing or treating a disease mediated by or related to LRRK2, comprising administering the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0258] The present invention provides a method for preventing or treating Parkinson's disease, comprising administering the compound or a pharmaceutically acceptable salt thereof to a Parkinson's patient.

[0259]

[0260] The novel compound of the present invention has excellent inhibitory activity against LRRK2 protein kinase, and is therefore useful for preventing or treating diseases mediated by or related to LRRK2.

[0261] In addition, the novel compound of the present invention is useful not only for disease modifying therapy but also for symptomatic treatment of diseases related to dopamine secretion by acting as an A2AR antagonist.

[0262] Therefore, the novel compound of the present invention can be usefully used to treat or prevent Parkinson's disease.

[0263]

[0264] Figure 1 shows the results of the ADP-glo assay showing the degree of inhibition of the enzyme activity of the LRRK2 protein.

[0265] Figure 2 shows the results of a NanoBRET assay performed in HEK 293 cells to show the degree of inhibition of LRRK2 protein activity.

[0266] Figure 3 shows the results of quantitatively evaluating the level of inhibition of phosphorylation by binding to LRRK2 protein in the T-REx™ 293 LRRK2 Wild type cell line.

[0267] Figure 4 shows the results of Western Blot verifying the intracellular activity of compounds against the LRRK2 kinase domain in the T-REx™ 293 LRRK2 Wild type cell line.

[0268] Figure 5 shows the results of a cell viability assay confirming the cytotoxicity of a compound against the LRRK2 kinase domain in the T-REx™ 293 LRRK2 Wild type cell line.

[0269] Figure 6 is a result of molecular calculations that show that the LRRK2 kinase domain can act as both a type I inhibitor and a type II inhibitor and that the racemic mixture can bind more stably than the individual structural isomers.

[0270]

[0271] Hereinafter, with reference to the attached drawings, embodiments and manufacturing examples of the present invention will be described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and manufacturing examples described herein.

[0272] Throughout this specification, whenever a part is said to “include” a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0273] "used in the chemical formula of the present invention " means that the residue or substituent "R" is attached to the skeletal structure, according to the convention used in the art.

[0274] The term "alkyl" as used herein refers to a hydrocarbon group having substituted or unsubstituted primary, secondary, tertiary and / or quaternary carbon atoms, and includes saturated aliphatic groups having straight-chain, branched, cyclic, or combinations thereof, or their stereochemical structures. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C1-C6 alkyl.Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-Methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3). Moreover, the term "alkyl" as used throughout the specification, preparation examples, and claims is intended to encompass both unsubstituted and substituted alkyl groups, the latter of which refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl.

[0275] The term “alkenyl” as used herein refers to a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, including straight-chain, branched and cyclic groups, or combinations thereof, and having one or more regions of unsaturation, i.e., carbon-carbon sp2 double bonds. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0276] The term "alkynyl" as used in the present invention refers to a group having one or more carbon-carbon triple bonds.

[0277] The term "C" used in the present invention x-y " or "C x -C y " is considered to include groups containing x to y carbons in the chain when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy. C0 alkyl represents hydrogen when the group is terminal and a bond when it is internal. For example, a (C1-C6) alkyl group contains 1 to 6 carbon atoms in the chain.

[0278] The term "alkoxy" as used herein refers to an alkyl group attached to a parent compound via an oxygen atom, which may be represented by -O-alkyl, wherein the alkyl group is as defined herein and may be substituted or unsubstituted. The alkyl group of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C10 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu).

[0279] The term "alkoxyalkyl" as used in the present invention refers to an alkyl group substituted with an alkoxy group as defined herein, and may also be represented as -alkyl-O-alkyl.

[0280] The term “acyl” used in the present invention refers to a -C(=O)- group.

[0281] The term "arylacyl" as used herein refers to an acyl group as defined herein in which at least one hydrogen atom is replaced by an aryl group as defined herein.

[0282] The term "-C(=O)heteroaryl" as used herein refers to an acyl group as defined herein, wherein at least one hydrogen atom is replaced by a heteroaryl group as defined herein.

[0283] The terms “cycloalkyl” and “carbocyclyl” as used herein mean a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C3-C12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocyclyl having 7 to 12 carbon atoms can be arranged in, for example, a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocyclyl having 9 to 10 ring atoms can be arranged in a bicyclo[5,6] or [6,6] system, or a bridged system such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0284] The term "heterocycloalkyl" as used herein refers to a substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms, within the ring. "Heterocycloalkyl" also refers to a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. The bicyclic or polycyclic ring system can be a fused, bridged, or spiro ring system. “Heterocycloalkyl” includes, for example, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, lactonyl, lactamyl, azetidinyl, dihydropyridinyl, dihydroindolyl, tetrahydropyridinyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, 4-piperidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, quinuclidinyl, and oxazolidinyl, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like (each of which may be substituted or unsubstituted).

[0285] The term "aryl" as used herein includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups, which are monocyclic, bicyclic, or polycyclic, each ring atom being carbon. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. The aryl group may be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, and / or a heterocycloalkyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, and aniline.

[0286] The term "heteroaryl" as used herein refers to a substituted or unsubstituted monovalent or divalent aromatic group, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. "Heteroaryl" refers to a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. “Heteroaryl” includes, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, each of which may be substituted or unsubstituted.

[0287] The term "amino" or "amine" used in the present invention refers to -NH2 in which a hydrogen atom is substituted or unsubstituted with a substituent such as alkyl, aryl, etc., wherein the substituent such as alkyl, aryl, etc. replacing the hydrogen atom is as defined herein, may be substituted or unsubstituted, and may form a ring structure together with the N atom. Examples of suitable amino groups include, but are not limited to, -NH2, -N(CH3)2, -N(CH3)-CH2CH2-N(CH3)2, etc. The term "aminealkyl" used in the present invention refers to an alkyl group as defined herein in which at least one hydrogen atom is substituted with an amine group as defined herein.

[0288] The terms “halo” and “halogen” as used herein both mean halogen, and include chloro, fluoro, bromo, and iodo.

[0289] The term “cyano” used in the present invention refers to a -CN group.

[0290] The term “carboxyl” used in the present invention refers to a -C(=O)OH group.

[0291] The term “hydroxy” as used in the present invention refers to an -OH group.

[0292] The term "substituted," as used herein, e.g., "substituted alkyl," means that one or more hydrogen atoms of the alkyl are each independently replaced by a non-hydrogen substituent. Unless otherwise indicated, "substituted" may mean substituted by one or more substituents. The substituent may include, but is not limited to, any of the substituents described herein, for example, halogen, hydroxyl, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxyalkyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl. The substituted moiety on the hydrocarbon chain may itself be substituted, if desired.

[0293] The term "pharmaceutically acceptable salt" as used herein means any acid addition salt or base addition salt which is non-toxic and harmless to the patient and the side effects attributable to said salt do not diminish the beneficial efficacy of the compound of the present invention.

[0294] The compound according to the present invention can be converted into its pharmaceutically acceptable salt by reacting with a pharmaceutically acceptable acid or base.

[0295] The present invention will be described in more detail through the following manufacturing examples. However, the following manufacturing examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0296]

[0297]

[0298] [Manufacturing Example 1]

[0299] Preparation of 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5)

[0300]

[0301]

[0302] 1-1. Step 1: 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2)

[0303]

[0304] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.66 mmol) and N-iodosuccinimide (2.93 mmol) were added to dimethylformamide and stirred at 50°C for one hour. The solvent of the reaction solution was concentrated under reduced pressure and washed with ethyl acetate and brine. The target compound (2) of Preparation Example 1 was obtained (592 mg, 1.89 mmol, 71%, m / z = 311.3, 313.8 [M - H] - ).

[0305]

[0306] 1-2. Step 2: 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine (3)

[0307]

[0308] 2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.89 mmol) was added to dimethylformamide containing sodium hydride (1.89 mmol) and stirred at room temperature for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (2.26 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. The reaction solution was washed with ethyl acetate and brine. The organic layer was removed with sodium sulfate and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the target compound (3) of Preparation Example 1 (710 mg, 1.60 mmol, 85%).

[0309]

[0310] 1-3. Step 3: 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-iodo-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (4)

[0311]

[0312] 2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.563 mmol) was added to ethanol containing 1-ethyl-3-azabicyclo[3.1.0]hexane (0.675 mmol) and triethylamine (0.844 mmol). The reaction solution was stirred at 90°C for 2 hours. The solvent of the reaction solution was concentrated under reduced pressure, and the residue was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the target compound (4) of Preparation Example 1 (265 mg, 0.511 mmol, 91%, m / z = 519.1 [M + H] + ).

[0313]

[0314] 1-4. Step 4: 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5)

[0315]

[0316] 2-Chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.578 mmol) was added to 1-methyl-2-pyrrolidine containing copper cyanide (1.16 mmol). The reaction solution was stirred at 120°C for 3 hours. After cooling to room temperature, water and ethyl acetate were added, and the mixture was filtered through a Celite pad. The filtrate was extracted with ethyl acetate. The separated organic layer was washed with sodium sulfate to remove the remaining water and concentrated under reduced pressure. The concentrated mixture (SiO2, hexane: ethyl acetate = 10:1 to 1:1) was purified to obtain the target compound (5) of Manufacturing Example 1 (210 mg, 0.502 mmol, 86.9%, m / z = 418.1 [M + H] + ).

[0317]

[0318] [Example 1]

[0319] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02097)

[0320]

[0321]

[0322] 1-1. Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0323]

[0324] 2-Chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.239 mmol) was added to sec-BuOH containing 1-methyl-3-pyrazoylamine (0.311 mmol) and potassium carbonate (0.478 mmol). Degassing was performed with nitrogen gas for 5 minutes. Pd2(dba)3 (0.012 mmol) and Xphos (0.024 mmol) were added. The reaction solution was stirred at 100°C for 4 hours. The reaction solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by reversed-phase column chromatography (C 18 The compound was separated using a solvent (resin, water: acetonitrile = 9:1 to 1:9) and obtained (25 mg, 0.052 mmol, 21.8%, m / z = 479.2 [M + H] + ).

[0325]

[0326] 1-2. Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02097)

[0327]

[0328] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.094 mmol) was added to dichloromethane containing trifluoroacetic acid (4.7 mmol). The reaction solution was stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 1 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (0.9 mg, 2.58 μmol, 2.75%, m / z = 349.1 [M + H] + ).

[0329]

[0330] [Example 2]

[0331] Preparation of 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02099)

[0332]

[0333]

[0334] 2-1. Step 1: 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine-5-carbonitrile

[0335]

[0336] 2-Chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.240 mmol) was added to 1,4-dioxane containing 1-(4-amino-5-chloro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.237 mmol) and cesium carbonate (0.712 mmol). Degassing was performed with nitrogen gas for 5 minutes. Pd(OAc)2 (0.024 mmol) and BINAP (0.024 mmol) were added. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by reversed-phase column chromatography (C 18 The compound was separated using a solvent (resin, water: acetonitrile = 9:1 to 1:9) and obtained (96 mg, 0.094 mmol, 40%, m / z = 571.2 [M + H] + ).

[0337]

[0338] 2-2. Step 2: 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02099)

[0339]

[0340] 1 M tetra-n-butylammonium fluoride (0.931 mmol) was added to tetrahydrofuran containing 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.093 mmol). The reaction solution was stirred at 90°C for 1 hour. The solvent of the reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 2 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (10 mg, 22.7 μmol, 24%, m / z = 441.1 [M + H] + ).

[0341] 1 H-NMR (400 MHz, CDCl3-d) δ 8.11 (d,J= 3.6 Hz, 1H), 7.39 - 7.33 (m, 1H), 6.18 (s, 1H), 4.23 (d,J= 10.6 Hz, 1H), 4.16 (d,J= 11.0 Hz, 1H), 4.07 (d,J= 3.8 Hz, 2H), 3.88 (d,J= 11.0 Hz, 1H), 3.70 (d,J= 10.8 Hz, 1H), 1.80 (dq,J= 14.6, 7.3 Hz, 2H), 1.56 - 1.38 (m, 2H), 1.21 - 1.16 (m, 6H), 1.09 - 0.94 (m, 3H), 0.73 (dd,J= 8.0, 4.7 Hz, 1H), 0.33 (t,J= 4.4 Hz, 1H), 0.09 - 0.03 (m, 2H).

[0342]

[0343] [Example 3]

[0344] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02076)

[0345]

[0346]

[0347] 3-1. Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine-5-carbonitrile

[0348]

[0349] The compound 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.837 mmol) of the above Preparation Example 1 was added to 2-butanol (8 ml) containing (4-amino-3-methoxyphenyl)morpholinomethanone (0.837 mmol) and potassium carbonate (1.67 mmol). Degassing was performed with nitrogen gas for 5 minutes. Pd2(dba)3 (0.0419 mmol) and XPhos (0.0837 mmol) were added. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by reversed-phase column chromatography (C 18 The compound was separated using a solvent (resin, water: acetonitrile = 9:1 to 1:9) and obtained (150 mg, 0.243 mmol, 29%, m / z = 618.2 [M + H] + ).

[0350]

[0351] 3-2. Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile(NRX02076)

[0352]

[0353] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2-methoxy-4-morpholinocarbonylphenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,5,7-triazaindene-3-carbonitrile (0.0486 mmol) was added to a dichloromethane (0.4 ml) solution. Trifluoroacetic acid (4.86 mmol) was added and stirred at 40°C for 4 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 3 was obtained by separation using resin, water: acetonitrile = 9: 1 to 1: 9) (20 mg, 0.041 mmol, 84%, m / z = 488.2 [M + H] + ).

[0354] 1H-NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.52 (d,J= 8.2 Hz, 1H), 8.02 (s, 1H), 7.49 (s, 1H),7.07 - 6.97 (m, 2H), 4.17 (d,J= 10.3 Hz, 1H), 4.08 (d,J= 10.9 Hz, 1H), 3.91 (s, 3H), 3.79 (dd,J= 10.9,4.4 Hz, 1H), 3.66 (d,J= 10.3 Hz, 1H), 3.60 (s, 3H), 3.59 (s, 1H), 3.52 (s, 4H), 2.53 (d,J= 1.0 Hz, 1H),1.80 (dd,J= 14.1, 7.2 Hz, 1H), 1.54 (dt,J= 8.3, 4.1 Hz, 1H), 1.43 (dd,J= 14.1, 7.3 Hz, 1H), 1.00 (t,J=7.4 Hz, 3H), 0.72 (dd,J= 8.0, 4.7 Hz, 1H), 0.31 (t,J= 4.2 Hz, 1H).

[0355]

[0356] [실시예 4]

[0357] 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-5-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile의 제조(NRX02169)

[0358]

[0359]

[0360] 4-1 단계 1: 2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0361]

[0362] Compound (5) (120 mg, 0.287 mmol) of the above Preparation Example 1, 1-methyl-5-methyl-4-pyrazoylamine (35 mg, 0.316 mmol), and cesium carbonate (281 mg, 0.861 mmol) were dissolved in 1,4-dioxane (2.8 mL). Pd(OAc)2 (6.44 mg, 28.7 μmol) and BINAP (17.9 mg, 28.7 μmol) were added. The reaction solution was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was filtered through a Celite Pad. After concentrating the reaction solvent under reduced pressure, the residue was purified by column chromatography (SiO2, hexane: ethyl acetate = 5:1 to 1:1) to obtain the desired compound (23 mg, 46.7 μmol, 16.3%, m / z = 493.1 [M + H] + ).

[0363]

[0364] 4-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-5-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02169)

[0365]

[0366] 2-((1,5-Dimethyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (23 mg, 46.7 μmol) was dissolved in dichloromethane, and then trifluoroacetic acid (17.6 μL, 0.233 mmol) was added. The reaction solution was stirred at 50°C for 16 hours. After the reaction solvent was concentrated under reduced pressure, 7N ammonia water was added, and the mixture was stirred for 30 minutes. After the reaction solution was concentrated under reduced pressure, ether was added, and the solid was filtered to obtain the target compound of Example 4 (4 mg, 11 mol, 24%, m / z = 363.1 [M+ H] + ).

[0367] 1 H-NMR (400 MHz, CDCl3-d) δ 7.50 (s, 1H), 6.92 (s, 1H), 6.34 (s, 1H), 4.23 (d,J= 10.9 Hz, 1H), 4.15 (d,J= 11.1 Hz, 1H), 3.86 (d,J= 8.8 Hz, 1H), 3.70 (s, 4H), 3.47 (q,J= 7.0 Hz, 1H), 2.15 (s, 3H), 1.79 (dq,J= 14.6, 7.3 Hz, 1H), 1.52 - 1.43 (m, 2H), 1.20 (t,J= 7.0 Hz, 1H), 1.03 (t,J= 7.4 Hz, 3H), 0.72 (dd,J= 8.0, 5.1 Hz, 1H), 0.31 (t,J= 4.5 Hz, 1H).

[0368]

[0369] [실시예 5]

[0370] 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-3-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile의 제조 (NRX02170)

[0371]

[0372]

[0373] 5-1 단계 1: 2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0374]

[0375] Compound (5) (120 mg, 0.287 mmol) of the above Preparation Example 1, 1-methyl-3-methyl-4-pyrazoylamine (35 mg, 0.316 mmol), and potassium carbonate (119 mg, 0.861 mmol) were dissolved in 2-butanol (1.0 mL). Pd2(dba)3 (26.3 mg, 28.7 μmol) and XPhos (13.7 mg, 28.7 μmol) were added. The reaction solution was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was filtered through a Celite Pad. The reaction solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain the compound (120 mg, 244 μmol, 85%, m / z = 493.1 [M + H] + ).

[0376]

[0377] 5-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-3-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02170)

[0378]

[0379] 2-((1,3-Dimethyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (120 mg, 244 μmol) was dissolved in dichloromethane, and then trifluoroacetic acid (93.2 μL, 1.22 mmol) was added. The reaction solution was stirred at 50°C for 16 hours. After the reaction solvent was concentrated under reduced pressure, 7 N ammonia water was added, and the mixture was stirred for 30 minutes. After concentrating the reaction solvent under reduced pressure, the residue was purified by column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 5 (55.4 mg, 153 μmol, 63%, m / z = 363.1 [M + H] + ).

[0380] 1 H-NMR (400 MHz, CDCl3-d) δ 7.56 (s, 1H), 6.93 (s, 1H), 6.08 (s, 1H), 4.23 (d,J= 10.7 Hz, 1H), 4.16 (d,J= 10.9 Hz, 1H), 3.90 - 3.79 (m, 1H), 3.78 (s, 3H), 3.67 (d,J= 10.7 Hz, 1H), 2.19 (s, 3H), 1.81 (dq,J= 14.6, 7.3 Hz, 1H), 1.54 - 1.40 (m, 2H), 1.04 (t,J= 7.4 Hz, 3H), 0.71 (dd,J= 8.0, 4.9 Hz, 1H), 0.33 (t,J= 4.4 Hz, 1H).

[0381]

[0382] [Example 6]

[0383] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02176)

[0384]

[0385]

[0386] 6-1 Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0387]

[0388] Compound (5) (110 mg, 0.263 mmol) of the above Preparation Example 1, 1-methyl-4-pyrazoylamine (97 mg, 0.316 mmol), and potassium carbonate (109 mg, 0.789 mmol) were dissolved in 2-butanol (1.0 mL). Pd2(dba)3 (24.1 mg, 26.3 μmol) and XPhos (12.5 mg, 26.3 μmol) were added. The reaction solution was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was filtered through a Celite Pad. The reaction solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain the compound (51 mg, 107 μmol, 41%, m / z = 479.1 [M + H] + ).

[0389]

[0390] 6-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(1-methyl-4-pyrazolylamino)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02176)

[0391]

[0392] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (51 mg, 107 μmol) was dissolved in tetrahydrofuran (1.0 mL), and 1 M tetra-n-butylammonium fluoride (1.07 mL, 1.07 mmol) was added. The reaction solution was stirred at 90°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by reverse-phase column chromatography (C 18 The target compound of Example 6 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (20.6 mg, 59.1 μmol, 55%, m / z = 349.1 [M + H] + ).

[0393] 1 H-NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.49 (d,J= 0.7 Hz, 1H), 4.17 (d,J= 10.3 Hz, 1H), 4.08 (d,J= 10.8 Hz, 1H), 3.78 (s, 3H), 3.78 (d,J= 14.4 Hz, 1H), 3.63 (d,J= 10.3 Hz, 1H), 1.82 (dq,J= 14.5, 7.3 Hz, 1H), 1.53 (dt,J=8.1, 4.0 Hz, 1H), 1.43 (dq,J= 14.7, 7.4 Hz, 1H), 1.01 (t,J= 7.4 Hz, 3H), 0.72 (dd,J= 8.0, 4.6 Hz, 1H), 0.30 (t,J= 4.3 Hz, 1H).

[0394]

[0395] [Example 7]

[0396] Preparation of 2-((5-chloro-1-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02182)

[0397]

[0398]

[0399] 7-1 Step 1: 2-((5-chloro-1-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0400]

[0401] Compound (5) (120 mg, 0.29 mmol) from the above Preparation Example 1 was dissolved in dimethylformamide (1.2 mL), and 5-chloro-1-methyl-1H-pyrazol-4-amine (57 mg, 0.44 mmol), Xphos-Pd-G2 (45 mg, 0.058 mmol), Xphos (55 mg, 0.116 mmol) and cesium carbonate (238 mg, 0.87 mmol) were added under nitrogen. The reaction solution was stirred in a microwave reactor at 100°C for 2 hours. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated. The concentrated reaction solution was purified by column chromatography (SiO2, hexane: ethyl acetate = 5:1 to 1:1) to obtain the desired compound (100 mg, 68%, m / z = 513.2 [M + H] + ).

[0402]

[0403] 7-2 Step 2: 2-((5-chloro-1-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02182)

[0404]

[0405] 2-((5-Chloro-1-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran (1 mL), tetra-n-butylammonium fluoride (0.2 mL, 1 N in THF) was added, and the mixture was stirred at 90°C for 4 hours. The reaction mixture was poured into water (10 mL), and the solid was filtered. The filtered solid was washed with methanol to obtain the target compound of Example 7 (15.79 mg, 21.2%, m / z = 383.2 [M + H] + ).

[0406] 1 H-NMR (400 MHz, DMSO-d6) δ 12.09 (brs, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 4.15 (d,J= 10.4, 1H), 4.06 (d,J= 10.8, 1H), 3.77 (s, 3H), 3.73 (dd,J= 10.8, 4.4 Hz, 1H), 3.60 (d,J= 10.4 Hz, 1H), 1.83 - 1.74 (m, 1H), 1.52 - 1.46 (m, 1H), 1.44 - 1.37 (m, 1H), 1.00 (t,J= 7.2 Hz, 3H), 0.70 - 0.67 (m, 1H), 0.28-0.25 (m, 1H).

[0407]

[0408] [Example 8]

[0409] Preparation of 2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02173)

[0410]

[0411]

[0412] 8-1 Step 1: 2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0413]

[0414] Compound (5) (150 mg, 0.35 mmol) of the above Preparation Example 1, 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (69 mg, 0.42 mmol), Pd2(dba)3 (65 mg, 0.035 mmol), Sphos (29 mg, 0.070 mmol), and cesium carbonate (228 mg, 0.70 mmol) were dissolved in 1,4-dioxane (4 mL), and stirred at 100°C under nitrogen for 16 hours. Ammonium chloride (10 mL) was added to the reaction solution, and ethyl acetate (10 mL x 3) was extracted. The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated compound was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1 to 1:1) to obtain the desired compound (147 mg, 77.0%, m / z = 546.3 [M + H] + ) was obtained.

[0415]

[0416] 8-2 Step 2: 2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02173)

[0417]

[0418] 2-((1-(2-Cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (6 mL), and tetra-n-butylammonium fluoride (0.2 mL, 0.20 mmol, 1 N in THF) was added. The reaction mixture was stirred at 90°C for 3 hours. Water (20 mL) was added to the reaction mixture, and ethyl acetate (10 mL x 3) was extracted. The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated compound was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 8 (38.21 mg, 51.0%, m / z = 416.4 [M + H] + ) was obtained.

[0419] 1H-NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 8.15 (s, 2H), 7.91 (d,J= 2.4 Hz, 1H), 4.16 (d,J= 10.4 Hz, 1H), 4.08 (d,J= 10.6 Hz, 1H), 3.79 (dd,J= 10.6, 4.2 Hz, 1H), 3.63 (d,J= 10.4 Hz, 1H), 2.17 (s, 3H), 1.94 (s, 6H), 1.78 (m, 1H), 1.52 (m, 1H), 1.43 (m, 1H), 0.99 (t,J= 7.4 Hz, 3H), 0.71 (m, 1H), 0.30 (t,J= 4.2 Hz, 1H).

[0420]

[0421] [실시예 9]

[0422] 2-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile의 제조(NRX02077)

[0423]

[0424]

[0425] 9-1. 단계 1: 2-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0426]

[0427] The compound 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.311 mmol) of the above Preparation Example 1 was dissolved in ethanol (2 ml). 7 N ammonia in methanol (2 ml) was added and reacted using a microwave reactor at 130°C for 17 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The compound was separated using a solvent (resin, water: acetonitrile = 9:1 to 1:9) and obtained (25 mg, 0.0627 mmol, 20%, m / z = 399.1 [M + H] + ).

[0428]

[0429] 9-2. Step 2: 2-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-(hydroxymethyl)-7H-pyrrolo [2,3-d]pyrimidine-5-carbonitrile

[0430]

[0431] 2-Amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.0627 mmol) was added to dichloroethane (0.6 ml). Trifluoroacetic acid (1 ml) was added, and the mixture was reacted at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure and used in the next reaction without purification (20 mg, 0.067 mmol, 107%).

[0432]

[0433] 9-3. Step 3: 2-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02077)

[0434]

[0435] 2-Amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.067 mmol) was added to methanol (0.6 ml). Potassium carbonate (0.67 mmol) was added to the reaction solution, and the mixture was stirred at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure and separated using reverse-phase column chromatography (C18 resin, water: acetonitrile = 9:1 to 1:9) to obtain the target compound of Example 9 (2.8 mg, 0.0104 mmol, 15%, m / z = 269.1 [M + H] + ).

[0436] 1 H-NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.81 (s, 1H), 5.86 (s, 2H), 4.13 (d,J= 10.4 Hz, 1H), 4.04 (d,J= 10.8 Hz, 1H), 3.68 (dd,J= 10.8, 4.3 Hz, 1H), 3.57 - 3.50 (m, 1H), 1.78 (dq,J= 14.6, 7.3 Hz,1H), 1.48 (dt,J= 8.0, 4.0 Hz, 1H), 1.41 (dq,J= 14.7, 7.5 Hz, 1H), 0.98 (t,J= 7.4 Hz, 3H), 0.67 (dd,J=8.0, 4.5 Hz, 1H), 0.25 (t,J= 4.2 Hz, 1H).

[0437]

[0438] [Manufacturing Example 2]

[0439] Preparation of (4-amino-3-methoxyphenyl)(morpholino)methanone (8)

[0440]

[0441]

[0442] 2 g (12.0 mmol) of 4-amino-3-methoxybenzoic acid (6) was dissolved in 29.9 ml of dimethylformamide, and 5.73 g (29.9 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 2.75 g (17.9 mmol) of 1-hydroxybenzotriazole hydrate were added, and the mixture was stirred at room temperature for 20 minutes. Then, 6.25 ml (35.9 mmol) of N,N'diisopropylethylamine and 10.3 ml (120 mmol) of morpholine (7) were added, and the mixture was stirred at room temperature for 21 hours. 30 ml of water and 30 ml of dichloromethane were added to the reaction solution, and the desired compound (8) was extracted with the dichloromethane layer. Afterwards, 30 ml of water was added to the dichloromethane layer to extract the byproducts into the water layer, and 30 ml of brine was additionally added to extract other byproducts into the brine layer. Through this process, sodium sulfate was added to the dichloromethane solution in which the compound was dissolved to remove the residual water, and then concentrated under reduced pressure. The filtrate was then purified by reverse phase column chromatography (C 18 Resin, water: acetonitrile = 9: 1 to 1: 9) was used to separate the target compound (8) of manufacturing example 2 (1.47 g, 6.22 mmol, 52%, m / z = 237.3 [M + H] + ).

[0443]

[0444] [Manufacturing Example 3]

[0445] Preparation of 2,5-dichloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-(2-((trimethylsilyl) methoxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidine (11)

[0446]

[0447]

[0448] 3-1. Step 1: 2,4,5-trichloro-7-(2-((trimethylsilyl)methoxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidine (10)

[0449]

[0450] 170 mg (764 μmol) of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine(9) was dissolved in 2.6 ml of dimethylformamide, placed in an ice water container, and the solution temperature was set to 0°C. 36.7 mg (917 μmol) of sodium hydride was added and stirred for 30 minutes. 162 μl (917 μmol) of [2-(chloromethoxy)ethyl]trimethylsilane was added and stirred at room temperature for 3 hours. After confirming the completion of the reaction, 20 ml of water and 20 ml of ethyl acetate were added to the reaction solution, and the desired compound was extracted with the ethyl acetate layer. The ethyl acetate layer obtained by repeating the above extraction process three times was concentrated under reduced pressure, and the filtrate was purified using column chromatography (SiO2, ethyl acetate: hexane = 1:10) to obtain the target compound (10) of step 1 of manufacturing example 3 (218 mg, 618 μmol, 80.9%, m / z = 353.7 [M + H] + ).

[0451]

[0452] 3-2. Step 2: 2,5-dichloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-(2-((trimethylsilyl) methoxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidine (11)

[0453]

[0454] 180 mg (510 μmol) of compound (10) obtained in step 1 of the above manufacturing example 3 was dissolved in 5.1 ml of dimethylformamide, and then 82.9 mg (561 μmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane hydrochloride and 333 mg (1.02 mmol) of cesium carbonate were added, and the mixture was stirred in a microwave for 1 hour. After confirming the completion of the reaction, 25 ml of water and 25 ml of ethyl acetate were added to the reaction solution, and the desired compound was extracted into the ethyl acetate layer. The ethyl acetate layer obtained by repeating the above extraction process three times was concentrated under reduced pressure, and the filtrate was purified using column chromatography (SiO2, ethyl acetate: hexane = 1:10) to obtain the target compound (11) of the above manufacturing example 3 (190 mg, 444 μmol, 87.1%, m / z = 428.4 [M + H] + ).

[0455]

[0456] [Example 10]

[0457] Preparation of (4-((5-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (NRX02075)

[0458]

[0459]

[0460] 10-1. Step 1: (4-((5-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-(2-((trimethylsilyl) methoxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl) (morpholino)methanone (12)

[0461]

[0462] 50 mg (117 μmol) of the compound (11) obtained in the above Preparation Example 3 was dissolved in 1.2 ml of 2-butanol, and then 34.5 mg (146 μmol) of the compound (8) obtained in the above Preparation Example 2, 32.3 mg (234 μmol) of potassium carbonate, 6.43 mg (7.02 μmol) of tris(dibenzylideneacetone)dipalladium(0), and 5.58 mg (11.7 μmol) of dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]propane were added, and the mixture was stirred at 90°C for 6 hours. After confirming the completion of the reaction, the mixture was filtered using a syringe filter and concentrated under reduced pressure. 10 ml of water and 10 ml of ethyl acetate were added to the filtrate, and the desired compound was extracted into the ethyl acetate layer. The ethyl acetate layer obtained by repeating the above extraction process three times was concentrated under reduced pressure to obtain the target compound (12) of Example 10 Step 1 (73.4 mg, 117 μmol, 100%, m / z = 628.3 [M + H] + ).

[0463]

[0464] 10-2. Step 2: (4-((5-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (NRX02075)

[0465]

[0466] 73 mg (117 μmol) of the compound (12) obtained in step 1 of the above Example 10 was dissolved in 1.2 ml of dichloromethane, 869 μl (11.7 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 50°C for 3 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure. The filtrate was dissolved in 1.2 ml of tetrahydrofuran, and 10 ml of a saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred for 6 hours to neutralize. Thereafter, 5 ml of water and 5 ml of ethyl acetate were added to the reaction solution, and the desired compound was extracted with the ethyl acetate layer. The ethyl acetate layer obtained by repeating the above extraction process three times was concentrated under reduced pressure, and the compound was purified through a Prep-HPLC device to obtain the target compound (13) of Example 10 (12.3 mg, 24.7 μmol, 21.2%, m / z = 498.0 [M + H] + ).

[0467]

[0468] [Manufacturing Example 4]

[0469] Preparation of 1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (18)

[0470]

[0471]

[0472] 4-1. Step 1: (3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol (15)

[0473]

[0474] 0.1 g (0.408 mmol) of ethyl-3-benzyl-3-azabicyclo[3.1.0]hexene-1-carboxylate (14) was added to 2.04 mL of tetrahydrofuran and the temperature was lowered to 0°C. Lithium aluminum hydride was added and stirred at 0°C for 30 minutes. The reaction solution was stirred at room temperature for 1 hour. Sodium sulfate decahydrate was added to the reaction solution and stirred at room temperature for 30 minutes. Tetrohydrofuran was added and the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain compound (15) (72 mg, 0.354 mmol, 87%, m / z = 204.1 [M + H] + ).

[0475]

[0476] 4-2. Step 2: 3-benzyl-1-(chloromethyl)-3-azabicyclo[3.1.0]hexane (16)

[0477]

[0478] 790 mg (3.89 mmol) of (3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol was added to 19.4 ml of dichloromethane and the temperature was lowered to 0°C. 889 mg (4.66 mmol) of tosyl chloride, 47.5 mg (0.389 mmol) of 4-dimethylaminopyridine and 865 mg (8.55 mmol) of triethylamine were added and stirred at 0°C for 30 minutes. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and water and dichloromethane were added and filtered. The reaction solution was separated using column chromatography (SiO2, ethyl acetate) to obtain the target compound (16) (598 mg, 2.7 mmol, 69%, m / z = 222.1 [M + H] + ).

[0479]

[0480] 4-3. Step 3: 3-benzyl-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (17)

[0481]

[0482] 20 mg (0.090 mmol) of 3-benzyl-1-(chloromethyl)-3-azabicyclo[3.1.0]hexane and 18.7 mg (0.135 mmol) of potassium carbonate were added to 0.45 ml of methanol and stirred at 100°C for 24 hours. The reaction solution was concentrated under reduced pressure and filtered to obtain compound (17) (19 mg, 0.090 mmol, 100%, m / z = 218.1 [M + H] + ).

[0483]

[0484] 4-4. Step 4: 1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane (18)

[0485]

[0486] 93.6 mg (0.431 mmol) of 3-benzyl-1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane was dissolved in 2.15 ml of ethanol. 5 mg of 10% Pd / C was added to the reaction mixture and placed in a hydrogen autoclave. The reaction mixture was stirred at room temperature for 24 hours under 20-30 psi of hydrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound (18) (47 mg, 0.37 mmol, 86%).

[0487]

[0488] [Example 11]

[0489] Preparation of 4-{1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02096)

[0490]

[0491] 44 mg (0.246 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 47 mg (0.370 mmol) of 1-(methoxymethyl)-3-azabicyclo[3.1.0]hexane, 85.8 μl (0.62 mmol) of triethylamine, and 1.64 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 11 (15.3 mg, 0.057 mmol, 23%, m / z = 270.1 [M + H] + ).

[0492] 1 H-NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.20 (s, 1H), 4.16 (dd, 2H), 3.80 (m, 2H), 3.51 (m, 2H), 3.30 (s, 3H), 1.68 (dt,J= 8.4, 4.3 Hz, 1H), 0.87 (dd,J= 8.0, 4.8 Hz, 1H), 0.43 (t,J= 4.6 Hz, 1H).

[0493]

[0494] [Manufacturing Example 5]

[0495] Preparation of (3-azabicyclo[3.1.0]hexan-1-yl)methanol (20)

[0496]

[0497] 0.1 g (0.469 mmol) of tert-butyl-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (19) was dissolved in 2.34 ml of dichloromethane, and 1 N hydrogen chloride (ethyl acetate) was added. The reaction solution was stirred at room temperature for 2 hours, and the residual solvent was concentrated under reduced pressure to obtain the target compound (20) (29.2 mg, 195 mmol, 42%).

[0498]

[0499] [Example 12]

[0500] Preparation of 4-(1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02098)

[0501]

[0502]

[0503] 44 mg (0.246 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 29.2 mg (0.195 mmol) of the compound (20) of Preparation Example 5, 90.6 μl (0.65 mmol) of triethylamine, and 0.9 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 12 (1.0 mg, 0.004 mmol, 3%, m / z = 256.1 [M + H] + ).

[0504]

[0505] [Example 13]

[0506] Preparation of 4-(isoindolin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02088)

[0507]

[0508]

[0509] The same procedure as Example 12 was followed, except that isoindole was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 13 (21.2 mg, 0.081 mmol, 48%, m / z = 262.1 [M + H]+ ).

[0510] 1 H-NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.68 (s, 1H), 7.41 (dd,J= 5.4, 3.3 Hz, 2H), 7.29 (dd,J= 5.6, 3.2 Hz, 2H), 5.73 (dd,J= 7.7 Hz, 2H), 5.29 (s, 2H), 4.86 (s, 2H), 0.87 (dd,J= 8.0, 4.8 Hz, 1H), 0.43 (t,J= 4.6 Hz, 1H).

[0511]

[0512] [Example 14]

[0513] Preparation of 4-((3aR,7aS)-octahydro-2H-isoindol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02087)

[0514]

[0515]

[0516] The same procedure as Example 12 was followed, except that (3aR,7aS)-octahydro-1H-isoindole was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 14 (20.2 mg, 0.0755 mmol, 45%, m / z = 268.1 [M + H] + ).

[0517] 1H-NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.68 (s, 1H), 7.41 (dd,J= 5.4, 3.3 Hz, 2H), 7.29 (dd,J= 5.6, 3.2 Hz, 2H), 5.73 (dd,J= 7.7 Hz, 2H), 5.29 (s, 2H), 4.86 (s, 2H), 0.87 (dd,J= 8.0, 4.8 Hz, 1H), 0.43 (t,J= 4.6 Hz, 1H).

[0518]

[0519] [Example 15]

[0520] Preparation of 4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX67086)

[0521]

[0522]

[0523] The same procedure as Example 12 was followed, except that octahydrocyclopenta[c]pyrrole was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 15 (14.8 mg, 0.058 mmol, 34%, m / z = 254.1 [M + H] + ).

[0524] 1 H-NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.20 (s, 1H), 3.99 (dd,J= 11.3, 7.7 Hz, 2H), 3.61 (dd,J= 11.3, 3.9 Hz, 2H), 2.78 (dq,J= 8.0, 4.4 Hz, 2H), 1.91 - 1.80 (m, 2H), 1.82 - 1.70 (m, 1H), 1.67 - 1.56 (m, 1H), 1.54 - 1.44 (m, 2H).

[0525]

[0526] [Example 16]

[0527] Preparation of 4-((1R,5S)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02085)

[0528]

[0529]

[0530] The same procedure as Example 12 was followed, except that (1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonitrile was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 16 (8.0 mg, 0.032 mmol, 19%, m / z = 251.1 [M + H] + ).

[0531] 1 H-NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 4.23 (d,J= 11.4 Hz, 2H), 3.78 (dt,J= 11.5, 1.9 Hz, 2H), 2.55 - 2.50 (m, 2H), 1.68 (t,J= 3.5 Hz, 1H).

[0532]

[0533] [Example 17]

[0534] Preparation of 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02084)

[0535]

[0536]

[0537] The same procedure as Example 12 was followed, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 17 (1.0 mg, 0.004 mmol, 2%, m / z = 262.0 [M + H] + ).

[0538]

[0539] [Example 18]

[0540] Preparation of 4-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02083)

[0541]

[0542]

[0543] The same procedure as Example 12 was followed, except that 6,6-dimethyl-3-azabicyclo[3.1.0]hexane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 18 (19.3 mg, 0.076 mmol, 45%, m / z = 254.1 [M + H] + ).

[0544] 1 H-NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.20 (s, 1H), 3.92 (d,J= 11.6 Hz, 2H), 3.81 (d,J= 11.4 Hz, 2H), 1.62 (s, 2H), 1.07 (s, 3H), 0.82 (s, 3H).

[0545]

[0546] [Example 19]

[0547] Preparation of 4-(3,3-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02082)

[0548]

[0549] The same procedure as Example 12 was followed, except that 3,3-dimethylpyrrolidine was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 19 (9.4 mg, 0.039 mmol, 23%, m / z = 242.1 [M + H] + ).

[0550] 1 H-NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 3.86 (t,J= 7.0 Hz, 2H), 3.55 (s, 2H), 1.82 (t,J= 7.0 Hz, 2H), 1.12 (s, 6H).

[0551]

[0552] [Example 20]

[0553] Preparation of 4-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02081)

[0554]

[0555]

[0556] The same procedure as Example 12 was followed, except that 6-fluoro-2-azaspiro[3.3]heptene was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 20 (16.2 mg, 0.063 mmol, 37%, m / z = 258.1 [M + H] + ).

[0557] 1 H-NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.22 (s, 1H), 5.05 (dp,J= 56.0, 6.6 Hz, 1H), 4.36 (d,J= 9.7 Hz, 4H), 2.70 (dtd,J= 13.3, 6.7, 3.2 Hz, 2H), 2.42 (dddd,J= 20.0, 13.5, 6.4, 3.2 Hz, 2H).

[0558]

[0559] [Example 21]

[0560] Preparation of 4-morpholino-1H-1,5,7-triazaindene-3-carbonitrile (NRX02120)

[0561]

[0562]

[0563] The same procedure as Example 12 was followed, except that 48.8 mg (0.560 mmol) of morpholine was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 21 (44 mg, 0.192 mmol, 69%, m / z = 230.1 [M + H] + ).

[0564] 1 H-NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.31 (s, 1H), 3.73 (dd,J= 5.6, 3.4 Hz, 1H), 3.64 (dd,J= 5.5, 3.6 Hz, 1H).

[0565]

[0566] [Example 22]

[0567] Preparation of 4-{3-[(dimethylamino)methyl]-1-pyrrolidinyl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02121)

[0568]

[0569]

[0570] The same procedure as Example 12 was followed, except that N,N-dimethyl[(3-pyrrolidinyl)methyl]amine was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 22 (62 mg, 0.229 mmol, 109%, m / z = 271.1 [M + H] + ).

[0571] 1 H-NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.19 (s, 1H), 3.98 (s, 2H), 3.64 (m, 2H), 3.52 (m, 2H), 2.50 (s, 1H), 2.43 (s, 2H), 1.35 (d,J=4 Hz, 6H), 1.32 (d,J=4 Hz, 2H).

[0572]

[0573] [Example 23]

[0574] Preparation of 4-(3-oxa-7-azabicyclo[3.3.0]oct-7-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02125)

[0575]

[0576]

[0577] The same procedure as Example 12 was followed, except that 3-oxa-7-azabicyclo[3.3.0]octane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 23 (61 mg, 0.237 mmol, 85%, m / z = 256.1 [M + H] + ).

[0578] 1H-NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.19 (s, 1H), 3.98 (ddt,J= 11.0, 7.5, 4.2 Hz, 2H), 3.86 - 3.77 (m, 2H), 3.81 - 3.69 (m, 2H), 3.57 (dq,J= 8.6, 3.3 Hz, 2H), 3.05 (s, 2H).

[0579]

[0580] [Example 24]

[0581] Preparation of 4-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02126)

[0582]

[0583]

[0584] The same procedure as Example 12 was followed, except that 6-oxa-3-azabicyclo[3.1.1]heptane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 24 (31 mg, 0.126 mmol, 45%, m / z = 242.1 [M + H] + ).

[0585] 1 H-NMR (400 MHz, DMSO-d6) δ 8.33 - 8.24 (m, 2H), 4.74 (dd,J= 16.2, 6.6 Hz, 2H), 4.24 - 4.12 (m, 2H), 3.96 (s, 2H), 1.93 - 1.84 (m, 1H).

[0586]

[0587] [Example 25]

[0588] Preparation of 1-(3-cyano-1H-1,5,7-triazainden-4-yl)-3-piperidinecarboxamide (NRX02127)

[0589]

[0590]

[0591] The same procedure as Example 12 was followed, except that 3-piperidine carboxamide (43 mg, 0.336 mmol) was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 25 (62 mg, 0.230 mmol, 82%, m / z = 270.3 [M + H] + ).

[0592] 1 H-NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.27 (s, 1H), 7.29 (s, 1H), 6.84 (s, 1H), 4.33 (d,J= 13.2 Hz, 1H), 4.24 (d,J= 13.1 Hz, 1H), 3.08 - 2.96 (m, 3H), 1.92 (s, 1H), 1.75 (d,J= 7.5 Hz, 1H), 1.59 (s, 2H).

[0593]

[0594] [Example 26]

[0595] Preparation of 4',5',6',7'-tetrahydro-1H,3'H-1,2',3',5,5',7-hexaaza-[4,5'-biindenyl]-3-carbonitrile (NRX02143)

[0596]

[0597]

[0598] The same procedure as Example 12 was followed, except that 4,5,6,7-tetrahydro-1H-1,2,6-triazeindine (41.4 mg, 0.336 mmol) was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 26 (37.9 mg, 0.143 mmol, 51%, m / z = 266.1 [M + H] + ).

[0599] 1 H-NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 12.53 (s, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 4.75 (s, 2H), 3.93 (t,J= 5.7 Hz, 2H), 2.82 (t,J= 5.4 Hz, 2H).

[0600]

[0601] [Example 27]

[0602] Preparation of 4',5',6',7'-tetrahydro-1H,2'H-1,2',3',5,5',7-hexaaza-[4,5'-biindenyl]-3-carbonitrile (NRX02144)

[0603]

[0604]

[0605] The same procedure as Example 12 was followed, except that 4,5,6,7-tetrahydro-1H-1,2,6-triazeindine (41.4 mg, 0.336 mmol) was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 27 (38.9 mg, 0.147 mmol, 52%, m / z = 266.1 [M + H] + ).

[0606] 1 H-NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 12.53 (s, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 4.75 (s, 2H), 3.93 (t,J= 5.6 Hz, 2H), 2.82 (s, 2H).

[0607]

[0608] [Example 28]

[0609] Preparation of 4-(5-aza-5-spiro[2.4]heptyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02145)

[0610]

[0611]

[0612] The same procedure as Example 12 was followed, except that 5-azaspiro[2.4]heptane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 28 (47.5 mg, 0.199 mmol, 71%, m / z = 240.1 [M + H] + ).

[0613] 1 H-NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.20 (s, 1H), 3.94 (t,J= 6.8 Hz, 2H), 3.67 (s, 2H), 1.94 (t,J= 6.8 Hz, 2H), 0.65 (s, 4H).

[0614]

[0615] [Example 29]

[0616] Preparation of 4-{[(1-methyl-4-piperidyl)methyl]amino}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02146)

[0617]

[0618]

[0619] The same procedure as Example 12 was followed, except that [(1-methyl-4-piperidyl)methyl]amine was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 29 (12.7 mg, 0.047 mmol, 17%, m / z = 271.1 [M + H] + ).

[0620] 1 H-NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.11 (s, 1H), 6.39 (t,J= 5.8 Hz, 1H), 3.43 (t,J= 6.2 Hz, 2H), 3.16 (s, 1H), 2.73 (dd,J= 11.6, 3.5 Hz, 2H), 2.12 (s, 3H), 1.79 (td,J= 11.6, 2.3 Hz, 2H), 1.62 (tq,J= 10.5, 3.0 Hz, 3H), 1.25 - 1.17 (m, 2H).

[0621]

[0622] [Example 30]

[0623] Preparation of 4-(2-aza-2-spiro[4.4]nonyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02150)

[0624]

[0625]

[0626] The same procedure as Example 12 was followed, except that 2-azaspiro[4.4]nonane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 30 (55 mg, 0.206 mmol, 73%, m / z = 268.1 [M + H] + ).

[0627] 1 H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 3.79 (t,J= 6.9 Hz, 2H), 3.61 (s, 2H), 1.87 (t,J= 7.0 Hz, 2H), 1.68 - 1.49 (m, 8H).

[0628]

[0629] [Example 31]

[0630] Preparation of 4-(6-aza-6-spiro[3.4]octyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02151)

[0631]

[0632]

[0633] The same procedure as Example 12 was followed, except that 6-azaspiro[3.4]octane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 31 (55 mg, 0.217 mmol, 78%, m / z = 254.1 [M + H] + ).

[0634] 1 H-NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 3.72 (d, J= 7.0 Hz, 4H), 2.04 - 1.79 (m, 8H).

[0635]

[0636] [Example 32]

[0637] Preparation of 4-(2-aza-2-spiro[4.5]decyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02166)

[0638]

[0639]

[0640] The same procedure as Example 12 was followed, except that 2-azaspiro[4.5]decane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 32 (19.7 mg, 0.070 mmol, 25%, m / z = 282.1 [M + H] + ).

[0641] 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 3.77 (t,J= 7.1 Hz, 2H), 3.60 (s, 2H), 1.80 (t,J= 7.1 Hz, 2H), 1.52 - 1.35 (m, 10H).

[0642]

[0643] [Example 33]

[0644] 4-(2-oxa-7-aza-7-spiro[4.4]nonyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02168)

[0645]

[0646]

[0647] The same procedure as Example 12 was followed, except that 2-oxa-7-azaspiro[4.4]nonane was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 33 (48 mg, 0.178 mmol, 64%, m / z = 270.1 [M + H] + ).

[0648] 1 H-NMR (400 MHz, CDCl3-d) δ 8.36 (s, 1H), 7.76 (s, 1H), 4.05 (ddd,J= 17.3, 10.9, 7.0 Hz, 2H), 3.99 (s, 1H), 3.99 - 3.93 (m, 3H), 3.93 - 3.84 (m, 3H), 3.80 - 3.68 (m, 3H), 2.21 - 1.94 (m, 6H), 1.24 (s, 1H).

[0649]

[0650] [Example 34]

[0651] Preparation of 4-(8-oxo-2,7-diaza-2-spiro[4.4]nonyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02171)

[0652]

[0653]

[0654] The same procedure as Example 12 was followed, except that 2,7-diaza-3-spiro[4.4]nonanone was used instead of (3-azabicyclo[3.1.0]hexan-1yl)methanol, to obtain the target compound of Example 34 (35 mg, 0.124 mmol, 44%, m / z = 283.1 [M + H] + ).

[0655] 1 H-NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.22 (s, 1H), 7.66 (s, 1H), 3.88 (t,J= 7.0 Hz, 1H), 3.84 - 3.72 (m, 1H), 3.25 (d,J= 0.8 Hz, 1H), 2.26 (s, 1H), 2.06 (td,J= 6.7, 1.5 Hz, 1H), 1.30 - 1.19 (m, 1H).

[0656]

[0657] [Example 35]

[0658] Preparation of 6-(isoindolin-2-yl)-9H-purin-2-amine (NRX02095)

[0659]

[0660]

[0661] 30 mg (0.119 mmol) of 6-chloro-9H-purin-2-amine, 21.3 mg (0.178 mmol) of isoindole, 62 μl (0.445 mmol) of triethylamine, and 0.8 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 35 (3.1 mg, 0.012 mmol, 10%, m / z = 253.1 [M + H] + ).

[0662] 1 H-NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.68 (s, 1H), 7.41 (dd,J= 5.4, 3.3 Hz, 2H), 7.29 (dd,J= 5.6, 3.2 Hz, 2H), 5.73 (d,J= 7.7 Hz, 2H), 5.29 (s, 2H), 4.86 (s, 2H).

[0663]

[0664] [Example 36]

[0665] Preparation of 6-((3aR,7aS)-octahydro-2H-isoindol-2-yl)-9H-purin-2-amine (NRX02094)

[0666]

[0667]

[0668] The same procedure as Example 35 was followed, except that (3aR,7aS)-octahydro-1H-isoindole was used instead of isoindole, to obtain the target compound of Example 36 (29.0 mg, 0.112 mmol, 63%, m / z = 259.1 [M + H] + ).

[0669] 1 H-NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.60 (s, 1H), 5.61 (s, 2H), 3.93 (s, 2H), 3.46 (s, 1H), 2.25 (d,J= 37.8 Hz, 3H), 1.65 - 1.26 (m, 6H).

[0670]

[0671] [Example 37]

[0672] Preparation of 6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-9H-purin-2-amine (NRX02093)

[0673]

[0674]

[0675] The same procedure as Example 35 was followed, except that octahydrocyclopenta[c]pyrrole was used instead of isoindole, to obtain the target compound of Example 37 (27.5 mg, 0.112 mmol, 63%, m / z = 245.1 [M + H] + ).

[0676] 1 H-NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.58 (s, 1H), 5.59 (s, 2H), 2.65 (s, 2H), 1.82 - 1.35 (m, 6H).

[0677]

[0678] [Example 38]

[0679] Preparation of (1R,5S)-3-(2-amino-9H-purin-6-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (NRX02092)

[0680]

[0681] The same procedure as Example 35 was followed, except that (1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonitrile was used instead of isoindole, to obtain the target compound of Example 38 (27.5 mg, 0.112 mmol, 63%, m / z = 242.1 [M + H] + ).

[0682] 1H-NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.63 (s, 1H), 5.72 (s, 2H), 4.07 (q,J= 5.3 Hz, 1H), 3.56 (s, 2H), 3.13 (d,J= 5.2 Hz, 1H), 2.38 (s, 2H), 1.61 (t,J= 3.5 Hz, 1H).

[0683]

[0684] [Example 39]

[0685] Preparation of 6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-9H-purin-2-amine (NRX02091)

[0686]

[0687]

[0688] The same procedure as Example 35 was followed, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane was used instead of isoindole, to obtain the target compound of Example 39 (26.3 mg, 0.104 mmol, 58%, m / z = 253.1 [M + H] + ).

[0689]

[0690] [Example 40]

[0691] Preparation of 6-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-9H-purin-2-amine (NRX02090)

[0692]

[0693]

[0694] The same procedure as Example 35 was followed, except that 6,6-dimethyl-3-azabicyclo[3.1.0]hexane was used instead of isoindole, to obtain the target compound of Example 40 (23.5 mg, 0.096 mmol, 54%, m / z = 245.1 [M+ H] + ).

[0695] 1 H-NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.62 (s, 1H), 5.65 (s, 2H), 4.15 (s, 1H), 3.95 (s, 1H), 3.60 (d,J= 20.2 Hz, 2H), 1.54 (s, 1H), 1.44 (s, 1H), 1.05 (s, 3H), 0.83 (s, 3H).

[0696]

[0697] [Example 41]

[0698] Preparation of 6-(6-fluoro-2-azaspiro[3.3]heptan-2-yl)-9H-purin-2-amine (NRX02089)

[0699]

[0700]

[0701] The same procedure as Example 35 was followed, except that 6-fluoro-2-azaspiro[3.3]heptene was used instead of isoindole, to obtain the target compound of Example 41 (15.8 mg, 0.064 mmol, 36%, m / z = 249.1 [M + H] + ).

[0702] 1 H-NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 7.67 (s, 1H), 5.98 (s, 2H), 5.02 (dp,J= 56.0, 6.6 Hz, 1H), 4.28 (s, 4H), 2.66 (s, 2H).

[0703]

[0704] [Example 42]

[0705] Preparation of 6-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-9H-purin-2-amine (NRX02004)

[0706]

[0707]

[0708] 100 mg (0.467 mmol) of 6-bromo-9H-purin-2-amine, 62.3 mg (0.561 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 97.7 μl (0.701 mmol) of triethylamine, and 3.1 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 42 (110 mg, 0.45 mmol, 96%, m / z = 245.1 [M + H] + ).

[0709] 1 H-NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.63 (s, 1H), 5.67 (s, 2H), 1.73 (dq,J= 14.6, 7.4 Hz, 1H), 1.46 (dq,J= 15.6, 8.0 Hz, 2H), 0.95 (td,J= 7.4, 1.0 Hz, 3H), 0.64 (dd,J= 8.0, 4.5 Hz, 1H), 0.24 (t,J= 4.2 Hz, 1H).

[0710]

[0711] [Example 43]

[0712] Preparation of 3-(2-amino-7H-purin-6-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (NRX02070)

[0713]

[0714]

[0715] The same procedure as Example 42 was followed, except that 3-azabicyclo[3.1.0]hexane-1-carbonitrile was used instead of 1-ethyl-3-azabicyclo[3.1.0]hexane, to obtain the target compound of Example 43 (6.7 mg, 0.028 mmol, 52%, m / z = 242.1 [M + H] + ).

[0716] 1 H-NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.65 (s, 1H), 5.75 (s, 2H), 4.01 (s, 1H), 3.65 (s, 3H), 1.47 (dd,J= 8.5, 5.3 Hz, 2H), 0.95 (t,J= 5.3 Hz, 2H).

[0717]

[0718] [Example 44]

[0719] Preparation of 6-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-purine (NRX02069)

[0720]

[0721]

[0722] 10 mg (0.05 mmol) of 6-bromo-7H-purine, 6.7 mg (0.06 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 10.5 μl (0.075 mmol) of triethylamine, and 0.5 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 44 (15.9 mg, 0.069 mmol, 138%, m / z = 230.1 [M + H] + ).

[0723] 1H-NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.03 (s, 1H), 4.07 - 3.45 (m, 3H), 1.71 (dq,J= 14.7, 7.4 Hz, 1H), 1.45 (dq,J= 14.5, 7.4 Hz, 1H).

[0724]

[0725] [Example 45]

[0726] Preparation of 3-(9H-purin-6-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (NRX02072)

[0727]

[0728]

[0729] The same procedure as Example 44 was followed, except that 3-azabicyclo[3.1.0]hexane-1-carbonitrile was used instead of 1-ethyl-3-azabicyclo[3.1.0]hexane, to obtain the target compound of Example 45 (22.4 mg, 0.099 mmol, 187%, m / z = 227.1 [M + H] + ).

[0730]

[0731] [Example 46]

[0732] Preparation of 3-(9H-purin-6-yl)-3-azabicyclo[3.1.0]hexane-2-carbonitrile (NRX02074)

[0733]

[0734]

[0735] The same procedure as Example 44 was followed, except that 3-azabicyclo[3.1.0]hexane-2-carbonitrile was used instead of 1-ethyl-3-azabicyclo[3.1.0]hexane, to obtain the target compound of Example 46 (6.3 mg, 0.028 mmol, 30%, m / z = 227.1 [M + H]+ ).

[0736]

[0737] [Example 47]

[0738] Preparation of 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (NRX02071)

[0739]

[0740]

[0741] 7.96 mg (0.042 mmol) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyridine and 10 mg (0.053 mmol) of 3-azabicyclo[3.1.0]hexane-2-carbonitrile hydrobromide, 11.1 μl (0.079 mmol) of triethylamine, and 0.53 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 47 (6 mg, 0.023 mmol, 44%, m / z = 260.0 [M + H] + ).

[0742] 1 H-NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.15 (dd,J= 3.6, 2.3 Hz, 1H), 6.59 (d,J= 3.3 Hz, 1H), 4.26 (d,J= 10.6 Hz, 1H), 4.01 (d,J= 10.3 Hz, 1H), 3.82 (s, 2H), 2.53 (s, 1H), 1.55 (dd,J= 8.6, 5.4 Hz, 1H), 1.05 (t,J= 5.5 Hz, 1H).

[0743]

[0744] [Example 48]

[0745] Preparation of 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (NRX02068)

[0746]

[0747]

[0748] The same procedure as Example 47 was followed, except that 1-ethyl-3-azabicyclo[3.1.0]hexane was used instead of 3-azabicyclo[3.1.0]hexane-2-carbonitrile hydrobromide, to obtain the target compound of Example 48 (6 mg, 0.023 mmol, 44%, m / z = 263.1 [M + H] + ).

[0749]

[0750] [Example 49]

[0751] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1,5,7-triaza-1H-indene-3-carbonitrile (NRX02067)

[0752]

[0753]

[0754] 28.9 mg (0.162 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile, 20 mg (0.18 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 62.7 μl (0.450 mmol) of triethylamine, and 0.9 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 49 (25.9 mg, 0.102 mmol, 56%, m / z = 254.1 [M + H] + ).

[0755] 1 H-NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.19 (s, 1H), 4.17 (d,J= 10.4 Hz, 1H), 4.08 (d,J= 11.0 Hz, 1H), 3.77 (dd,J= 10.9, 4.4 Hz, 1H), 3.64 (d,J= 10.5 Hz, 1H), 1.80 (dd,J= 14.0, 7.2 Hz, 1H), 1.53 (dt,J= 8.1, 4.1 Hz, 1H), 1.42 (dq,J= 14.9, 7.5 Hz, 1H), 0.99 (t,J= 7.4 Hz, 3H), 0.71 (dd,J= 8.0, 4.6 Hz, 1H), 0.71 (dd,J= 8.0, 4.6 Hz, 1H).

[0756]

[0757] [Example 50]

[0758] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (NRX02066)

[0759]

[0760]

[0761] 10 mg (0.060 mmol) of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine, 7.96 mg (0.072 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 12.5 μl (0.089 mmol) of triethylamine, and 0.6 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 50 (24.2 mg, 0.10 mmol, 166%, m / z = 243.1 [M + H] + ).

[0762]

[0763] [Example 51]

[0764] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (NRX02065)

[0765]

[0766]

[0767] 27.3 mg (0.162 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 20 mg (0.18 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 62.7 μl (0.45 mmol) of triethylamine, and 1.6 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 51 (16.1 mg, 0.066 mmol, 37%, m / z = 244.2 [M + H] + ).

[0768] 1 H-NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.13 (s, 1H), 6.66 (dd,J= 3.6, 2.1 Hz, 1H), 6.30 (dd,J= 3.7, 1.7 Hz, 1H), 5.43 (s, 2H), 3.92 (dd,J= 25.6, 10.4 Hz, 2H), 1.71 (dd,J= 14.1, 7.2 Hz, 1H), 1.53 - 1.40 (m, 2H), 0.95 (t,J= 7.4 Hz, 3H), 0.67 (dd,J= 8.0, 4.4 Hz, 1H), 0.67 (dd,J= 8.0, 4.4 Hz, 1H).

[0769]

[0770] [Manufacturing Example 6]

[0771] Preparation of 1-methyl-3-azabicyclo[3.1.0]hexane (27)

[0772]

[0773]

[0774] 6-1. Step 1: diethyl 1-methylcyclopropane-1,2-dicarboxylate (22)

[0775]

[0776] 5 g (36.6 mmol) of ethyl-2-chloropropanoate (21) and 3.98 ml (36.6 mmol) of ethyl acrylate were added to 26.1 ml of toluene and the mixture was cooled to 0°C. Tert-butoxide (tetrahydrofuran) was added dropwise to the reaction mixture and stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added and filtered to obtain compound (22) (7.3 g, 36.4 mmol, 99%).

[0777]

[0778] 6-2. Step 2: 1-methylcyclopropane-1,2-dicarboxylic acid (23)

[0779]

[0780] 7.33 g (36.6 mmol) of diethyl 1-methylcyclopropane-1,2-dicarboxylic acid (22) and 4.39 g (110 mmol) of sodium hydroxide were added to 36.6 ml of methanol and 36.6 ml of water, and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added, followed by filtration to obtain compound (23) (5.35 g, 37.1 mmol, 101%).

[0781]

[0782] 6-3. Step 3: 1-methyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (24)

[0783]

[0784] 787 mg (4.98 mmol) of 1-methylcyclopropane-1,2-dicarboxylate (23) was added to 3.18 ml (44.8 mmol) of acetyl chloride, refluxed, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound (24) (798 g, 5.69 mmol, 114%).

[0785]

[0786] 6-4. Step 4: 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione (25)

[0787]

[0788] 697 mg (4.97 mmol) of 1-methyl-3-oxabicyclo[3.1.0]hexane-2,4,-dione (24) was added to 0.54 ml (4.97 mmol) of benzylamine and stirred at 190°C for 7 hours. The reaction solution was concentrated under reduced pressure, and isopropyl alcohol, ethyl acetate and hexane were added and filtered to obtain compound (25) (559 mg, 2.44 mmol, 49%, m / z = 216.1 [M + H] + ).

[0789]

[0790] 6-5. Step 5: 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane (26)

[0791]

[0792] 4.35 g (20.2 mmol) of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione (25) was added to 57.7 ml of diethyl ether and the mixture was cooled to 0°C. 18.6 g (91.9 mmol) of sodium bis-(2-methoxyethoxy)-aluminum dihydride was added to the reaction solution and stirred at 0°C for 30 minutes and then at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and water and diethyl ether were added and filtered to obtain compound (26) (2.25 g, 12 mmol, 60%, m / z = 188.2 [M + H] + ).

[0793]

[0794] 6-6. Step 6: 1-methyl-3-azabicyclo[3.1.0]hexane (27)

[0795]

[0796] 250 mg (1.33 mmol) of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane (26) was added to 3.34 ml of ethanol. 17.5 mg of 10% Pd / C was added to the reaction solution, which was then placed in a hydrogen autoclave and stirred at room temperature for 22 hours under 50-55 psi of hydrogen. The reaction solution was concentrated under reduced pressure, and isopropyl alcohol, ethyl acetate, and hexane were added, followed by filtration to obtain compound (27) (100 mg, 1.03 mmol, 77%).

[0797]

[0798] [Example 52]

[0799] Preparation of 4-(1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02100)

[0800]

[0801]

[0802] 50 mg (0.28 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile, 45.3 mg (0.467 mmol) of the compound (27) of the above Preparation Example 6, 108 μl (0.778 mmol) of triethylamine, and 1.56 ml of ethanol were added and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 52 (25.4 mg, 0.106 mmol, 34%, m / z = 240.1 [M + H] + ).

[0803] 1 H-NMR (400 MHz, DMSO-d6) δ 8.27 - 8.22 (m, 1H), 8.21 - 8.14 (m, 1H), 4.19 (dd,J= 10.7, 3.4 Hz, 1H), 4.09 (dd,J= 10.8, 3.3 Hz, 1H), 3.58 (dd,J= 10.7, 3.3 Hz, 1H), 1.50 (dd,J= 8.4, 4.4 Hz, 1H), 1.35 - 1.28 (m, 3H), 0.68 (dt,J= 12.7, 6.0 Hz, 1H), 0.31 (q,J= 4.4 Hz, 1H).

[0804]

[0805] [Manufacturing Example 7]

[0806] Preparation of 4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (35)

[0807]

[0808]

[0809] 7-1. Step 1: ethyl 1-benzyl-2,5-dihydro-1H-pyrrole-3-carboxylate (29)

[0810]

[0811] 24.3 g (102 mmol) of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (28) and 7.42 ml (73.2 mmol) of ethyl propiolate were added to 293 ml of dichloromethane and the temperature was lowered to 0°C. Trifluoroacetic acid was added dropwise to the reaction solution and stirred at room temperature for 4 hours. The reaction solution was neutralized by adding saturated aqueous sodium bicarbonate solution. Water and dichloromethane were added to the reaction solution and filtered. The reaction solution was separated using column chromatography (SiO2, ethyl acetate) to obtain the target compound (29) (13.3 g, 57.4 mmol, 78.45%, m / z = 232.1 [M + H] + ).

[0812]

[0813] 7-2. Step 2: ethyl 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylate (30)

[0814]

[0815] It was added to 135 ml of dimethyl sulfoxide and lowered to 0℃. 2.94 g (73.5 mmol) of sodium hydride was added to 135 ml of dimethyl sulfoxide and lowered to 0℃. Trimethylsulfoxonium iodide was added dropwise to the reaction solution and stirred at room temperature for 1 hour. 13.1 g (56.6 mmol) of ethyl 1-benzyl-2,5-dihydro-1H-pyrrole-3-carboxylate (29) was added to the reaction solution and stirred at room temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to neutralize. Water and ethyl acetate were added to the reaction solution and filtered. The reaction solution was separated using column chromatography (SiO2, ethyl acetate) to obtain the target compound (30) (3.1 g, 12.6 mmol, 22.35%, m / z = 246.1 [M + H] + ).

[0816]

[0817] 7-3. Step 3: (3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol (31)

[0818]

[0819] 0.1 g (0.408 mmol) of ethyl-3-benzyl-3-azabicyclo[3.1.0]hexene-1-carboxylate (30) was added to 2.04 ml of tetrahydrofuran and the temperature was lowered to 0°C. Lithium aluminum hydride was added and stirred at 0°C for 30 minutes. The reaction solution was stirred at room temperature for 1 hour. Sodium sulfate decahydrate was added and stirred at room temperature for 30 minutes. Tetrohydrofuran was added and the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (31) (72 mg, 0.354 mmol, 87%, m / z = 204.1 [M + H] + ).

[0820]

[0821] 7-4. Step 4: 3-benzyl-1-(chloromethyl)-3-azabicyclo[3.1.0]hexane (32)

[0822]

[0823] 790 mg (3.89 mmol) of (3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methanol was added to 19.4 ml of dichloromethane and the temperature was lowered to 0°C. 889 mg (4.66 mmol) of tosyl chloride, 47.5 mg (0.389 mmol) of 4-dimethylaminopyridine and 865 mg (8.55 mmol) of triethylamine were added and stirred at 0°C for 30 minutes. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and water and dichloromethane were added and filtered to obtain the target compound (32) (598 mg, 2.7 mmol, 69%, m / z = 222.1 [M + H] + ).

[0824]

[0825] 7-5. Step 5: 2-((3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methyl)isoindoline-1,3-dione (33)

[0826]

[0827] 3-Benzyl-1-(chloromethyl)-3-azabicyclo[3.1.0]hexane (398 mg, 1.79 mmol) was added to 3.59 ml of dimethylformamide. 349 mg (1.88 mmol) of potassium phthalimide and 397 mg (2.87 mmol) of potassium carbonate were added to the reaction solution, and the mixture was refluxed and stirred for 20 hours. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and water and dichloromethane were added and filtered to obtain the target compound (33) (515 mg, 1.55 mmol, 86%, m / z = 333.1 [M + H] + ).

[0828]

[0829] 7-6. Step 6: 2-((3-azabicyclo[3.1.0]hexan-1-yl)methyl)isoindoline-1,3-dione (34)

[0830]

[0831] 515 mg (1.55 mmol) of 2-((3-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)methyl)isoindoline-1,3-dione was added to 5.16 ml of ethanol. 36 mg of 10% Pd / C was added to the reaction solution, which was then placed in a hydrogen autoclave. The reaction solution was stirred at room temperature for 20 hours under 50 psi of hydrogen. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain the target compound (34) (324 mg, 1.34 mmol, 86%, m / z = 243.1 [M + H] + ).

[0832]

[0833] 7-7. Step 7: 4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (35)

[0834]

[0835] 100 mg (0.560 mmol) of 4-chloro-7H-pyrrole[2,3-d]pyrimidine-5-carbonitrile, 187 mg (0.672 mmol) of 2-((3-azabicyclo[3.1.0]hexan-1-yl)methyl)isoindoline-1,3-dione, and 197 μl (1.4 mmol) of triethylamine were added to 2.8 ml of ethanol and stirred at 85°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18resin, water: acetonitrile = 9:1 to 1:9) to obtain the target compound (35) (160 mg, 0.416 mmol, 74%, m / z = 385.1 [M + H] + ).

[0836]

[0837] [Example 53]

[0838] Preparation of 4-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02101)

[0839]

[0840] 160 mg (0.416 mmol) of 4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrole[2,3-d]pyrimidine-5-carbonitrile and 278 mg (1.66 mmol) of hydrazine monohydrate were added to 4.16 ml of ethanol and stirred at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and water and dichloromethane were added and filtered. The filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 53 (3.4 mg, 0.21 mmol, 50%, m / z = 255.1 [M + H] + ).

[0841] 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.94 (s, 1H), 4.93 (d,J= 10.8 Hz, 1H), 4.84 (d,J= 10.6 Hz, 1H), 4.59 (dd,J= 10.6, 4.4 Hz, 1H), 4.51 (d,J= 10.8 Hz, 1H), 3.55 (s, 2H), 2.45 - 2.35 (m, 1H), 1.60 (dd,J= 8.0, 4.5 Hz, 1H), 1.07 (t,J= 4.3 Hz, 1H).

[0842]

[0843] [Manufacturing Example 8]

[0844] Preparation of 4-(1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d] pyrimidine-5-carbonitrile (36)

[0845]

[0846] 160 mg (0.416 mmol) of 4-(1-((1,3-dioxoisoindolin-2-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrole[2,3-d]pyrimidine-5-carbonitrile and 278 mg (1.66 mmol) of hydrazine monohydrate were added to 4.16 ml of ethanol and stirred at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and water and dichloromethane were added and filtered. The filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound (36) of Manufacturing Example 8 (3.4 mg, 0.21 mmol, 50%, m / z = 255.1 [M + H] + ).

[0847] 1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.94 (s, 1H), 4.93 (d,J= 10.8 Hz, 1H), 4.84 (d,J= 10.6 Hz, 1H), 4.59 (dd,J= 10.6, 4.4 Hz, 1H), 4.51 (d,J= 10.8 Hz, 1H), 3.55 (s, 2H), 2.45 - 2.35 (m, 1H), 1.60 (dd,J= 8.0, 4.5 Hz, 1H), 1.07 (t,J= 4.3 Hz, 1H).

[0848]

[0849] [Example 54]

[0850] Preparation of 4-(1-((dimethylamino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02102)

[0851]

[0852] 50 mg (0.197 mmol) of compound (36) of the above Preparation Example 8, 18.5 mg (0.295 mmol) of sodium cyanoborohydride, and 8.86 mg (0.295 mmol) of formaldehyde were stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 54 (5.4 mg, 0.019 mmol, 9%, m / z = 283.1 [M + H] + ).

[0853] 1H-NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.16 (s, 1H), 4.10 (dd,J= 13.1, 10.9 Hz, 2H), 3.82 (dd,J= 10.7, 4.4 Hz, 1H), 3.70 (d,J= 11.0 Hz, 1H), 2.50 (s, 1H), 2.31 (d,J= 12.6 Hz, 1H), 2.17 (s, 6H), 1.52 (dt,J= 8.3, 4.2 Hz, 1H), 0.72 (dd,J= 8.1, 4.8 Hz, 1H), 0.39 (t,J= 4.5 Hz, 1H).

[0854]

[0855] [Example 55]

[0856] Preparation of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (NRX02073)

[0857]

[0858] 6.5 mg (0.042 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 10 mg (0.053 mmol) of 3-azabicyclo[3.1.0]hexane-1-carbonitrile hydrobromide were added to 0.53 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was purified to obtain the target compound of Example 55 (4.1 mg, 0.018 mmol, 34%, m / z = 226.1 [M + H] + ).

[0859]

[0860] [Manufacturing Example 9]

[0861] Preparation of (6-hydroxypyridin-3-yl)(piperidin-3-yl)methanone (39)

[0862]

[0863]

[0864] 9-1. Step 1:tert-butyl 3-(6-(benzyloxy)nicotinoyl)piperidine-1-carboxylate (38)

[0865]

[0866] 100 mg (502 μmol) of tert-butyl 3-oxopiperidine-1-carboxylate (37) was dissolved in 2.5 ml of methanol, and 93.5 mg (502 μmol) of 4-methylbenzenesulfonohydrazide was added. The mixture was stirred at room temperature for 3 hours. The production of tert-butyl (E)-3-(2-tosylhydrazinylridine)piperidine-1-carboxylate intermediate (37-1) was confirmed using LC / MS. The reaction solution was concentrated under reduced pressure, dissolved in 2.5 ml of 1,4-dioxane, and 107 mg (502 μmol) of 6-(benzyloxy)nicotinaldehyde and 245 mg (753 μmol) of cesium carbonate were added. The mixture was stirred at 100°C for 18 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The filtrate was then purified using reverse phase column chromatography (C18 resin, water: acetonitrile = 9:1 to 1:9) to obtain compound (38) of step 1 of manufacturing example 9 (61 mg, 154 μmol, 30.7%, m / z = 397.7 [M + H] + ).

[0867]

[0868] 9-2. Step 2: (6-hydroxypyridin-3-yl)(piperidin-3-yl)methanone (39)

[0869]

[0870] 61 mg (154 μmol) of the compound (38) obtained in step 1 of the above Preparation Example 9 was dissolved in 1.0 ml of 1,4-dioxane, and 515 μl (15.4 mmol) of 4 N hydrochloric acid dissolved in dioxane was added. The mixture was stirred at room temperature for 19 hours. The production of (6-(benzyloxy)pyridin-3-yl)(piperidin-3-yl)methanone intermediate (38-1) was confirmed using an LC / MS instrument. After concentrating the reaction solution under reduced pressure, it was dissolved in 513 μl of ethanol, 6 mg of palladium charcoal was added, and the flask was sealed using a septum. After that, a hydrogen balloon was inserted, and the mixture was stirred at room temperature for 3 hours to confirm the completion of the reaction. Afterwards, the reaction solution was filtered using a syringe filter to remove palladium and other byproducts, and the filtrate was concentrated under reduced pressure to obtain the target compound (39) of Manufacturing Example 9 (47.7 mg, 154 μmol, 99%, m / z = 207.2 [M + H] + ).

[0871]

[0872] [Example 56]

[0873] Manufacture of (1-(2-amino-7H-purin-6-yl)piperidin-3-yl)(6-hydroxypyridin-3-yl)methanone (NRX02078)

[0874]

[0875]

[0876] 47.4 mg (231 μmol) of compound (39) obtained in the above Preparation Example 9 was dissolved in 2.31 ml of ethanol, and then 44.5 mg (208 μmol) of 6-bromo-7H-purin-2-amine and 80.6 μl (578 μmol) of triethylamine were added and stirred at 80°C for 18 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure and then purified by reverse phase column chromatography (C 18The target compound (40) of Example 56 was obtained by purification using resin, water: acetonitrile = 9: 1 to 1: 9 (13.5 mg, 39.8 μmol, 17.2%, m / z = 340.4 [M + H] + ).

[0877] 1 H-NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.45 (d, 1H), 8.11 (s, 1H), 7.86 (dd, 1H), 7.67 (s, 1H), 6.36 (d, 1H), 5.72 (s, 2H), 3.13 (s, 1H), 2.90 (s, 2H), 2.65 (s, 1H), 1.82-1.87 (m, 1H), 1.66-1.75 (m, 2H), 1.52-1.56 (m, 1H).

[0878]

[0879] [Manufacturing Example 10]

[0880] Preparation of 3-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole (47)

[0881]

[0882]

[0883] 10-1. Step 1:tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (42)

[0884] 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (41) 315 mg (1.39 mmol) was dissolved in 6.93 ml of tetrahydrofuran, cooled to 0°C in an ice bath, and then 105 mg (2.77 mmol) of lithium aluminum hydride was slowly added little by little and stirred for 10 minutes. After 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour to confirm the completion of the reaction. 100 μl each of water and 1 M sodium hydroxide were added, and 300 μl of water was additionally added, stirred for 15 minutes, and the reaction mixture was stirred to terminate the reaction. Afterwards, anhydrous sodium sulfate was added in excess to the filtrate to remove moisture, and the mixture was filtered using Celite. The filtered filtrate was concentrated under reduced pressure to obtain compound (42) of step 1 of manufacturing example 10 (272 mg, 1.27 mmol, 91.9%, m / z = 214.3 [M + H] + ).

[0885]

[0886] 10-2. Step 2:tert-butyl 1-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (43)

[0887] 300 mg (1.41 mmol) of the substance (42) obtained in step 1 of the above manufacturing example 10 was dissolved in 7.0 ml of dichloromethane, placed in an ice bath, cooled to 0°C, and then 795 mg (1.69 mmol) of Dess-Martin periodinane was slowly added, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, 2 ml of a saturated sodium bicarbonate solution and a solution of 2 g of thiosulfate dissolved in 5 ml of water were added, stirred for 30 minutes, and then 30 ml of dichloromethane and 30 ml of water were added, and the desired compound was extracted into the dichloromethane layer using a separatory funnel. The above process was repeated 3 times, and anhydrous sodium sulfate was added to the collected dichloromethane layer to remove the remaining moisture, and filtered. The filtrate was concentrated under reduced pressure to obtain compound (43) of step 2 (297 mg, 1.41 mmol, 99.9%, m / z = 212.3 [M + H] + ).

[0888]

[0889] 10-3. Step 3: tert-butyl (E)-1-((hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (44)

[0890] 297 mg (1.41 mmol) of the material (43) obtained in step 2 of the above manufacturing example 10 was dissolved in 14.1 ml of methanol, and 195 mg (2.81 mmol) of hydroxylamine hydrochloride and 224 mg (2.11 mmol) of sodium carbonate were added, and the mixture was stirred at room temperature for 19 hours. After confirming the completion of the reaction, 40 ml of ethyl acetate and 40 ml of water were added, and the desired compound was extracted into the ethyl acetate layer using a separatory funnel. The above process was repeated three times, and the collected ethyl acetate layer was concentrated under reduced pressure, and the filtrate was purified using column chromatography (SiO2, ethyl acetate: hexane = 1: 3) to obtain compound (44) of step 3 (82.0 mg, 362 μmol, 25.8%, m / z = 227.3 [M + H] + ).

[0891]

[0892] 10-4. Step 4: tert-butyl (Z)-1-(chloro(hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (45)

[0893] 82 mg (362 μmol) of the material (44) obtained in step 3 of the above manufacturing example 10 was dissolved in 1.81 ml of dimethylformamide, cooled to 0°C in an ice bath, and 194 mg (1.45 mmol) of N-chlorosuccinimide was added, and stirred at room temperature for 19 hours. After confirming the completion of the reaction, 20 ml of ethyl acetate and 20 ml of water were added, and the desired compound was extracted into the ethyl acetate layer using a separatory funnel. The above process was repeated three times, and anhydrous sodium sulfate was added to the collected ethyl acetate layer to remove the remaining moisture, and filtered through a filter. The filtrate was concentrated under reduced pressure to obtain compound (45) of step 4 (83.0 mg, 318 μmol, 87.9%, m / z = 261.7 [M + H] + ).

[0894]

[0895] 10-5. Step 5: tert-butyl -1-(5-(trifluoromethyl)isoxazole-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (46)

[0896] 83 mg (318 μmol) of the substance (45) obtained in step 4 of the above manufacturing example 10 was dissolved in 3.2 ml of chloroform and cooled to 0°C in an ice bath. Then, 139 mg (796 μmol) of 2-bromo-3,3,3-trifluoropropene and 65.1 μl (478 μmol) of triethylamine were slowly added and stirred at room temperature for 3 hours. After confirming the completion of the reaction, 15 ml of ethyl acetate and 15 ml of water were added and the desired compound was extracted into the ethyl acetate layer using a separatory funnel. The above process was repeated three times, the collected ethyl acetate layer was concentrated under reduced pressure, and the filtrate was purified using column chromatography (SiO2, ethyl acetate: hexane = 1:5 to 1:3) to obtain compound (46) of step 5 (22.0 mg, 69.1 μmol, 21.7%, m / z = 319.3 [M + H] + ).

[0897] 19 F-NMR (400 MHz, DMSO-d6) δ -63.12 (d,J= 11.8 Hz, 3F).

[0898]

[0899] 10-6. Step 6: 3-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole (47)

[0900] 22 mg (69.1 μmol) of the material (46) obtained in step 5 of the above Preparation Example 10 was dissolved in 138 μl of ethyl acetate, and 11.2 μl (276 μmol) of 2 M hydrochloric acid dissolved in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The filtrate was purified using a Prep-HPLC device to obtain the target compound (47) of the above Preparation Example 10 (10.7 mg, 42.0 μmol, 60.8%, m / z = 219.2 [M + H] + ).

[0901]

[0902] [Example 57]

[0903] Preparation of 4-(1-(5-(trifluoromethyl)isoxazole-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2.3-d]pyrimidine-5-carbonitrile (NRX02103)

[0904]

[0905] 10.7 mg (42.0 μmol) of compound (47) obtained in the above Preparation Example 10 was dissolved in 210 μl of ethanol, and 6.75 mg (37.8 μmol) of 4-chloro-7H-pyrrolo[2.3-d]pyrimidine-5-carbonitrile and 14.6 μl (105 μmol) of triethylamine were added, and stirred at 80°C for 13 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The filtrate was purified by reverse phase column chromatography (C 18 The target compound (48) of Example 57 was obtained by purification using resin, water: acetonitrile = 9: 1 to 1: 9 (10.4 mg, 28.9 μmol, 68.7%, m / z = 361.3 [M + H] + ).

[0906] 1H-NMR (400 MHz, DMSO-d6) δ 8.28-8.20 (m, 2H), 7.44 (q,J=1.0Hz, 1H), 4.50 (d,J=11.0Hz, 1H), 4.27 (d,J=10.6Hz, 1H), 4.19 (d,J=11.0Hz, 1H), 3.92 (dd,J=10.5, 4.3Hz, 1H), 2.45 (s, 1H), 2.34 (dt,J=8.8, 4.7Hz, 1H), 1.50 (dd,J=8.4, 5.2Hz, 1H), 1.19 (s, 1H), 1.08 (t,J=5.1Hz, 1H).

[0907]

[0908] [Manufacturing Example 11]

[0909]

[0910] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 30) was separated by SFC (Daicel AD (25*250 mm, 10 μm), CO2 / MeOH[0.2% NH3(7 M in MeOH)] = 80 / 20) to obtain the desired target compounds (49:594.40 mg, ee 97.32%, 50:590.00 mg, 99.83% purity, ee 100.00%), respectively.

[0911]

[0912] [Example 58]

[0913] Preparation of 4-((1R,5S)-1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02104)

[0914]

[0915] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 30) was separated by SFC (Daicel AD (25*250 mm, 10 μm), CO2 / MeOH[0.2% NH3(7 M in MeOH)] = 80 / 20) to obtain the target compound (594.40 mg, ee 97.32%).

[0916] 1 H-NMR (400 MHz, CDCl3-d): δ 8.33 (s, 1H), 7.76 (s, 1H), 4.32 (d,J= 10.8 Hz, 1H), 4.25 (d,J= 11.0 Hz, 1H), 3.98 (dd,J= 10.8, 3.8 Hz, 1H), 3.77 (d,J= 10.8 Hz, 1H), 1.84 (m, 1H), 1.57 - 1.45 (m, 2H), 1.06 (t,J= 7.6 Hz, 3H), 0.77 (dd,J= 8.0, 5.2 Hz, 1H), 0.36 (t,J= 4.6 Hz, 1H).

[0917]

[0918] [Example 59]

[0919] Preparation of 4-((1S,5R)-1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02105)

[0920]

[0921] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 30) was purified by SFC (Daicel AD (25*250 mm, 10 μm), CO2 / MeOH[0.2% NH3(7 M in MeOH)] = 80 / 20) to obtain the target compound (590.00 mg, 99.83% purity, ee 100.00%).

[0922] 1H-NMR (400 MHz, CDCl3-d): δ 8.33 (s, 1H), 7.76 (s, 1H), 4.32 (d,J= 10.8 Hz, 1H), 4.24 (d,J= 11.0 Hz, 1H), 3.98 (dd,J= 10.6, 3.6 Hz, 1H), 3.77 (d,J= 10.8 Hz, 1H), 1.84 (m, 1H), 1.57 - 1.45 (m, 2H), 1.07 (t,J= 7.4 Hz, 3H), 0.77 (dd,J= 7.8, 5.2 Hz, 1H), 0.36 (t,J= 4.4 Hz, 1H).

[0923]

[0924] [Manufacturing Example 12]

[0925]

[0926] 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 2) was separated by SFC (Daicel AD-3 (4.6*100 mm, 3 μm), CO2 / EtOH[0.2% NH3(7 M in MeOH)] = 65 / 35 to give the target compound (51:603.4 mg, ee 99.27%, m / z = 441.4 [M + H] + , 52: 632.3 mg, ee 97.9%, m / z = 414.4 [M + H] + ) were obtained respectively.

[0927]

[0928] [Example 60]

[0929] Preparation of 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-((1R,5S)-1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02106)

[0930]

[0931] 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 2) was separated by SFC (Daicel AD-3 (4.6*100 mm, 3μm), CO2 / EtOH[0.2% NH3(7 M in MeOH)] = 65 / 35) to give the target compound (603.4 mg, ee 99.27%, m / z = 441.4 [M + H] + ) was obtained.

[0932] 1 H-NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 7.98 (s, 1H), 7.88 (d,J= 3.0 Hz, 1H), 7.74 (s, 1H), 4.72 (s, 1H), 4.12 (d,J= 10.4 Hz, 1H), 4.03 (d,J= 11.0 Hz, 1H), 3.99 (s, 2H), 3.70 (dd,J= 11.0, 4.2 Hz, 1H), 3.57 (d,J= 10.4 Hz, 1H), 1.77 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H), 1.13 (s, 6H), 0.98 (t,J= 7.4 Hz, 3H), 0.68 (dd,J= 7.8, 4.6 Hz, 1H), 0.26 (t,J= 4.2 Hz, 1H).

[0933]

[0934] [Example 61]

[0935] Preparation of 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-((1S,5R)-1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NRX02107)

[0936]

[0937] 2-((5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Example 2) was separated by SFC (Daicel AD-3 (4.6*100 mm, 3 μm), CO2 / EtOH[0.2% NH3(7 M in MeOH)] = 65 / 35 to give the target compound (632.3 mg, ee 97.9%, m / z = 414.4 [M + H] + ) was obtained.

[0938] 1 H-NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 7.98 (s, 1H), 7.88 (d,J= 2.8 Hz, 1H), 7.74 (s, 1H), 4.72 (s, 1H), 4.12 (d,J= 10.4 Hz, 1H), 4.03 (d,J= 11.0 Hz, 1H), 3.99 (s, 2H), 3.70 (dd,J= 11.0, 4.2 Hz, 1H), 3.57 (d,J= 10.4 Hz, 1H), 1.77 (m, 1H), 1.48 (m, 1H), 1.45 - 1.32 (m, 1H), 1.13 (s, 6H), 0.98 (t,J= 7.4 Hz, 3H), 0.68 (dd,J= 7.8, 4.6 Hz, 1H), 0.26 (t,J= 4.2 Hz, 1H).

[0939]

[0940] [Manufacturing Example 13]

[0941] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (54)

[0942]

[0943]

[0944] 13-1. Step 1: 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (53)

[0945]

[0946] 2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (17.9 mmol) was added to tetrahydrofuran containing sodium hydride (17.9 mmol) and stirred at room temperature for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (19.3 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. The reaction solution was washed with ethyl acetate and brine. The organic layer was removed with sodium sulfate and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the target compound (5.48 mg, 13.4 mmol, 75%).

[0947]

[0948] 13-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (54)

[0949]

[0950] 4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3]pyrimidine (4.88 mmol) was added to n-butanol containing 1-ethyl-3-azabicyclo[3.1.0]hexane (5.37 mmol) and triethylamine (14.6 mmol). The reaction solution was stirred at 120°C for 16 hours. The solvent of the reaction solution was concentrated under reduced pressure, and the residue was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the target compound (54) of Preparation Example 13 (2.06 g, 4.25 mmol, 87%, m / z = 485.1 [M + H] + ).

[0951]

[0952] [Example 62]

[0953] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02108)

[0954]

[0955]

[0956] 62-1. Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0957]

[0958] Compound (54) (0.239 mmol) obtained in the above Preparation Example 13 was added to 1,4-dioxane / water containing (1-methyl-1H-pyrazo-4-yl-)boronic acid (0.206 mmol) and potassium carbonate (0.619 mmol). Degassing was performed with nitrogen gas for 5 minutes. Pd(dppf)Cl2 (0.010 mmol) was added. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain the compound (28 mg, 0.064 mmol, 31%, m / z = 439.1 [M + H] + ).

[0959]

[0960] 62-2. Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02108)

[0961]

[0962] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.064 mmol) was added to dichloromethane containing trifluoroacetic acid (1.91 mmol). The reaction solution was stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and potassium carbonate (0.32 mmol) was added. The reaction solution was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by reversed-phase column chromatography (C 18 The target compound of Example 62 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (7 mg, 22.7 μmol, 36%, m / z = 349.1 [M+ H] + ).

[0963]

[0964] [Example 63]

[0965] Preparation of 3-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (NRX02109)

[0966]

[0967]

[0968] 63-1. Step 1: 3-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile

[0969] The same procedure as in Example 62 Step 1 was followed except that (3-cyanophenyl)boronic acid was used instead of (1-methyl-1H-pyrazo-4-yl-)boronic acid to obtain the target compound of Example 63 Step 1 (10 mg, 0.022 mmol, 21%, m / z = 460.1 [M + H] + ).

[0970]

[0971] 63-2 Step 2: 3-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (NRX02109)

[0972] The target compound of Example 63 was obtained by performing the same method as in Step 2 of Example 62 above (16 mg, 0.049 mmol, 35%, m / z = 330.1 [M + H] + ).

[0973] 1H-NMR (400 MHz, CDCl3-d) δ 8.33 (s, 1H), 7.74 - 7.58 (m, 3H), 7.51 (td,J= 7.7, 0.7 Hz, 1H), 7.25 (s, 1H), 7.08 (d,J= 5.0 Hz, 1H), 3.78 (d,J= 10.6 Hz, 1H), 3.69 (d,J= 10.8 Hz, 1H), 3.18 (dd,J= 10.7, 3.8 Hz, 1H), 2.99 (d,J= 10.5 Hz, 1H), 1.60 - 1.50 (m, 1H), 1.31 - 1.18 (m, 1H), 1.08 (dt,J= 7.7, 3.7 Hz, 1H), 0.76 (t,J= 7.5 Hz, 3H), 0.42 (dd,J= 7.8, 5.0 Hz, 1H), 0.26 - 0.16 (m, 1H).

[0974]

[0975] [실시예 64]

[0976] 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine의 제조(NRX02110)

[0977]

[0978]

[0979] 64-1 단계 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0980] The same procedure as in Example 62, Step 1 was followed except that (2-(trifluoromethyl)pyridin-4-yl)boronic acid was used instead of (1-methyl-1H-pyrazo-4-yl-)boronic acid, to obtain the desired compound (67 mg, 0.206 mmol, 39%, m / z = 504.1 [M + H] + ).

[0981]

[0982] 64-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(2-(trifluoromethyl)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (NRX02110)

[0983] The target compound of Example 64 was obtained by performing the same method as in Step 2 of Example 62 above (25.6 mg, 0.069 mmol, 52%, m / z = 374.1 [M + H] + ).

[0984] 1 H-NMR (400 MHz, CDCl3-d) δ 10.58 (s, 1H), 8.73 (d,J= 5.1 Hz, 1H), 8.38 (s, 1H), 7.75 (s, 1H), 7.56 (d,J= 5.4 Hz, 1H), 7.26 (dd,J= 2.5, 1.2 Hz, 5H), 7.24 (s, 3H), 3.87 (d,J= 10.4 Hz, 1H), 3.75 (d,J= 10.6 Hz, 1H), 3.25 (dd,J= 10.8, 3.9 Hz, 1H), 3.08 (d,J= 10.5 Hz, 1H), 1.59 (s, 8H), 1.34 - 1.24 (m, 1H), 1.25 (s, 2H), 1.10 (s, 1H), 0.83 - 0.75 (m, 1H), 0.78 (s, 3H), 0.46 - 0.38 (m, 1H), 0.25 (t,J= 4.4 Hz, 1H).

[0985]

[0986] [Example 65]

[0987] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(2-methyl-4-pyridyl)-1H-1,5,7-triazaindene (NRX02111)

[0988]

[0989]

[0990] 65-1 Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(2-methylpyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0991] The same procedure as in Example 62 Step 1 was followed, except that (2-methyl-pyridin-4-yl)boronic acid was used instead of (1-methyl-1H-pyrazo-4-yl-)boronic acid, to obtain the target compound of Example 65 Step 1 (47 mg, 0.106 mmol, 35%, m / z = 450.1 [M + H] + ).

[0992]

[0993] 65-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(2-methyl-4-pyridyl)-1H-1,5,7-triazaindene (NRX02111)

[0994] The target compound of Example 65 was obtained by performing the same method as in Step 2 of Example 62 above (37.1 mg, 0.116 mmol, 40%, m / z = 321.1 [M + H] + ).

[0995] 1H-NMR (400 MHz, CDCl3-d) δ 11.10 (s, 1H), 8.50 (d,J= 5.1 Hz, 1H), 8.36 (d,J= 2.7 Hz, 1H), 7.33 - 7.15 (m, 3H), 3.88 (d,J= 10.4 Hz, 1H), 3.76 (d,J= 10.7 Hz, 1H), 3.26 (dd,J= 10.9, 3.8 Hz, 1H), 3.10 (d,J= 10.7 Hz, 1H), 1.59 (dd,J= 14.3, 7.3 Hz, 1H), 1.33 - 1.23 (m, 3H), 1.11 (dt,J= 7.6, 3.8 Hz, 1H), 0.80 (td,J= 7.5, 3.1 Hz, 3H), 0.46 - 0.38 (m, 1H), 0.27 (t,J= 4.3 Hz, 1H).

[0996]

[0997] [실시예 66]

[0998] 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(2-morpholino-4-pyridyl)-1H-1,5,7-triazaindene의 제조(NRX02112)

[0999]

[1000]

[1001] 66-1 단계 1: 4-(4-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)morpholine

[1002] The same procedure as in Example 62 Step 1 was followed except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) was used instead of (1-methyl-1H-pyrazo-4-yl-)boronic acid to obtain the compound of Example 66 Step 1 (58 mg, 0.111 mmol, 54%, m / z = 521.1 [M + H] + ).

[1003]

[1004] 66-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(2-morpholino-4-pyridyl)-1H-1,5,7-triazaindene (NRX02112)

[1005] The target compound of Example 66 was obtained by performing the same method as in Step 2 of Example 62 above (52.7 mg, 0.135 mmol, 52%, m / z = 391.1 [M + H] + ).

[1006] 1 H-NMR (400 MHz, CDCl3-d) δ 10.32 (s, 1H), 8.21 (s, 1H), 7.31 - 7.24 (m, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.70 (s, 1H), 3.86 (s, 4H), 3.56 (s, 4H), 3.30 (s, 1H), 3.12 (s, 1H), 1.63 (s, 1H), 1.27 (s, 1H), 1.12 (s, 1H), 0.82 (s, 3H), 0.41 (s, 1H), 0.20 (s, 1H).

[1007]

[1008] [Example 67]

[1009] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-3-pyrazolyl)-1H-1,5,7-triazaindene (NRX02135)

[1010]

[1011]

[1012] 67-1 Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1-methyl-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[1013] The same procedure as in Example 62 Step 1 was followed, except that 4,4,5,5-tetramethyl-2-(1-methyl-3-pyrazoyl)-1,3,2-dioxaborolane (0.1 g, 0.206 mmol) was used instead of (1-methyl-1H-pyrazo-4-yl-)boronic acid, to obtain the target compound of Example 67 Step 1 (37 mg, 0.084 mmol, 41%, m / z = 439.1 [M + H] + ).

[1014]

[1015] 67-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-3-pyrazolyl)-1H-1,5,7-triazaindene (NRX02135)

[1016] The target compound of Example 8 was obtained by performing the same method as in Example 67, Step 2 (11.1 mg, 0.036 mmol, 43%, m / z = 309.1 [M + H] + ).

[1017] 1H-NMR (400 MHz, CDCl3-d) δ 10.99 (s, 1H), 8.23 (s, 1H), 7.39 (d,J= 2.1 Hz, 1H), 7.10 (s, 1H), 6.29 (d,J= 2.2 Hz, 1H), 3.95 (s, 3H), 3.82 (dd,J= 21.9, 11.1 Hz, 2H), 3.71 (s, 3H), 3.37 (dd,J= 11.2, 4.1 Hz, 1H), 3.12 (dd,J= 11.0, 1.2 Hz, 1H), 1.60 (dq,J= 14.5, 7.3 Hz, 1H), 1.34 - 1.20 (m, 2H), 1.14 (dt,J= 7.9, 3.9 Hz, 1H), 0.82 (t,J= 7.4 Hz, 3H), 0.44 (ddt,J= 7.9, 4.8, 1.1 Hz, 1H), 0.28 - 0.19 (m, 1H)

[1018]

[1019] [제조예 14]

[1020] 1-ethynyl-3-azabicyclo[3.1.0]hexane의 제조(57)

[1021]

[1022]

[1023] 14-1 단계 1: tert-butyl 1-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (55)

[1024]

[1025] IBX (2.95 g, 10.5 mmol) was added to dimethyl sulfoxide (24 mL) containing tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (19) (1.5 g, 7.03 mmol) and stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture and filtered through a Celite pad. The filtrate was washed with sodium bicarbonate, and the organic layer was washed with sodium sulfate to remove the remaining water and concentrated under reduced pressure to obtain compound (55) of Preparation Example 14. It was used in the next reaction without purification.

[1026]

[1027] 14-2 Step 2: tert-butyl 1-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (56)

[1028]

[1029] Bestmann-Ohira reagent (2.46 g, 12.8 mmol) was added to tert-butyl 1-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (55) (1.5 g, 7.1 mmol) and potassium carbonate (6.78 g, 21.3 mmol) in methanol (28 mL) at 0°C, and stirred at room temperature for 16 hours. The reaction mixture was washed with water and ethyl acetate. The remaining water was removed from the organic layer using sodium sulfate. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 1: 1) to obtain compound (56) of Preparation Example 14 (977 mg, 4.71 mmol, 66%).

[1030]

[1031] 14-3 Step 3: 1-ethynyl-3-azabicyclo[3.1.0]hexane (57)

[1032]

[1033] Tert-Butyl 1-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (56) (94 mg, 0.454 mmol) was added to dichloromethane containing trifluoroacetic acid (4.54 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with ethanol and basic resin, and filtered to obtain compound (57) of Preparation Example 14. It was used in the next reaction without purification.

[1034]

[1035] [Example 68]

[1036] Preparation of 4-(1-ethynyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02113)

[1037]

[1038] 50 mg (0.28 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 36 mg (0.336 mmol) of the compound (57) of Preparation Example 14, 142 mg (1.4 mmol) of triethylamine, and 1.5 ml of ethanol were added and stirred at 80°C for 12 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (19.1 mg, 27%, m / z = 250.1 [M + H] + ).

[1039] 1H-NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.23 ​​(s, 1H), 4.36 (d,J= 10.6 Hz, 1H), 4.20 (d,J= 10.8 Hz, 1H), 3.85 (dd,J= 10.8, 4.2 Hz, 1H), 3.78 (d,J= 10.6 Hz, 1H), 3.08 (s, 1H), 2.13 (dt,J= 8.7, 4.7 Hz, 1H), 1.24 (s, 1H), 1.18 (dd,J= 8.2, 4.8 Hz, 1H), 0.76 (t,J= 4.9 Hz, 1H).

[1040]

[1041] [Manufacturing Example 15]

[1042] Preparation of 1-(prop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane (59)

[1043]

[1044]

[1045] 15-1 Step 1: tert-butyl 1-(prop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (58)

[1046]

[1047] 2.5 Mn-butyl lithium (0.580 μL, 1.45 mmol) was added dropwise to anhydrous tetrahydrofuran (2.4 mL) containing compound (56) (100 mg, 0.482 mmol) of Preparation Example 14 at -78°C. The reaction solution was stirred at the same temperature for 1 hour. Iodomethane (342 mg, 2.41 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water and ether were added to the reaction solution, and the mixture was washed several times with ether. The organic layer was treated with magnesium sulfate to remove the remaining water, and concentrated under reduced pressure to obtain compound (58) of Preparation Example 15. It was used in the next reaction without purification.

[1048]

[1049] 15-2 Step 2: 1-(prop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane (59)

[1050]

[1051] Tert-Butyl 1-(pro-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (58) (107 mg, 0.484 mmol) was added to dichloromethane containing trifluoroacetic acid (9.67 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with ethanol and basic resin, and filtered to obtain compound (59) of Preparation Example 15. It was used in the next reaction without purification.

[1052]

[1053] [Example 69]

[1054] Preparation of 4-{1-(1-propynyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02114)

[1055]

[1056] 80 mg (0.448 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 54 mg (0.448 mmol) of the compound (59) of Preparation Example 15, 227 mg (2.24 mmol) of triethylamine, and 2.2 ml of ethanol were added and stirred at 80°C for 12 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound (87 mg, 74%, m / z = 264.1 [M + H] + ).

[1057] 1H-NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.18 (s, 1H), 4.29 (d,J= 10.5 Hz, 1H), 4.13 (d,J= 10.8 Hz, 1H), 3.78 (dd,J= 10.9, 4.1 Hz, 1H), 3.69 (d,J= 10.6 Hz, 1H), 1.98 (dt,J= 8.4, 4.5 Hz, 1H), 1.76 (s, 3H),1.07 (s, 1H), 0.63 (s, 1H).

[1058]

[1059] [제조예 16]

[1060] 1-(3,3,3-trifluoroprop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane의 제조(61)

[1061]

[1062]

[1063] 16-1 단계 1: tert-butyl 1-(3,3,3-trifluoroprop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (60)

[1064]

[1065] In a 50 mL flask, CuI (138 mg, 0.724 mmol), potassium carbonate (200 mg, 1.45 mmol), TMEDA (84 mg, 0.724 mmol), and dimethylformamide (5 mL) were added and stirred for 15 minutes. Additionally, TMSCF3 (0.12 μL, 0.95 mmol) was added, and the reaction solution was cooled to 0°C. Compound (56) (100 mg, 0.482 mmol) of Preparation Example 14 and TMSCF3 (0.12 μL, 0.95 mmol) were added, and the reaction solution was stirred at room temperature for 24 hours. Water and ether were added to the reaction solution, and the mixture was washed several times with ether. The organic layer was purified by removing the remaining water using magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (60) of Preparation Example 16. It was used in the next reaction without purification.

[1066]

[1067] 16-2 Step 2 1-(3,3,3-trifluoroprop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane (61)

[1068]

[1069] Tert-Butyl 1-(3,3,3-trifluoroprop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (60) (133 mg, 0.484 mmol) was added to dichloromethane containing trifluoroacetic acid (9.67 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with ethanol and basic resin, and filtered to obtain the target compound (61) of Preparation Example 16. It was used in the next reaction without purification.

[1070]

[1071] [Example 70]

[1072] Preparation of 4-{1-(3,3,3-trifluoro-1-propynyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02115)

[1073]

[1074] 80 mg (0.448 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 54 mg (0.448 mmol) of the compound (61) of the above Preparation Example 16, 227 mg (2.24 mmol) of triethylamine, and 2.2 ml of ethanol were added and stirred at 80°C for 12 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound (87 mg, 74%, m / z = 264.1 [M + H] + ).

[1075] 1 H-NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.21 (s, 1H), 4.42 (d,J= 10.5 Hz, 1H), 4.22 (d,J= 10.8 Hz, 1H), 3.90 - 3.80 (m, 2H), 3.13 (d,J= 5.2 Hz, 1H), 1.43 (dd,J= 8.4, 5.1 Hz, 1H), 0.98 (t,J= 5.3 Hz, 1H).

[1076]

[1077] [Example 71]

[1078] Preparation of m-{4-(1-ethynyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02116)

[1079]

[1080]

[1081] 71-1 Step 1: 3-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (62)

[1082] Compound (53) (1.0 g, 2.44 mmol) obtained in the above Preparation Example 13 was dissolved in 1,4-dioxane / water, and (3-cyanophenyl)boronic acid (394 mg, 2.68 mmol), potassium carbonate (2.33 g, 7.32 mmol), and Pd(dppf)2Cl2 (110 mg, 0.122 mmol) were added, and the mixture was stirred at 100°C for 2 hours. The reaction solution was filtered through a Celite pad and concentrated under reduced pressure. The reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1) to obtain the target compound (62) (796 mg, 85%, m / z = 385.1 [M + H] + ).

[1083]

[1084] 71-2 Step 2: 3-(4-(1-ethynyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (63)

[1085] Compound (62) (100 mg, 0.260 mmol) obtained in the above Example 71 was added to 33 mg (0.312 mmol) of compound (57) of the above Preparation Example 14, N-ethylbis(isopropyl)amine (101 mg, 0.779 mmol) and 1.3 ml of ethanol and stirred at 80°C for 16 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1) to obtain the target compound (63) (83 mg, 70%, m / z = 456.1 [M + H] + ).

[1086]

[1087] 71-3 Step 3: m-{4-(1-ethynyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02116)

[1088] Compound (63) (80 mg, 0.176 mmol) obtained in the above Example 71 was added to dichloromethane containing trifluoroacetic acid (1.76 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and potassium carbonate (0.88 mmol) was added. The reaction solution was stirred at 50°C for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1) to obtain the target compound (64) of the above Example 71 (14 mg, 43.6 μmol, 25%, m / z = 326.1 [M + H] + ).

[1089] 1 H-NMR (400 MHz, CDCl3-d) δ 10.16 (s, 1H), 8.36 (d,J= 1.0 Hz, 1H), 7.72 (tt,J= 1.6, 0.8 Hz, 1H), 7.64 (dddd,J= 13.2, 8.9, 2.2, 1.2 Hz, 2H), 7.57 - 7.48 (m, 1H), 7.16 - 7.11 (m, 1H), 4.14 - 4.02 (m, 1H), 3.79 (d,J= 11.0 Hz, 1H), 3.20 (d,J= 10.9 Hz, 2H), 1.93 (d,J= 0.9 Hz, 1H), 1.66 (dt,J= 8.3, 4.3 Hz, 1H), 0.95 (dd,J= 8.0, 5.1 Hz, 1H), 0.59 (t,J= 4.9 Hz, 1H).

[1090]

[1091] [Example 72]

[1092] Preparation of m-{4-(3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02132)

[1093]

[1094]

[1095] 72-1 Step 1: 3-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (65)

[1096] Compound (62) (120 mg, 0.312 mmol) obtained in the above Example 71 was added to 3-azabicyclo[3.1.0]hexane (41 mg, 0.343 mmol), N-ethylbis(isopropyl)amine (121 mg, 0.935 mmol) and 1.6 ml of ethanol and stirred at 80°C for 16 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1) to obtain the compound (80 mg, 0.186 mmol, 60%, m / z = 432.1 [M + H] + ).

[1097]

[1098] 72-2 Step 2: m-{4-(3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02132)

[1099] Compound (65) (80 mg, 0.186 mmol) obtained in the above Example 72 was added to dichloromethane containing trifluoroacetic acid (3.72 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and potassium carbonate (0.88 mmol) was added. The reaction solution was stirred at 50°C for 1 hour. After concentrating under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (66) of the above Example 72 (35 mg, 117 μmol, 63%, m / z = 302.1 [M + H] + ).

[1100] 1 H-NMR (400 MHz, CDCl3-d) δ 9.56 (s, 1H), 8.33 (d,J= 1.4 Hz, 1H), 7.72 (td,J= 1.8, 0.6 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.50 (td,J= 7.7, 0.6 Hz, 1H), 7.11 - 7.04 (m, 1H), 3.80 (d,J= 10.9 Hz, 2H), 3.14 (d,J= 10.8 Hz, 2H), 1.33 (dddd,J= 7.7, 3.8, 2.4, 1.2 Hz, 2H), 0.48 (td,J= 7.7, 5.1 Hz, 1H), 0.09 - 0.03 (m, 1H)

[1101]

[1102] [Example 73]

[1103] m-{4-(1-methyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02133)

[1104]

[1105]

[1106] 73-1 Step 1: 3-(4-(1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (67)

[1107] The same procedure as in Step 1 of Example 72 was followed, except that 1-methyl-3-azabicyclo[3.1.0]hexane (27) (39.4 mg, 0.405 mmol) was used instead of 3-azabicyclo[3.1.0]hexane in Example 72, to obtain the target compound (67) (121 mg, 0.272 mmol, 80%, m / z = 446.1 [M + H] + ).

[1108]

[1109] 73-2 Step 2: m-{4-(1-methyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02133)

[1110] The target compound (68) was obtained by performing the same method as in the above Example 72 Step 2 (29.3 mg, 0.093 mmol, 35%, m / z = 316.1 [M + H] + ).

[1111] 1H-NMR (400 MHz, CDCl3-d) δ 10.46 (s, 1H), 8.34 (d,J= 0.9 Hz, 1H), 7.75 - 7.57 (m, 2H), 7.50 (t,J= 7.7 Hz, 1H), 7.10 (s, 1H), 3.86 (d,J= 10.7 Hz, 1H), 3.65 (d,J= 10.7 Hz, 1H), 3.16 (dd,J= 10.8, 3.8 Hz, 1H), 2.99 (d,J= 10.7 Hz, 1H), 1.12 (d,J= 2.9 Hz, 3H), 1.03 (dt,J= 7.7, 3.9 Hz, 1H), 0.39 (dd,J= 7.7, 5.0 Hz, 1H), 0.24 (t,J= 4.4 Hz, 1H).

[1112]

[1113] [Example 74]

[1114] Preparation of m-{4-(1-isopropyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02138)

[1115]

[1116]

[1117] 74-1 Step 1: 3-(4-(1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (69)

[1118] The same procedure as in Step 1 of Example 72 was followed, except that 1-isopropyl-3-azabicyclo[3.1.0]hexane hydrochloride (75.6 mg, 0.468 mmol) was used instead of 3-azabicyclo[3.1.0]hexane in Example 72, to obtain the target compound (69) (164 mg, 0.346 mmol, 89%, m / z = 474.1 [M + H]+ ).

[1119]

[1120] 74-2 Step 2: m-{4-(1-isopropyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02138)

[1121] The target compound (70) was obtained by performing the same method as in the above Example 72 Step 2 (31.6 mg, 0.092 mmol, 27%, m / z = 344.1 [M + H] + ).

[1122] 1 H-NMR (400 MHz, CDCl3-d) δ 10.20 (s, 1H), 8.35 (s, 1H), 7.75 - 7.59 (m, 3H), 7.52 (td,J= 7.7, 0.6 Hz, 1H), 7.08 (d,J= 3.4 Hz, 1H), 3.77 (d,J= 10.8 Hz, 1H), 3.63 (d,J= 10.5 Hz, 1H), 3.22 (dd,J= 10.9, 3.8 Hz, 1H), 3.07 - 2.98 (m, 1H), 1.45 (dq,J= 13.0, 6.5 Hz, 1H), 1.14 (dt,J= 7.8, 3.8 Hz, 1H), 0.82 (d,J= 6.8 Hz, 3H), 0.71 (d,J= 6.9 Hz, 3H), 0.46 (dd,J= 7.9, 4.9 Hz, 1H), 0.24 - 0.17 (m, 1H).

[1123]

[1124] [Example 75]

[1125] Preparation of m-{4-(1-isobutyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02139)

[1126]

[1127]

[1128] 75-1 Step 1: 3-(4-(1-isobutyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (71)

[1129] The target compound (71) was obtained by performing the same method as in Step 1 of Example 72, except that 1-isobutyl-3-azabicyclo[3.1.0]hexane hydrochloride (86.5 mg, 0.493 mmol) was used instead of 3-azabicyclo[3.1.0]hexane in Example 72 (166 mg, 0.340 mmol, 83%, m / z = 489.1 [M + H] + ).

[1130]

[1131] 75-2 Step 2: m-{4-(1-isobutyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-3-yl}benzonitrile (NRX02139)

[1132] The target compound (72) was obtained by performing the same method as in the above Example 72 Step 2 (53.2 mg, 0.149 mmol, 44%, m / z = 358.1 [M + H] + ).

[1133] 1H-NMR (400 MHz, CDCl3-d) δ 10.67 (s, 1H), 8.36 (s, 1H), 7.75 - 7.58 (m, 3H), 7.51 (td,J= 7.7, 0.6 Hz, 1H), 7.10 (s, 1H), 3.74 (dd,J= 13.2, 10.7 Hz, 2H), 3.28 (dd,J= 10.8, 3.9 Hz, 1H), 2.97 (d,J= 10.5 Hz, 1H), 1.56 (ddd,J= 13.8, 6.2, 1.1 Hz, 1H), 1.41 (ddt,J= 14.5, 12.9, 6.6 Hz, 1H), 1.03 (dt,J= 7.8, 3.9 Hz, 1H), 0.98 (dd,J= 13.9, 8.2 Hz, 1H), 0.79 (dd,J= 10.0, 6.6 Hz, 6H), 0.47 (dd,J= 7.7, 5.0 Hz, 1H), 0.38 - 0.31 (m, 1H).

[1134]

[1135] [제조예 17]

[1136] 1-isopropyl-3-azabicyclo[3.1.0]hexane hydrochloride의 제조(78)

[1137]

[1138]

[1139] 17-1 단계 1: diethyl 1-isopropylcyclopropane-1,2-dicarboxylate (73)

[1140] Ethyl 2-bromo-3-methylbutanoate (10 g, 47.82 mmol) was dissolved in toluene (50 mL), and ethyl acrylate (4837 mg, 47.82 mmol) and tert-butoxide (5903 mg, 52.61 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with ammonium chloride (150 mL), and extracted with ethyl acetate (250 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate. The mixture was concentrated under reduced pressure to obtain the desired compound (73) (9.8 g, crude, m / z = 229.3 [M + H] + ).

[1141]

[1142] 17-2 Step 2: 1-isopropylcyclopropane-1,2-dicarboxylic acid (74)

[1143] Compound (73) (9.8 g, 38.54 mmol) obtained in the above Preparation Example 17 was dissolved in methanol (40 mL), and then sodium hydroxide (9.3 g, 231.34 mmol) dissolved in water (20 mL) was added. The reaction solution was stirred at 90°C for 12 hours. After concentrating the reaction solution under reduced pressure, water (100 mL) was added, and the mixture was washed with ethyl acetate (50 mL). 3 M hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and then extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure to obtain the desired compound (74) (6.9 g, crude, m / z = 171.0 [M - H] - ).

[1144]

[1145] 17-3 Step 3: 1-isopropyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (75)

[1146] Compound (74) (6.9 g, 38.54 mmol) obtained in the above Preparation Example 17 was dissolved in dichloromethane (55 mL), and TFAA (12.1 g, 57.81 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the desired compound (75) (6.4 g, crude, m / z = 187.2 [M + MeOH] + ).

[1147]

[1148] 17-4 Step 4: 3-benzyl-1-isopropyl-3-azabicyclo[3.1.0]hexane-2,4-dione (76)

[1149] Compound (75) (6.4 g, 38.54 mmol) and benzylamine (4129 mg, 38.54 mmol) obtained in the above Preparation Example 17 were stirred at 150°C for 3 hours. The reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain compound (76) (3.2 g, 34.1%, m / z = 244.3 [M + H] + ).

[1150]

[1151] 17-5 Step 5: 3-benzyl-1-isopropyl-3-azabicyclo[3.1.0]hexane (77)

[1152] Compound (76) (3.2 g, 13.16 mmol) obtained in the above Preparation Example 17 was dissolved in THF (20 mL), and then lithium aluminum hydride (999 mg, 26.33 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 16 hours, quenched with ammonium chloride (150 mL), and filtered through a Celite Pad. The filtrate was extracted with ethyl acetate (200 mL x 3), washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure. Compound (77) was obtained (1.64 g, 57.8%, m / z = 230.3 [M + H] + ).

[1153]

[1154] 17-6 Step 6: 1-isopropyl-3-azabicyclo[3.1.0]hexane hydrochloride (78)

[1155] Compound (77) (1.64 g, 7.61 mmol) obtained in the above Preparation Example 17 was dissolved in ethanol (10 mL), and then 10% Pd / C (50% wt. H2O) (300 mg) was added. The reaction solution was stirred at room temperature under hydrogen for 6 hours. After adding 4 M hydrochloric acid (4 mL), the mixture was stirred for another 30 minutes. The reaction solution was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the desired compound (78) (1.306 g, crude, m / z = 126.1 [M + H] + ).

[1156] 1H-NMR (400 MHz, CDCl3): δ 9.92 (s, 1H), 9.44 (s, 1H), 3.49 - 3.31 (m, 3H), 3.26 (m, 1H), 1.66 (m, 1H), 1.44 (m, 1H), 0.99 (dd,J= 9.8, 5.6 Hz, 4H), 0.91 (d,J= 7.0 Hz, 3H), 0.75 (t,J= 7.4 Hz, 1H).

[1157]

[1158] [Example 76]

[1159] Preparation of 4-(1-isopropyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02117)

[1160]

[1161] 150 mg (0.84 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 149 mg (0.92 mmol) of the compound (78) of Preparation Example 17, 254 mg (2.52 mmol) of triethylamine, and 3.0 ml of ethanol were added and stirred at 50°C for 12 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the target compound of Example 76 (76.85 mg, 34.2%, m / z = 268.4 [M + H] + ).

[1162] 1H-NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 4.10 (d,J= 4.0 Hz, 1H), 4.07 (d,J= 3.2 Hz, 1H), 3.80 - 3.68 (m, 2H), 1.75 - 1.63 (m, 1H), 1.57 (m, 1H), 1.04 (d,J= 6.8 Hz, 3H), 0.93 (d,J= 7.0 Hz, 3H), 0.76 (dd,J= 7.8, 4.8 Hz, 1H), 0.26 (t,J= 4.4 Hz, 1H).

[1163]

[1164] [Manufacturing Example 18]

[1165] Preparation of 1-isobutyl-3-azabicyclo[3.1.0]hexane hydrochloride (85)

[1166]

[1167]

[1168] 18-1 Step 1: ethyl 2-bromo-4-methylpentanoate (79)

[1169] 2-Bromo-4-methylpentaonic acid (10 g, 51.26 mmol) was dissolved in ethanol (60 mL), and sulfuric acid (0.3 mL) was added. The reaction solution was stirred at 80°C for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired target compound (79) (9.8 g, crude).

[1170] 1H-NMR (400 MHz, CDCl3): δ 4.30 - 4.16 (m, 3H), 1.96 - 1.86 (m, 2H), 1.83 - 1.71 (m, 1H), 1.30 (t,J= 7.2 Hz, 3H), 0.96 (d,J= 6.6 Hz, 3H), 0.91 (d,J= 6.6 Hz, 3H).

[1171]

[1172] 18-2 Step 2: diethyl 1-isobutylcyclopropane-1,2-dicarboxylate (80)

[1173] Compound (79) (9.8 g, 43.92 mmol) obtained in the above Preparation Example 18 was dissolved in toluene (50 mL), and then ethyl acrylate (4398 mg, 43.92 mmol) and tert-butoxide (5421 mg, 48.31 mmol) were added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 12 hours. After the reaction was terminated with ammonium chloride (150 mL), it was extracted with ethyl acetate. The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and concentrated under reduced pressure to obtain the desired target compound (10.6 g, crude, m / z = 243.3 [M + H] + )

[1174]

[1175] 18-3 Step 3: 1-isobutylcyclopropane-1,2-dicarboxylic acid (81)

[1176] Compound (80) (10.6 g, 43.74 mmol) obtained in the above Preparation Example 18 was dissolved in methanol (50 mL), and then sodium hydroxide (10.5 g, 262.44 mmol) dissolved in water (20 mL) was added. The reaction solution was stirred at 90°C for 12 hours. After concentrating the reaction solvent under reduced pressure, water (100 mL) was added and washed with ethyl acetate (50 mL). The aqueous layer was adjusted to pH 1 with 3 M hydrochloric acid and extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired target compound (81) (9.8 g, crude, m / z = 187.2 [M + H] + )

[1177]

[1178] 18-4 Step 4:1-isobutyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (82)

[1179] Compound (81) (9.8 g, 43.74 mmol) obtained in the above Preparation Example 18 was dissolved in dichloromethane (50 mL), and then trifluoroacetic anhydride (13.7 g, 65.61 mmol) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the desired compound (82) (9.8 g, crude, m / z = 169.2 [M + MeOH] + ).

[1180]

[1181] 18-5 Step 5: 3-benzyl-1-isobutyl-3-azabicyclo[3.1.0]hexane-2,4-dione (83)

[1182] Compound (82) (9.8 g, 43.74 mmol) and benzylamine (4686 mg, 43.74 mmol) obtained in the above Preparation Example 18 were stirred at 150°C for 3 hours. The reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain the target compound (83) (6.0 g, 45.4%, m / z = 258.3 [M + H] + ).

[1183]

[1184] 18-6 Step 6: 3-benzyl-1-isobutyl-3-azabicyclo[3.1.0]hexane (84)

[1185] Compound (83) (6.0 g, 23.31 mmol) obtained in the above Preparation Example 18 was dissolved in tetrahydrofuran (25 mL), and LAH (1769 mg, 46.63 mmol) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 16 hours. The reaction was quenched with ammonium chloride (150 mL) and filtered through a Celite Pad. The filtrate was extracted with ethyl acetate (200 mL x 3), washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure. Compound (84) was obtained by separation using column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1). (3.2 g, 59.8%, m / z = 230.3 [M + H] + ).

[1186]

[1187] 18-7 Step 7: Preparation of 1-isobutyl-3-azabicyclo[3.1.0]hexane hydrochloride (85)

[1188] Compound (84) (1.9 g, 8.28 mmol) obtained in the above Preparation Example 18 was dissolved in ethanol (10 mL), and 10% Pd / C (50% wt. H2O) (350 mg) was added. The reaction solution was stirred at room temperature under hydrogen for 6 hours. 4 M hydrochloric acid was added and stirred for an additional 30 minutes. The reaction solution was filtered through a Celite Pad and concentrated under reduced pressure to obtain the desired compound (85) (1.3 g, crude, m / z = 140.1 [M + H] + ).

[1189] 1 H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 9.44 (s, 1H), 3.42 (m, 3H), 3.21 (m, 1H), 1.73 - 1.61 (m, 2H), 1.36 (d,J= 3.4 Hz, 1H), 1.22 (m, 1H), 1.11 - 1.04 (m, 1H), 1.00 - 0.84 (m, 6H), 0.74 (t,J= 7.0 Hz, 1H).

[1190]

[1191] [Example 77]

[1192] Preparation of 4-(1-isobutyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02118)

[1193]

[1194] 100 mg (0.57 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 112 mg (0.63 mmol) of the compound (85) of Preparation Example 18, 176 mg (1.74 mmol) of triethylamine, and 3.0 ml of ethanol were added and stirred at 50°C for 12 hours. After concentrating the reaction solution under reduced pressure, the filtrate was purified by prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the target compound of Example 18 (36.61 mg, 24.0%, m / z = 282.3 [M + H] + ).

[1195] 1 H-NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 4.18 (d,J= 10.6 Hz, 1H), 4.10 (d,J= 11.0 Hz, 1H), 3.78 (dd,J= 11.0, 4.4 Hz, 1H), 3.66 (d,J= 10.6 Hz, 1H), 1.87 - 1.74 (m, 2H), 1.45 (m, 1H), 1.25 - 1.13 (m, 1H), 0.96 (dd,J= 9.6, 6.4 Hz, 6H), 0.74 (dd,J= 7.8, 4.8 Hz, 1H), 0.37 (t,J= 4.4 Hz, 1H).

[1196]

[1197] [Manufacturing Example 19]

[1198] Preparation of 4-(1-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (93)

[1199]

[1200]

[1201] 19-1 Step 1: 2-bromo-3-cyclopropylpropanoic acid (86)

[1202] 2-Amino-3-cyclopropylformanoic acid (1 g, 7.74 mmol) was dissolved in water (9 mL), and 40% hydrobromic acid (12 mL) was added. The reaction solution was stirred at 0°C for 10 minutes, and sodium nitrite (801 mg, 11.61 mmol) dissolved in water (3 mL) was added. The reaction solution was stirred at room temperature for 12 hours. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired compound (86) (1.52 g, crude, m / z = 190.9 [M - H] - ).

[1203]

[1204] 19-2 Step 2: ethyl 2-bromo-3-cyclopropylpropanoate (87)

[1205] Compound (86) (1.52 g, 7.74 mmol) obtained in the above Preparation Example 19 was dissolved in ethanol (8 mL), and sulfuric acid (0.3 mL) was added. The reaction solution was stirred at 80°C for 2 hours. After the reaction solution was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired compound (87) (1.70 g, crude, m / z = 221.1 [M + H] + ).

[1206]

[1207] 19-3 Step 3: diethyl 1-(cyclopropylmethyl)cyclopropane-1,2-dicarboxylate (88)

[1208] Compound (87) (1.70 g, 7.74 mmol) obtained in the above Preparation Example 19 was dissolved in toluene (10 mL), and then ethyl acrylate (738 mg, 7.37 mmol) and tert-butoxide (910 mg, 8.11 mmol) were added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 12 hours. After the reaction was terminated with ammonium chloride (150 mL), it was extracted with ethyl acetate (250 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired target compound (88) (1.72 g, crude, m / z = 241.3 [M + H] + ).

[1209]

[1210] 19-4 Step 4: 1-(cyclopropylmethyl)cyclopropane-1,2-dicarboxylic acid (89)

[1211] Compound (88) (1.72 g, 7.15 mmol) obtained in the above Preparation Example 19 was dissolved in methanol (25 mL), and then sodium hydroxide (1.71 g, 42.90 mmol) in water (25 mL) was added. The reaction solution was stirred at 90°C for 12 hours. After the reaction, the reaction solvent was concentrated under reduced pressure, water (100 mL) was added, and extracted with ethyl acetate (50 mL). The aqueous layer was adjusted to pH 1 with 3 M hydrochloric acid and extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure to obtain the desired target compound (89) (1.56 g, crude, m / z = 185.2 [M + H] + ).

[1212]

[1213] 19-5 Step 5: 1-(cyclopropylmethyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (90)

[1214] Compound (89) (1.56 g, 7.15 mmol) obtained in the above Preparation Example 19 was dissolved in tetrahydrofuran (25 mL), and then trifluoroacetic anhydride (3.00 g, 14.30 mmol) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction solvent was concentrated under reduced pressure to obtain the desired compound (90) (1.56 g, crude, m / z = 199.2 [M + MeOH] + ).

[1215]

[1216] 19-6 Step 6: 1-(cyclopropylmethyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (91)

[1217] Compound (90) (1.56 g, 7.15 mmol) and benzylamine (766 mg, 7.15 mmol) obtained in the above Preparation Example 19 were stirred at 150°C for 3 hours. The reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1 to 1: 1) to obtain the desired compound (91) (363 mg, 18.9%, m / z = 256.3 [M + H] + ).

[1218]

[1219] 19-7 Step 7: 3-benzyl-1-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexane (92)

[1220] Compound (91) (363 mg, 1.42 mmol) obtained in the above Preparation Example 19 was dissolved in tetrahydrofuran (6 mL), and LAH (142 mg, 3.55 mmol) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 16 hours. After quenching the reaction with ammonium chloride (150 mL), the solution was filtered through a Celite Pad, and the filtrate was extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure. The mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1 to 1: 1) to obtain the desired compound (92) (184 mg, 57.0%, m / z = 228.3 [M + H] + ).

[1221]

[1222] 19-8 Step 8: 1-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexane hydrochloride (93)

[1223] Compound (92) (184 mg, 0.81 mmol) obtained in the above Preparation Example 19 was dissolved in ethanol (4 mL), and then 10% Pd / C (50% wt. H 2 O) (40 mg) was added. The reaction solution was stirred at room temperature for 12 hours. After the reaction, 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added and stirred for an additional 0.5 hours. The catalyst was removed by filtration through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the desired compound (93) (120 mg, crude, m / z = 138.2 [M + H] + ).

[1224]

[1225] [Example 78]

[1226] Preparation of 4-{1-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02119)

[1227]

[1228] 118 mg (0.66 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 120 mg (0.72 mmol) of the compound (93) of Preparation Example 19, 201 mg (1.98 mmol) of triethylamine, and 4.0 ml of ethanol were added and stirred at 80°C for 4 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound of Example 78 (170 mg, 0.608 mol, 92%, m / z = 280.8 [M + H] + ).

[1229] 1 H-NMR (400 MHz, DMSO-d6): δ 12.79 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 4.25 (d,J= 10.6 Hz, 1H), 4.12 (d,J= 11.0 Hz, 1H), 3.82 - 3.73 (m, 2H), 1.63 (dd,J= 14.2, 7.0 Hz, 1H), 1.56 (m, 1H), 1.41 (dd,J= 14.2, 6.8 Hz, 1H), 0.86 - 0.74 (m, 2H), 0.47 - 0.42 (m, 2H), 0.32 (t,J= 4.4 Hz, 1H), 0.17 - 0.08 (m, 2H).

[1230]

[1231] [Example 79]

[1232] Preparation of 4-(7-amino-5-aza-5-spiro[2.4]heptyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02122)

[1233]

[1234]

[1235] 79-1. Step 1: tert-butyl (5-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate

[1236]

[1237] 50 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 89.2 mg (0.420 mmol) of tert-butyl 5-aza-7-spiro[2.4]heptylcarbamate, 195 μl (1.40 mmol) of triethylamine, and 1.5 ml of ethanol were added and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (50 mg, 0.135 mmol, 48%, m / z = 355.1 [M + H] + ).

[1238]

[1239] 79-2. Step 2: 4-(7-amino-5-aza-5-spiro[2.4]heptyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02122)

[1240]

[1241] 4 M hydrochloric acid was added to 1,4-dioxane containing tert-butyl (5-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate. The reaction solution was stirred at 70°C for 16 hours. The solid of the reaction solution was filtered to obtain the target compound of Example 79 (15.5 mg, 0.141 mmol, 43%, m / z = 255.1 [M + H]+ ).

[1242] 1 H-NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 8.27 (s, 2H), 8.25 (s, 1H), 4.33 (d,J= 10.7 Hz, 2H), 4.14 (s, 1H), 3.53 (d,J= 4.9 Hz, 2H), 3.50 (s, 2H), 1.22 - 1.11 (m, 2H), 0.94 - 0.87 (m, 2H), 0.77 - 0.74 (m, 3H).

[1243]

[1244] [Example 80]

[1245] Preparation of 4-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-1H-1,5,7-triazaindene-3-carbonitrile (NRX02123)

[1246]

[1247]

[1248] 80-1 Step 1: tert-butyl ((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate

[1249] 50 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 90 mg (0.420 mmol) of tert-butyl((3-methylproridin-3-yl)methyl)carbamate, 195 μl (1.40 mmol) of triethylamine, and 1.5 ml of ethanol were added and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (99.8 mg, 0.280 mmol, 100%, m / z = 357.1 [M + H] + ).

[1250]

[1251] 80-2 Step 2: 4-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-1H-1,5,7-triazaindene-3-carbonitrile (NRX02123)

[1252] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (99.8 mg, 0.280 mmol). The reaction solution was stirred at 70°C for 16 hours. The solid of the reaction solution was filtered to obtain the target compound of Example 80 (61 mg, 0.280 mmol, 85%, m / z = 257.1 [M + H] + ).

[1253] 1 H-NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.26 (s, 1H), 8.03 (s, 2H), 3.92 (q,J= 8.8 Hz, 2H), 3.75 (d,J= 11.5 Hz, 2H), 2.89 (d,J= 6.6 Hz, 2H), 2.11 - 2.03 (m, 1H), 1.88 (dd,J= 13.4, 7.6 Hz, 1H), 1.21 - 1.13 (m, 3H).

[1254]

[1255] [Example 81]

[1256] Preparation of 4-(3,7-diazabicyclo[3.3.0]oct-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02124)

[1257]

[1258]

[1259] 81-1 Step 1: tert-butyl ((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate

[1260] 37.5 mg (0.210 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 67 mg (0.315 mmol) of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, and 146 μl (1.40 mmol) of triethylamine were added to 1.0 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the compound (99.8 mg, 0.280 mmol, 100%, m / z = 355.1 [M + H] + )

[1261] .

[1262] 81-2 Step 2: 4-(3,7-diazabicyclo[3.3.0]oct-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02124)

[1263] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl ((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (99.8 mg, 0.280 mmol). The reaction solution was stirred at 70°C for 16 hours. The solid of the reaction solution was filtered to obtain the target compound of Example 81 (36 mg, 0.142 mmol, 51%, m / z = 255.1 [M + H] + ).

[1264] 1H-NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 4.05 (d,J= 10.7 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.80 (d,J= 9.3 Hz, 1H), 2.31 - 2.24 (m, 2H), 1.91 - 1.80 (m, 1H).

[1265]

[1266] [Example 82]

[1267] Preparation of 4-(2,7-diazabicyclo[3.3.0]oct-2-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02128)

[1268]

[1269]

[1270] 82-1 Step 1: Preparation of tert-butyl 1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate

[1271] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 71 mg (0.336 mmol) of tert-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the compound (99.8 mg, 0.280 mmol, 100%, m / z = 355.1 [M + H] + ).

[1272]

[1273] 82-2 Step 2: 4-(2,7-diazabicyclo[3.3.0]oct-2-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02128)

[1274] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (99.8 mg, 0.280 mmol). The reaction solution was stirred at 70°C for 16 hours. The solid of the reaction solution was filtered to obtain the target compound of Example 82 (70 mg, 0.276 mmol, 98%, m / z = 255.1 [M + H] + ).

[1275] 1 H-NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.12 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 4.85 (d,J= 3.9 Hz, 1H), 4.12 (dt,J= 15.1, 9.0 Hz, 1H), 3.98 (tt,J= 9.3, 3.9 Hz, 1H), 3.36 (s, 4H), 3.17 - 3.09 (m, 3H), 2.20 - 2.06 (m, 2H).

[1276]

[1277] [Example 83]

[1278] Preparation of 4-(1,8-diaza-8-spiro[5.5]undecyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02152)

[1279]

[1280]

[1281] 83-1 Step 1: tert-butyl 8-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,8-diazaspiro[5.5]undecane-1-carboxylate

[1282] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 85.5 mg (0.336 mmol) of tert-butyl 1,8-diaza-1-spiro[5.5]undecanecarboxylate, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (75 mg, 0.189 mmol, 68%, m / z = 397.1 [M + H] + ).

[1283]

[1284] 83-2 Step 2: 4-(1,8-diaza-8-spiro[5.5]undecyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02152)

[1285] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl 8-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,8-diazospiro[5.5]undecane-1-carboxylate (75 mg, 0.189 mmol). The reaction solution was stirred at 50°C for 16 h. After concentration under reduced pressure, the reaction solution was basified with 6 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with sodium sulfate to remove the remaining water and concentrated under reduced pressure. The concentrated mixture was purified by reverse phase column chromatography (C 18The target compound of Example 83 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (30 mg, 101 μmol, 54%, m / z = 297.1 [M + H] + ).

[1286] 1 H-NMR (400 MHz, DMSO-d6) δ 8.33 - 8.24 (m, 3H), 5.75 (s, 1H), 3.97 (d,J= 13.2 Hz, 1H), 3.82 (s, 1H), 3.76 - 3.61 (m, 2H), 2.76 (d,J= 5.4 Hz, 2H), 1.88 - 1.63 (m, 4H), 1.52 - 1.34 (m, 6H).

[1287]

[1288] [Example 84]

[1289] Preparation of 4-(1,7-diaza-7-spiro[4.5]decyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02158)

[1290]

[1291]

[1292] 84-1 Step 1: tert-butyl 7-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decane-1-carboxylate

[1293] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 80.8 mg (0.336 mmol) of tert-butyl 1,7-diaza-1-spiro[4.5]decanecarboxylate, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 2 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1) to obtain the compound (85.6 mg, 0.224 mmol, 80%, m / z = 383.1 [M + H] + ).

[1294]

[1295] 84-2 Step 2: 4-(1,7-diaza-7-spiro[4.5]decyl)-1H-1,5,7-triazaindene-3-carbonitrile(NRX02158)

[1296] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl 7-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazospiro[4.5]decane-1-carboxylate (86 mg, 0.224 mmol). The reaction solution was stirred at 50°C for 16 h. After concentration under reduced pressure, the reaction solution was basified with 6 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with sodium sulfate to remove the remaining water and concentrated under reduced pressure. The concentrated mixture was purified by reverse phase column chromatography (C 18 The target compound of Example 84 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (18 mg, 83.4 μmol, 28%, m / z = 283.1 [M + H] + ).

[1297] 1H-NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 3.89 (t,J= 10.8 Hz, 2H), 3.81 (td,J= 9.6, 4.2 Hz, 1H), 3.65 (d,J= 11.2 Hz, 1H), 2.82 (dt,J= 12.8, 4.7 Hz, 1H), 2.72 (ddd,J= 12.5, 7.7, 4.0 Hz, 1H), 2.07 (dt,J= 11.4, 6.9 Hz, 1H), 1.90 (dt,J= 12.4, 8.3 Hz, 1H), 1.67 - 1.51 (m, 3H), 1.46 (s, 3H).

[1298]

[1299] [Example 85]

[1300] Preparation of 4-(1,7-diaza-7-spiro[4.4]nonyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02159)

[1301]

[1302]

[1303] 85-1 Step 1: Preparation of tert-butyl 7-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate

[1304] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 76 mg (0.336 mmol) of tert-butyl 1,7-diaza-1-spiro[4.4]nonanecarboxylate, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 2 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 5: 1) to obtain the target compound (85 mg, 0.231 mmol, 82%, m / z = 369.1 [M+ H] + ).

[1305]

[1306] 85-2 Step 2: 4-(1,7-diaza-7-spiro[4.4]nonyl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02159)

[1307] 4 M hydrochloric acid (1.4 mL) was added to 1,4-dioxane containing tert-butyl 7-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazospiro[4.4]nonane-1-carboxylate (85 mg, 0.231 mmol). The reaction solution was stirred at 50°C for 16 h. After concentration under reduced pressure, the reaction solution was basified with 6 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with sodium sulfate to remove the remaining water and concentrated under reduced pressure. The concentrated mixture was purified by reverse phase column chromatography (C 18 The target compound of Example 85 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (45 mg, 170 μmol, 74%, m / z = 269.1 [M + H] + ).

[1308] 1 H-NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.04 (s, 1H), 3.91 - 3.75 (m, 2H), 3.65 (s, 2H), 2.94 - 2.77 (m, 2H), 1.96 - 1.89 (m, 2H), 1.74 (s, 3H), 1.77 - 1.69 (m, 2H), 1.24 (s, 1H).

[1309]

[1310] [Manufacturing Example 20]

[1311] Preparation of 3-azabicyclo[3.1.0]hexane-1-carboxamide (95)

[1312]

[1313] 20-1 Step 1: tert-butyl 1-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (94)

[1314] 3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (0.2 g, 0.880 mmol) was dissolved in ethyl acetate (1.3 mL), and then CDI (214 mg, 1.32 mmol) and 30% ammonium hydroxide (0.5 mL) were added. The reaction solution was stirred at 45°C for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was sequentially washed several times with water (50 mL), citric acid (50 mL), and sodium carbonate aqueous solution. The organic layer was removed with sodium sulfate and concentrated under reduced pressure to obtain compound (94) of Preparation Example 20.

[1315]

[1316] 20-2 Step 2: 3-azabicyclo[3.1.0]hexane-1-carboxamide (95)

[1317] Compound (94) (199 mg, 0.879 mmol) of the above preparation example was dissolved in dichloromethane, and then trifluoroacetic acid (17.6 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 by adding ethanol and basic resin, and then filtered to obtain the desired compound (95) of Preparation Example 20.

[1318]

[1319] [Example 86]

[1320] Preparation of 3-(3-cyano-1H-1,5,7-triazainden-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (NRX02129)

[1321]

[1322] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 42 mg (0.336 mmol) of the compound (95) obtained in Preparation Example 20, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound of Example 86 (6.7 mg, 0.025 mmol, 9%, m / z = 269.1 [M + H] + ).

[1323] 1 H-NMR (400 MHz, DMSO-d6) δ 8.21 (dt,J= 21.2, 7.1 Hz, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 4.28 - 4.17 (m, 1H), 4.12 (dd,J= 11.3, 4.6 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.86 (s, 1H), 2.11 (s, 1H), 1.44 - 1.36 (m, 1H), 0.66 (s, 1H).

[1324]

[1325] [Manufacturing Example 21]

[1326] Preparation of 3-azabicyclo[3.1.0]hexane-1-carboxamide (98)

[1327]

[1328]

[1329] 21-1 Step 1: tert-butyl 1-((tosyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (96)

[1330] Tert-Butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (19) (200 mg, 0.938 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (285 mg, 2.81 mmol), dimethylaminopyridine (11.5 mg, 0.094 mmol), and p-(chlorosulfonyl)toluene (268 mg, 1.41 mmol) were added to the reaction solution. The reaction solution was stirred at 4°C for 18 h. After the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and sodium carbonate aqueous solution were added. After washing the organic layer several times with 0.1 M hydrochloric acid and water, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the target compound (96) of Manufacturing Example 21 (275 mg, 0.748 mmol, 80%).

[1331]

[1332] 21-2 Step 2: tert-butyl 1-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (97)

[1333] Sodium cyanide (183 mg, 3.74 mmol) was added to dimethyl sulfoxide (30 mL) containing compound (96) (275 mg, 0.748 mmol) obtained in Preparation Example 21. The reaction solution was stirred at room temperature for 24 hours. After the reaction, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed several times with 0.1 M hydrochloric acid and water, and the remaining water was removed using sodium sulfate. The mixture was concentrated under reduced pressure to obtain compound (97) of Preparation Example 21.

[1334]

[1335] 21-3 Step 3: 3-azabicyclo[3.1.0]hexane-1-carboxamide (98)

[1336] Compound (97) (166 mg, 0.747 mmol) of the above Preparation Example 21 was dissolved in dichloromethane, and then trifluoroacetic acid (14.9 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 by adding ethanol and basic resin, and then filtered to obtain compound (98), which was used in the next reaction without purification.

[1337]

[1338] [Example 87]

[1339] Preparation of 4-{1-(cyanomethyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02130)

[1340]

[1341] 50.0 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 51 mg (0.420 mmol) of the compound (98) of Preparation Example 21, and 195 μl (1.40 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (43 mg, 0.163 mmol, 58%, m / z = 265.1 [M + H] + ).

[1342] 1H-NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.19 (s, 1H), 4.25 (d,J= 10.8 Hz, 1H), 4.11 (d,J= 10.7 Hz, 1H), 3.82 (dd,J= 10.7, 4.2 Hz, 1H), 3.67 (d,J= 10.9 Hz, 1H), 3.01 - 2.87 (m, 2H), 1.74 (dt,J= 8.2, 4.2 Hz, 1H), 0.91 (dd,J= 8.2, 5.0 Hz, 1H), 0.48 (t,J= 4.6 Hz, 1H).

[1343]

[1344] [제조예 22]

[1345] 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine의 제조(99)

[1346]

[1347] Compound (54) (695 mg, 1.43 mmol) of the above Preparation Example 13 was dissolved in 1,4-dioxane (14 mL), and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (734 mg, 5.74 mmol), triethylamine (581 mg, 5.74 mmol), Pd2(dba)3 (131 mg, 0.143 mmol), and XPhos (68.4 mg, 0.143 mmol) were sequentially added. The reaction solution was stirred at 95°C for 18 hours. After the reaction solution was cooled to room temperature, water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was removed with sodium sulfate to remove the remaining water, and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 5:1 to 1:1) to obtain compound (99) of Preparation Example 22 (500 mg, 1.03 mmol, 85%).

[1348]

[1349] [Example 88]

[1350] Preparation of 5-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazole (NRX02131)

[1351]

[1352]

[1353] 88-1 Step 1: 5-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazole (100)

[1354] The compound (99) (130 mg, 0.268 mmol), 5-bromo-1,3-thiazole (48.4 mg, 0.295 mmol), and potassium carbonate (256 mg, 0.805 mmol) of the above preparation example 22 were dissolved in 1,4-dioxane (1.1 mL). Then, Pd(pddf)Cl2 (9.8 mg, 0.013 mmol) was added to the reaction solution. The reaction solution was stirred at 100°C for 16 hours. After the reaction, it was filtered through a Celite pad and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 1: 1) to obtain the target compound (100) (105 mg, 0.238 mmol, 89%).

[1355]

[1356] 88-2 Step 2: 5-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazole (NRX02131)

[1357] The compound (100) (105 mg, 0.238 mmol) obtained in the above Example 88 was added to dichloromethane containing trifluoroacetic acid (3.72 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and potassium carbonate (0.88 mmol) was added. The reaction solution was stirred at 50°C for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (101) (35.8 mg, 115 μmol, 48%, m / z = 312.1 [M + H] + ).

[1358] 1H-NMR (400 MHz, CDCl3-d) δ 8.82 (d,J= 0.8 Hz, 1H), 8.32 - 8.27 (m, 1H), 7.80 (dd,J= 3.8, 0.7 Hz, 1H), 7.14 (d,J= 4.2 Hz, 1H), 3.84 (ddd,J= 21.5, 10.8, 5.0 Hz, 2H), 3.28 (dd,J= 10.9, 4.0 Hz, H), 3.11 - 3.01 (m, 1H), 1.34 - 1.21 (m, 1H), 1.12 (td,J= 7.3, 3.4 Hz, 1H), 1.02 (td,J= 7.5, 1.7 Hz, 1H), 0.81 (td,J= 7.5, 2.6 Hz, 3H), 0.47 - 0.36 (m, 1H), 0.19 (t,J= 4.3 Hz, 1H).

[1359]

[1360] [Example 89]

[1361] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(4-methyl-1,3-thiazol-2-yl)-1H-1,5,7-triazaindene (NRX02134)

[1362]

[1363] The same procedure as Example 88 was followed, except that 2-bromo-4-methyl-1,3-thiazole was used instead of 5-bromo-1,3-thiazole, to obtain the target compound of Example 89 (11 mg, 0.036 mmol, 44%, m / z = 326.1 [M + H] + ).

[1364] 1H-NMR (400 MHz, CDCl3-d) δ 10.39 (s, 1H), 8.29 (s, 1H), 7.26 (s, 1H), 6.90 (q,J= 1.0 Hz, 1H), 3.86 (d,J= 11.0 Hz, 1H), 3.78 (d,J= 10.6 Hz, 1H), 3.40 (dd,J= 11.0, 4.0 Hz, 1H), 3.20 - 3.12 (m, 1H), 2.57 - 2.48 (m, 3H), 1.65 - 1.53 (m, 2H), 1.34 - 1.21 (m, 2H), 1.19 - 1.08 (m, 1H), 0.82 (t,J= 7.4 Hz, 3H), 0.44 (dd,J= 7.8, 4.8 Hz, 1H), 0.32 - 0.21 (m, 1H).

[1365]

[1366] [실시예 90]

[1367] {3-[3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazainden-4-yl]-3-azabicyclo[3.1.0]hex-1-yl}methanol의 제조(NRX02136)

[1368]

[1369]

[1370] 90-1 단계 1: 4-chloro-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (102)

[1371] Compound (53) (200 mg, 0.488 mmol), (1-methyl-4-pyrazoyl)boranediol (73.8 mg, 0.586 mmol), and potassium carbonate (466 mg, 1.46 mmol) obtained in the above Preparation Example 13 were dissolved in 1,4-dioxane / water (1.1 mL). Then, Pd(pddf)Cl2 (22 mg, 0.024 mmol) was added to the reaction solution. The reaction solution was stirred at 100°C for 2 hours. After the reaction, it was filtered through a Celite Pad and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 1: 1) to obtain compound (102) (110 mg, 0.302 mmol, 62%).

[1372]

[1373] 90-2 Step 2: (3-(5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol (103)

[1374] Compound (102) (50 mg, 0.137 mmol) obtained in the above example, compound (20) (46.6 mg, 0.412 mmol) obtained in the above preparation example 5, and 95.8 μl (687 mmol) of triethylamine were added to 1.4 ml of ethanol and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (103) (27 mg, 0.062 mmol, 45%, m / z = 441.1 [M + H] + ).

[1375]

[1376] 90-3 Step 3: (3-(5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol (NRX02136)

[1377] The compound (103) (27 mg, 0.062 mmol) obtained in the above example was added to dichloromethane containing trifluoroacetic acid (0.617 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and potassium carbonate (0.309 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound (6.8 mg, 21.9 μmol, 35%, m / z = 311.1 [M + H] + ).

[1378] 1 H-NMR (400 MHz, CDCl3-d) δ 9.60 (s, 1H), 8.28 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 4.05 (d,J= 11.0 Hz, 1H), 3.96 (s, 3H), 3.83 (d,J= 11.1 Hz, 1H), 3.68 (d,J= 11.6 Hz, 1H), 3.61 (d,J= 11.5 Hz, 1H), 3.36 - 3.26 (m, 2H), 0.88 (d,J= 6.2 Hz, 1H), 0.64 (dd,J=8.0, 5.0 Hz, 1H), 0.39 (t,J= 4.5 Hz, 1H).

[1379]

[1380] [Example 91]

[1381] Preparation of 4-{1-(methoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl}-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02137)

[1382]

[1383]

[1384] 91-1 Step 1: 4-(1-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (105)

[1385] The target compound (105) was obtained by the same reaction as in Example 90, Step 2, except that the compound (18) (52.4 mg, 0.412 mmol) of Preparation Example 4 was used instead of the compound (20) obtained in Preparation Example 5 (51.7 mg, 114 μmol, 83%, m / z = 455.1 [M + H] + ).

[1386]

[1387] 91-2 Step 2: 4-{1-(methoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl}-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02137)

[1388] The target compound (106) was obtained by reacting in the same manner as in the above Example 90, Step 3 (28.6 mg, 88.2 μmol, 78%, m / z = 325.1 [M + H] + ).

[1389] 1H-NMR (400 MHz, CDCl3-d) δ 10.25 (s, 1H), 8.26 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 6.95 (s, 1H), 4.02 (d,J= 11.0 Hz, 1H), 3.96 (s, 2H), 3.83 (d,J= 11.1 Hz, 1H), 3.43 (d,J= 10.5 Hz, 1H), 3.37 (d,J= 10.4 Hz, 1H), 3.34 - 3.31 (m, 1H), 3.30 (s, 3H), 1.30 (dt,J= 8.0, 4.0 Hz, 1H), 0.64 (ddt,J= 8.1, 5.1, 1.0 Hz, 1H), 0.38 (t,J= 4.6 Hz, 1H).

[1390]

[1391] [Example 92]

[1392] Preparation of 4-(3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02149)

[1393]

[1394]

[1395] 92-1 Step 1: 4-(3-azabicyclo[3.1.0]hexan-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (107)

[1396] The target compound (107) was obtained by the same reaction as in Example 90, Step 2, except that 3-azabicyclo[3.1.0]hexane (43.4 mg, 0.363 mmol) was used instead of the compound (20) from the above Preparation Example 5 (88 mg, 214 μmol, 71%, m / z = 411.1 [M + H] + ).

[1397]

[1398] 92-2 Step 2: 4-(3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02149)

[1399] The target compound (108) was obtained by reacting in the same manner as in the above Example 90, Step 3 (21 mg, 59.9 μmol, 28%, m / z = 281.1 [M + H] + ).

[1400] 1 H-NMR (400 MHz, DMSO-d6) δ 11.76 (s, 2H), 8.12 (s, 1H), 7.74 - 7.67 (m, 2H), 7.45 - 7.39 (m, 2H), 7.10 (d,J= 2.4 Hz, 2H), 5.50 (d,J= 7.3 Hz, 1H), 3.88 (s, 1H), 3.87 (s, 5H), 3.78 (dd,J= 10.9, 4.5 Hz, 4H), 3.14 (dt,J= 11.0, 1.7 Hz, 4H), 1.40 (dddd,J= 7.3, 3.5, 2.2, 1.1 Hz, 3H), 0.45 (td,J= 7.6, 4.6 Hz, 2H), 0.06 (d,J= 4.1 Hz, 1H).

[1401]

[1402] [Example 93]

[1403] Preparation of 4-(1-isopropyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02155)

[1404]

[1405]

[1406] 93-1 Step 1: 4-(1-isopropyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (109)

[1407] The target compound (109) was obtained by the same reaction as in Step 2 of Example 90, except that the compound (78) (55.7 mg, 0.345 mmol) from Preparation Example 17 was used instead of the compound (20) from Preparation Example 5 (94 mg, 208 μmol, 72%, m / z = 453.1 [M + H] + ).

[1408]

[1409] 93-2 Step 2: 4-(1-isopropyl-3-azabicyclo[3.1.0]hex-3-yl)-3-(1-methyl-4-pyrazolyl)-1H-1,5,7-triazaindene (NRX02155)

[1410] The target compound (110) was obtained by reacting in the same manner as in the above Example 90, Step 3 (34 mg, 105 μmol, 59%, m / z = 323.1 [M + H] + ).

[1411] 1H-NMR (400 MHz, CDCl3-d) δ 10.92 (s, 1H), 8.27 (s, 1H), 7.49 (t,J= 1.0 Hz, 1H), 7.37 (t,J= 1.0 Hz, 1H), 7.25 (d,J= 2.4 Hz, 1H), 6.98 - 6.93 (m, 1H), 3.96 (t,J= 1.3 Hz, 3H), 3.91 - 3.84 (m, 1H), 3.74 (d,J= 10.8 Hz, 1H), 3.33 (dd,J= 11.1, 3.9 Hz, 1H), 3.13 (d,J= 10.8 Hz, 1H), 1.55 - 1.42 (m, 1H), 1.26 - 1.16 (m, 1H), 0.88 (dt,J= 6.9, 1.3 Hz, 3H), 0.78 (dt,J= 6.9, 1.3 Hz, 3H), 0.49 (dd,J= 8.0, 4.9 Hz, 1H), 0.20 - 0.13 (m, 1H).

[1412]

[1413] [제조예 23]

[1414] ((2S)-3-azabicyclo[3.1.0]hexan-2-yl)methanol (115) 와 ((2R)-3-azabicyclo[3.1.0]hexan-2-yl)methanol (116)의 제조

[1415]

[1416]

[1417] 23-1 단계 1: 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (111)

[1418] Tert-Butyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (4300 mg, 23.46 mmol) and 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane (6416 mg, 30.49 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL), and sec-butyllithium (27 mL) was added at -78°C under nitrogen. The reaction solution was stirred at -78°C for 1 hour, and then methyl carbonochlorate (2660 mg, 28.15 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) was added. The reaction solution was stirred at -78°C for 3 hours. The reaction was quenched with ammonium chloride (150 mL), and the mixture was extracted with ethyl acetate (250 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate and concentrated under reduced pressure. The concentrated reaction solution under reduced pressure was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the target compound (111) (1.60 g, 28.2%, m / z = 242.2 [M + H] + ).

[1419]

[1420] 23-2 Step 2:tert-butyl (2S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (112) andtert-butyl (2R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (113)

[1421] Compound (111) (1.00 g, 4.14 mmol) from the above Preparation Example 23 was dissolved in tetrahydrofuran (8 mL), and then lithium aluminum hydride (173 mg, 4.56 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with ammonium chloride (150 mL) and filtered through a Celite Pad. The filtrate was extracted with ethyl acetate (250 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated under reduced pressure. The concentrated reaction solution under reduced pressure was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1 to 1: 1) to obtain the desired target compound (112: 435 mg, 49.2%, m / z = 158.2 [M+H] + , 113: 87 mg, 9.85%, m / z = 158.2 [M+H] + ) were obtained respectively.

[1422]

[1423] 23-3 Step 3: ((2S)-3-azabicyclo[3.1.0]hexan-2-yl)methanol (114) and ((2R)-3-azabicyclo[3.1.0]hexan-2-yl)methanol (115)

[1424] Compound (112 or 113) (50 mg, 0.23 mmol) from the above Preparation Example 23 was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.2 mL) was added. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the desired target compound (114 or 115), which was used in the next reaction without purification (50 mg, crude, m / z = 114.1 [M+H] + ).

[1425]

[1426] [Example 94]

[1427] Preparation of 4-{(2S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02141)

[1428]

[1429] Compound (114) (50 mg, 0.23 mmol) from the above Preparation Example 23 was dissolved in ethanol (3 mL). Triethylamine (64 mg, 0.69 mmol) and 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile (38 mg, 0.21 mmol) were added. The reaction solution was stirred at 100°C for 12 hours. After concentrating the reaction solution under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated. After purification through the concentrated prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate), the desired target compound was obtained (22.78 mg, 38.8%, m / z = 256.2 [M + H] + ).

[1430] 1 H-NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 5.03 (s, 1H), 4.52 - 4.46 (m, 1H), 4.32 (d,J= 9.4 Hz, 1H), 4.04 (dd,J= 9.8, 4.2 Hz, 1H), 3.76 (dd,J= 9.4, 5.2 Hz, 1H), 3.24 (dd,J= 9.8, 8.2 Hz, 1H), 1.94 (m, 1H), 1.90 - 1.82 (m, 1H), 0.75 (m, 1H), 0.61 (m, 1H).

[1431]

[1432] [Example 95]

[1433] Preparation of 4-{(2R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02142)

[1434]

[1435] Compound (115) (50 mg, 0.23 mmol) from the above Preparation Example 23 was dissolved in ethanol (3 mL). Triethylamine (64 mg, 0.69 mmol) and 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile (38 mg, 0.21 mmol) were added. The reaction solution was stirred at 100°C for 12 hours. After concentrating the reaction solution under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated. The concentrated reaction solution was purified through prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the desired target compound (17.04 mg, 31.8%, m / z = 256.2 [M + H] + ).

[1436] 1 H-NMR (400 MHz, DMSO-d6): δ 12.77 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 4.89 - 4.78 (m, 2H), 4.03 (dd,J= 10.0, 4.0 Hz, 1H), 3.91 (d,J= 10.0 Hz, 1H), 3.66 - 3.57 (m, 1H), 3.57 - 3.47 (m, 1H), 1.73 (m, 1H), 1.67 (m, 1H), 0.70 (m, 1H), 0.05 - 0.01 (m, 1H).

[1437]

[1438] [Manufacturing Example 24]

[1439] Preparation of 4-(3-azabicyclo[3.1.0]hex-1-yl)-1-methylpiperidine (124)

[1440]

[1441]

[1442] 24-1 Step 1: tert-butyl 4-(1-bromo-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (116)

[1443] Tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (10.0 g, 38.86 mmol) was added to anhydrous tetrahydrofuran (50 mL), cooled to -78°C, LiHMDS (1 M, 70 mL) was added, and stirred at the same temperature for 1 hour. TMSCl (7.6 g, 69.95 mmol) was slowly added to the reaction solution, and stirred for an additional hour at -40°C. Additionally, bromine (7.4 g, 46.63 mmol) was added, and stirred for an additional 20 minutes. The reaction solution was poured into sodium bicarbonate (sat. aq., 300 mL), and extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and concentrated. The concentrated reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1 to 1: 1) to obtain compound (116) of Manufacturing Example 24 (10.2 g, 78%, m / z = 280.1 / 282.1 [Mt-Bu-1 / Mt-Bu + 1] + ).

[1444]

[1445] 24-2 Step 2: 2-ethyl 1-methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclopropane-1,2-dicarboxylate (117)

[1446] Compound (116) (10.2 g, 30.34 mmol) obtained in the above Preparation Example 24 was dissolved in toluene (150 mL), ethyl acrylate (2.7 g, 27.30 mmol) was added, and the mixture was cooled to -20°C. Tert-butoxide (3.7 g, 33.37 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with ammonium chloride (500 mL), and the mixture was extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure. The mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the desired compound (117) (5.3 g, 49.15%, m / z = 300.2 / 301.2 [Mt-Bu / Mt-Bu + H] + ).

[1447]

[1448] 24-3 Step 3: 2-ethyl 1-methyl 1-(piperidin-4-yl)cyclopropane-1,2-dicarboxylate (118)

[1449] Compound (117) (5.3 g, 1.51 mmol) from the above Preparation Example 24 was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (5 mL) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain the desired compound (118) (6 g, crude, m / z = 256.2 [M+H] + ).

[1450]

[1451] 24-4 Step 4: 2-ethyl 1-methyl 1-(1-methylpiperidin-4-yl)cyclopropane-1,2-dicarboxylate (119)

[1452] After dissolving the compound (118) (6 g, 23.05 mmol) from the above manufacturing example 24 in methanol (20 mL), (CH2O) n (7.1 g, 235.01 mmol) was added. After stirring the reaction for 0.5 h, sodium cyanoborohydride (4.4 g, 70.50 mmol) was added. The reaction solution was stirred at 50°C for 4 h. The reaction solution was filtered and concentrated under reduced pressure to obtain the desired compound (119) (6 g, crude, m / z = 270.3 [M+H] + ).

[1453]

[1454] 24-5 Step 5: 1-(1-methylpiperidin-4-yl)cyclopropane-1,2-dicarboxylic acid (120)

[1455] Compound (119) (6 g, 22.28 mmol) from the above Preparation Example 24 was dissolved in methanol (30 mL), sodium hydroxide (10.7 g, 267.32 mmol, in 8 mL H2O) was added, and the mixture was stirred at 50°C for 16 hours. After concentrating the reaction solvent under reduced pressure, hydrochloric acid (4 M, 67 mL) was added to obtain the desired compound (120) (15 g, crude, m / z = 228.2 [M+H] + ).

[1456]

[1457] 24-6 Step 6: 1-(1-methylpiperidin-4-yl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (121)

[1458] Compound (120) (15 g, crude) from the above Preparation Example 24 was dissolved in tetrahydrofuran (80 mL), trifluoroacetic anhydride (20 mL) was added, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solvent under reduced pressure, the desired compound (121) was obtained (18 g, crude).

[1459]

[1460] 24-7 Step 7: 3-benzyl-1-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione (121)

[1461] Compound (122) (18 g, 86.02 mmol) and benzylamine (18.4 g, 172.04 mmol) from the above Preparation Example 24 were stirred at 150°C for 3 hours. Water (500 mL) was added to the reaction solution, and extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate and concentrated. The concentrated reaction solution was purified through column chromatography (SiO2, dichloromethane: methanol = 10:1 (10% ammonium hydroxide) to obtain the desired compound (122) (2 g, 42.2% over 5 steps, m / z = 299.3 [M + H] + ).

[1462]

[1463] 24-8 Step 8: 3-benzyl-1-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane (123)

[1464] Compound (122) (2 g, 6.70 mmol) from the above Preparation Example 24 was dissolved in tetrahydrofuran (30 mL), LAH (1.5 g, 40.22 mmol) was slowly added, and the mixture was stirred at 50°C for 16 hours. Sodium sulfate decahydrate (2 g) and ethyl acetate (200 mL) were added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure and separated through prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the desired compound (123) (700 mg, 38.62%, m / z = 271.3 [M + H] + ).

[1465]

[1466] 24-9 Step 9: 1-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane dihydrochloride (123)

[1467] Compound (123) (700 mg, 0.11 mmol) from the above Preparation Example 24 was dissolved in ethyl acetate (25 mL), Pd / C (850 mg, 10% Pd / C) was added, and the mixture was stirred at room temperature under hydrogen for 16 hours. The reaction solution was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the desired compound (124) (562.98 mg, 85.89%, m / z 181.3 [M + H] + ).

[1468] 1 H-NMR (400 MHz, DMSO-d6) δ 9.62 (s, 2H), 3.26 - 3.14 (m, 6H), 3.09 (d,J= 11.2 Hz, 1H), 2.72 - 2.54 (m, 5H), 1.79 - 1.35 (m, 6H), 0.77 (t,J= 5.0 Hz, 1H), 0.71 - 0.61 (m, 1H).

[1469]

[1470] [Example 96]

[1471] Preparation of 4-{1-(1-methyl-4-piperidyl)-3-azabicyclo[3.1.0]hex-3-yl}-1H-1,5,7-triazaindene-3-carbonitrile (NRX02180)

[1472]

[1473] Compound (124) (72.8 mg, 0.336 mmol) from the above Preparation Example 24 was dissolved in ethanol (1.5 mL). Triethylamine (142 mg, 1.40 mmol) and 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile (50 mg, 0.280 mmol) were added. The reaction solution was stirred at 80°C for 12 hours. After concentrating the reaction solution under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated. The concentrated reaction solution was purified through column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the desired target compound of Example 96 (40 mg, 0.124 mmol, 44%, m / z = 323.1 [M + H] + ).

[1474] 1 H-NMR (400 MHz, CDCl3-d) δ 8.43 (s, 1H), 8.26 (d,J= 1.2 Hz, 1H), 7.71 (d,J= 1.0 Hz, 1H), 4.24 (t,J= 10.3 Hz, 2H), 3.88 (dd,J= 11.0, 4.3 Hz, 1H), 3.76 (d,J= 10.8 Hz, 1H), 3.42 (d,J= 11.8 Hz, 3H), 2.61 (t,J= 1.2 Hz, 3H), 2.56 - 2.46 (m, 3H), 2.08 - 1.93 (m, 1H), 1.88 (d,J=13.8 Hz, 1H), 1.82 - 1.73 (m, 2H), 1.62 (dq,J= 8.4, 4.7 Hz, 3H), 0.87 (dd,J= 8.8, 4.9 Hz, 1H), 0.36 (t,J= 4.8 Hz, 1H).

[1475]

[1476] [Example 97]

[1477] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,7-diazaindene-3-carbonitrile (NRX02147)

[1478]

[1479] 4-Chloro-1H-1,7-triazaindene-3-carbonitrile (100 mg 0.563 mmol), 1-ethyl-3-azabicyclo[3.1.0]hexane (166 mg, 1.13 mmol), triethylamine (235 μl, 1.69 mmol), and N-methyl-2-pyrrolidone 2.8 ml were added and stirred at 160°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 97 (20 mg, 0.079 mmol, 14%, m / z = 253.1 [M + H] + ).

[1480] 1 H-NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.22 (s, 1H), 7.94 (d,J= 5.6 Hz, 1H), 6.35 (d,J= 5.8 Hz, 1H), 3.99 (d,J= 9.5 Hz, 1H), 3.84 (d,J= 9.7 Hz, 1H), 3.59 (dd,J= 9.7, 4.2 Hz, 1H), 3.48 (dd,J= 9.4, 1.0 Hz, 1H), 1.79 (dq,J= 14.5, 7.3 Hz, 1H), 1.53 (dt,J= 8.0, 4.0 Hz, 1H), 1.44 (dt,J= 14.8, 7.4 Hz, 1H), 1.00 (t,J= 7.4 Hz, 3H), 0.69 (dd,J= 7.9, 4.5 Hz, 1H), 0.44 (t,J= 4.3 Hz, 1H).

[1481]

[1482] [Example 98]

[1483] Preparation of 3-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene (NRX02167)

[1484]

[1485] 3,4-Dichloro-1H-1,5,7-triazaindene (50 mg, 0.266 mmol), 1-ethyl-3-azabicyclo[3.1.0]hexane (43 mg, 0.293 mmol), and triethylamine (135 mg, 1.33 mmol) were dissolved in ethanol (1.3 mL). The reaction solution was stirred at 80°C for 18 hours. After concentrating the reaction solvent under reduced pressure, the residue was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 98 (16 mg, 0.060 mmol, 22%, m / z = 263.1 [M + H] + ).

[1486] 1 H-NMR (400 MHz, CDCl3-d) δ 10.47 (s, 1H), 8.23 ​​(s, 1H), 7.07 (s, 1H), 4.34 (d,J= 11.1 Hz, 1H), 4.27 (d,J= 11.1 Hz, 1H), 3.86 (dd,J= 11.1, 4.3 Hz, 1H), 3.64 (dt,J= 11.0, 0.8 Hz, 1H), 1.79 (dq,J= 14.6, 7.4 Hz, 1H), 1.50 (dt,J= 14.1, 7.4 Hz, 1H), 1.42 (dt,J= 8.1, 4.1 Hz, 1H), 1.02 (t,J= 7.5 Hz, 3H), 0.65 (ddt,J= 7.0, 4.9, 1.2 Hz, 1H), 0.29 (t,J= 4.4 Hz, 1H).

[1487]

[1488] [Manufacturing Example 25]

[1489] Preparation of 1-propyl-3-azabicyclo[3.1.0]hexane (130)

[1490]

[1491]

[1492] 25-1 Step 1: diethyl 1-propylcyclopropane-1,2-dicarboxylate (125)

[1493] Tert-butoxide (2951 mg, 26.30 mmol) was added to toluene (30 mL) containing ethyl 2-bromopentanoate (5 g, 23.91 mmol) and ethyl acrylate (2.42 g, 23.91 mmol) dissolved at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Ammonium chloride (300 mL) was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and the residue was concentrated to obtain the target compound (5.4 g, crude, m / z = 229.3 [M + H] + ).

[1494]

[1495] 25-2 Step 2: 1-propylcyclopropane-1,2-dicarboxylic acid (126)

[1496] Compound (125) (5.4 g, 23.65 mmol) from the above Preparation Example 25 was dissolved in methanol (25 mL), 6 M sodium hydroxide (25 mL) was added, and the mixture was stirred at 90°C for 3 hours. The reaction solvent was concentrated under reduced pressure, water (300 mL) was added, and the mixture was washed with ethyl acetate (100 mL). The aqueous layer was adjusted to pH 1 with 3 M hydrochloric acid and extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate, and concentrated to obtain the target compound (4.5 g, crude, m / z = 173.2 [M + H] + ).

[1497]

[1498] 25-3 Step 3: 1-propyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (127)

[1499] Compound (126) (4.5 g, 23.65 mmol) obtained in the above Preparation Example 25 was dissolved in methanol (30 mL), and then trifluoroacetic anhydride (7460 mg, 35.47 mmol) was added dropwise at 0°C. After stirring the reaction solution at room temperature for 3 hours, the reaction solvent was concentrated under reduced pressure to obtain the desired target compound (4.5 g, crude, m / z = 169.0 [M + MeOH-OH] + ).

[1500]

[1501] 25-4 Step 4: 3-benzyl-1-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione (128)

[1502] Compound (127) (4.5 g, 23.65 mmol) and benzylamine (2799 mg, 23.65 mmol) obtained in the above Preparation Example 25 were stirred at 150°C for 4 hours. The reaction solution was separated using column chromatography (SiO2, hexane: ethyl acetate = 10: 1) to obtain the target compound (2.67 g, 45.8% yield in 4 steps, m / z 244.1 [M + H] + ).

[1503]

[1504] 25-5 Step 5: 3-benzyl-1-propyl-3-azabicyclo[3.1.0]hexane (129)

[1505] Compound (128) (2.67 g, 10.97 mmol) obtained in the above Preparation Example 25 was dissolved in tetrahydrofuran (24 mL), and LAH (834 mg, 21.94 mmol) was slowly added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 16 hours. Ammonium chloride (300 mL) was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate and concentrated. After concentration, the target compound was obtained (1.14 g, 48.3%, m / z = 216.1 [M + H] + ).

[1506]

[1507] 25-6 Step 6: 1-propyl-3-azabicyclo[3.1.0]hexane (130)

[1508] Compound (129) (1.14 g, 5.29 mmol) obtained in the above Preparation Example 25 was dissolved in ethanol (8 mL), 10% Pd / C (50% wt. H2O) (300 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen. 4 N hydrochloric acid (1,4-dioxane, 5 mL) was added, and the mixture was stirred for an additional 0.5 hour. The Pd / C was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the target compound (720.08 mg, crude, 1 eq. HCl salt, m / z = 126.1 [M + H] + ).

[1509] 1H-NMR (400 MHz, CDCl3-d): δ 9.95 (s, 1H), 9.45 (s, 1H), 3.42 (m, 3H), 3.21 (dd,J= 16.2, 8.6 Hz, 1H), 1.73 - 1.60 (m, 1H), 1.45 - 1.27 (m, 4H), 1.04 (dd,J= 6.2, 4.6 Hz, 1H), 0.96 - 0.88 (m, 3H), 0.72 (t,J= 7.4 Hz, 1H).

[1510]

[1511] [Example 99]

[1512] Preparation of 4-(1-propyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02157)

[1513]

[1514] 50 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 54.2 mg (0.336 mmol) of the compound (130) of Preparation Example 25, 195 μl (1.40 mmol) of triethylamine, and 1.5 ml of ethanol were added and stirred at 80°C for 2 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound of Example 99 (28 mg, 0.105 mmol, 37%, m / z = 268.1 [M + H] + ).

[1515] 1H-NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.19 (s, 1H), 4.17 (d,J= 10.4 Hz, 1H), 4.09 (d,J= 11.0 Hz, 1H), 3.77 (dd,J= 10.9, 4.4 Hz, 1H), 3.64 (d,J= 10.4 Hz, 1H), 1.84 - 1.73 (m, 1H), 1.54 - 1.39 (m, 3H), 1.34 (ddd,J= 13.2, 9.2, 6.5 Hz, 1H), 0.94 (t,J= 7.3 Hz, 3H), 0.71 (dd,J=8.0, 4.6 Hz, 1H), 0.30 (t,J= 4.3 Hz, 1H).

[1516]

[1517] [Manufacturing Example 26]

[1518] Preparation of 1-cyclopropyl-3-azabicyclo[3.1.0]hexane hydrochloride (136)

[1519]

[1520]

[1521] 26-1 Step 1: diethyl [1,1'-bi(cyclopropane)]-1,2-dicarboxylate (131)

[1522] Ethyl 2-bromo-2-cyclopropyl acetate (10.0 g, 48.29 mmol) was dissolved in toluene (100 mL), and ethyl acrylate (4.8 g, 48.29 mmol) was added. The reaction solution was stirred at 0°C for 5 minutes, and tert-butoxide (6.0 g, 53.12 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by adding ammonium chloride (sat. aq., 200 mL), and then extracted with ethyl acetate (120 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate. The mixture was concentrated under reduced pressure to obtain the desired compound (9.5 g, crude, m / z = 227.3 [M + H]+ ).

[1523]

[1524] 26-2 Step 2: [1,1'-bi(cyclopropane)]-1,2-dicarboxylic acid (132)

[1525] Compound (131) (9.5 g, 41.99 mmol) from the above Preparation Example 26 was dissolved in methanol (50 mL), and then sodium hydroxide (10.1 g in 50 mL water, 251.91 mmol) was added. The reaction solution was stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, and 6 N hydrochloric acid was added to adjust the pH <1. The reaction solution was extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure to obtain the desired compound (132) (9.3 g, crude, m / z = 171.2 [M + H] + ).

[1526]

[1527] 26-3 Step 3: 1-cyclopropyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (133)

[1528] Compound (132) (9.3 g, 54.65 mmol) from the above Preparation Example 26 was dissolved in tetrahydrofuran (15 mL), and then trifluoroacetic anhydride (5 mL) was added at 0°C and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the desired compound (9.1 g, crude, m / z = 153.1 [M + H] + ).

[1529]

[1530] 26-4 Step 4: 3-benzyl-1-cyclopropyl-3-azabicyclo[3.1.0]hexane-2,4-dione (134)

[1531] Compound (133) (9.1 g, 59.81 mmol) and benzylamine (9.6 g, 89.71 mmol) from the above Preparation Example 26 were added and stirred at 150°C for 3 hours. After concentrating the reaction solution under reduced pressure, the desired compound was obtained by separation using column chromatography (SiO2, hexane: ethyl acetate = 10: 1) (5.3 g, 45.6% over 4 steps, m / z = 242.2 [M + H] + ).

[1532]

[1533] 26-5 Step 5: 3-benzyl-1-cyclopropyl-3-azabicyclo[3.1.0]hexane (135)

[1534] Compound (134) (5.3 g, 21.97 mmol) from the above Preparation Example 26 was dissolved in tetrahydrofuran (50 mL), and LAH (1.7 g, 43.93 mmol) was slowly added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 16 hours. Ammonium chloride (200 mL) was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate (110 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate and concentrated. After concentration, the target compound was obtained (2.2 g, 46.95%, m / z = 214.1 [M + H] + ).

[1535]

[1536] 26-6 Step 6: 1-cyclopropyl-3-azabicyclo[3.1.0]hexane hydrochloride (136)

[1537] Compound (135) (1.2 g, 5.63 mmol) from the above Preparation Example 26 was dissolved in methanol (10 mL), 10% Pd / C (300 mg) was added, and the mixture was stirred at room temperature under hydrogen for 16 hours. 4 N hydrochloric acid (in MeOH, 6 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain the desired compound (818.56 mg, 91.1%, m / z = 124.2 [M + H] + ).

[1538] 1 H-NMR (400 MHz, CDCl3-d) δ 9.64 (s, 1H), 9.18 (s, 1H), 3.61 - 3.24 (m, 4H), 1.37 - 1.23 (m, 1H), 1.12 (s, 1H), 0.95 (s, 1H), 0.67 (s, 1H), 0.49 (d,J= 7.2 Hz, 2H), 0.08 (d,J= 13.8 Hz, 2H).

[1539]

[1540] [Example 100]

[1541] Preparation of 4-(1-cyclopropyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene-3-carbonitrile (NRX02160)

[1542]

[1543] 50 mg (0.280 mmol) of 4-chloro-1H-1,5,7-triazaindene-3-carbonitrile, 53.6 mg (0.336 mmol) of the target compound (136) of Preparation Example 26, 195 μl (1.40 mmol) of triethylamine, and 1.5 ml of ethanol were added and stirred at 80°C for 2 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10: 1) to obtain the target compound of Example 100 (25.7 mg, 96.9 μmol, 35%, m / z = 266.1 [M + H]+ ).

[1544] 1 H-NMR (400 MHz, CDCl3-d) δ 8.32 (s, 1H), 7.74 (s, 1H), 4.38 (d,J= 10.9 Hz, 1H), 4.21 (d,J= 10.9 Hz, 1H), 3.92 (dd,J= 10.9, 4.4 Hz, 1H), 3.85 (d,J= 10.9 Hz, 1H), 1.42 (dt,J= 8.4, 4.2 Hz, 1H), 1.23 (tt,J= 8.2, 4.1 Hz, 2H), 0.76 - 0.68 (m, 1H), 0.56 - 0.42 (m, 2H), 0.30 (t,J= 4.6 Hz, 1H), 0.23 - 0.07 (m, 2H).

[1545]

[1546] [Manufacturing Example 27]

[1547] Preparation of 2-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (137)

[1548]

[1549] 2-Chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.311 mmol) was dissolved in n-butanol, and then ammonia water (31.1 mmol) was added. The reaction solution was stirred in a microwave reactor at 140°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was used to separate the target compound (137) of Manufacturing Example 27 (32 mg, 80.3 μmol, 26%, m / z = 399.1 [M + H] +).

[1550]

[1551] [Example 101]

[1552] Preparation of N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}cyclo propanecarboxamide (NRX02148)

[1553]

[1554]

[1555] 101-1 Step 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethyl lsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclo propane carboxamide

[1556]

[1557] Compound (137) (32 mg, 0.080 mmol) obtained in the above Preparation Example 27 was dissolved in pyridine (1 mL), and then cyclopropanecarbonyl chloride (42 mg, 0.401 mmol) was added. The reaction solution was stirred at 120°C for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the compound (17 mg, 0.036 mmol, 45%, m / z = 467.1 [M + H] + ).

[1558]

[1559] 101-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}cyclopropanecarboxamide (NRX02148)

[1560]

[1561] N-(5-Cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropenecarboxamide (17 mg, 0.036 mmol) was added to dichloromethane containing trifluoroacetic acid (1.91 mmol). The reaction solution was stirred at 40°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 101 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (8.2 mg, 24.4 μmol, 67%, m / z = 337.1 [M + H] + ).

[1562] 1 H-NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.08 (s, 1H), 8.06 (s, 1H), 4.15 (d,J= 10.5 Hz, 1H), 4.07 (d,J= 11.0 Hz, 1H), 3.72 (dd,J= 11.0, 4.3 Hz, 1H), 3.58 (d,J= 10.5 Hz, 1H), 1.75 (dq,J= 14.5, 7.3 Hz, 1H), 1.48 (dt,J= 8.1, 4.1 Hz, 1H), 1.39 (dq,J= 14.7, 7.5 Hz, 1H), 1.19 (s, 1H), 0.95 (t,J= 7.4 Hz, 3H), 0.74 (tt,J= 7.9, 3.0 Hz, 4H), 0.66 (dd,J= 8.0, 4.6 Hz, 1H), 0.24 (t,J= 4.3 Hz, 1H).

[1563]

[1564] [Example 102]

[1565] N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-3-furamide (NRX02175)

[1566]

[1567]

[1568] 102-1 Step 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)furan-3-carboxamide

[1569] The desired compound was obtained by performing the same procedure as in Example 101, Step 1, except that 3-furoyl chloride was used instead of cyclopropanecarbonyl chloride (43 mg, 87.3 μmol, 72%, m / z = 493.1 [M + H] + ).

[1570]

[1571] 102-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaind en-6-yl}-3-furamide (NRX02175)

[1572] Cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)furan-3-carboxamide (43 mg, 0.087 mmol) was dissolved in tetrahydrofuran (1.0 mL), and 1 M tetra-n-butylammonium fluoride (0.873 mL, 873 mmol) was added. The reaction solution was stirred at 90°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18The target compound of Example 102 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (12 mg, 33.1 μmol, 38%, m / z = 363.1 [M + H] + ).

[1573] 1 H-NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.44 (dd,J= 1.6, 0.8 Hz, 1H), 8.16 (d,J= 1.4 Hz, 1H), 7.77 (t,J= 1.7 Hz, 1H), 6.97 (dd,J= 1.9, 0.8 Hz, 1H), 4.19 (dd,J= 25.8, 10.8 Hz, 2H), 3.78 (dd,J= 11.0, 4.3 Hz, 1H), 3.64 (d,J= 10.6 Hz, 1H), 1.80 (dq,J= 14.7, 7.4 Hz, 1H), 1.58 - 1.38 (m, 2H), 1.00 (t,J= 7.4 Hz, 3H), 0.72 (dd,J= 8.0, 4.7 Hz, 1H), 0.29 (t,J= 4.3 Hz, 1H).

[1574]

[1575] [Example 103]

[1576] Preparation of N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-1-methyl-4-pyrazolecarboxamide (NRX02177)

[1577]

[1578]

[1579] 103-1 Step 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[1580] The same procedure as in Example 101, Step 1 was followed except that 1-methyl-4-pyrazolecarbonyl chloride was used instead of cyclopropanecarbonyl chloride to obtain the desired compound (60 mg, 118 μmol, 94%, m / z = 507.1 [M + H] + ).

[1581] 103-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-1-methyl-4-pyrazolecarboxamide (NRX02177)

[1582] The desired target compound was obtained by performing the same procedure as in Example 101, Step 2 (6.3 mg, 16.7 μmol, 14%, m / z = 377.1 [M + H] + ).

[1583] 1H-NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.02 (d,J= 0.7 Hz, 1H), 4.22 (d,J= 10.6 Hz, 1H), 4.16 (d,J= 11.0 Hz, 1H), 3.88 (s, 3H), 3.78 (dd,J= 11.0, 4.3 Hz, 1H), 3.64 (d,J= 10.6 Hz, 1H), 1.80 (dq,J= 14.5, 7.3 Hz, 1H), 1.58 - 1.38 (m, 2H), 1.00 (t,J= 7.4 Hz, 3H), 0.71 (dd,J= 8.0, 4.7 Hz, 1H), 0.29 (t,J= 4.3 Hz, 1H).

[1584]

[1585] [실시예 104]

[1586] N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-6-oxa-1-spiro[2.5]octanecarboxamide의 제조(NRX02153)

[1587]

[1588]

[1589] 104-1 단계 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-oxaspiro[2.5]octane-1-carboxamide

[1590]

[1591] Compound (137) (50 mg, 0.125 mmol) obtained in the above Preparation Example 27 was dissolved in dimethylformamide (0.6 mL), and then 6-oxa-1-spiro[2.5]othanecarboxylic acid (58.8 mg, 0.376 mmol), HATU (143 mg, 0.376 mmol), and triethylamine (63.5 mg, 627 mmol) were added. The reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was purified by reverse phase column chromatography (C 18 The compound was separated using a solvent (resin, water: acetonitrile = 9:1 to 1:9) and obtained (21 mg, 39.1 μmol, 31%, m / z = 537.1 [M + H] + ).

[1592]

[1593] 104-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-6-oxa-1-spiro[2.5]octanecarboxamide (NRX02153)

[1594]

[1595] N-(5-Cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-oxaspiro[2.5]octane-1-carboxamide (21 mg, 0.039 mmol) was added to dichloromethane containing trifluoroacetic acid (1.0 mL). The reaction solution was stirred at 40°C for 3 hours. After the reaction solution was concentrated under reduced pressure, acetonitrile and potassium carbonate (0.391 mmol) were added, and the mixture was stirred for an additional hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by reversed-phase column chromatography (C 18The target compound of Example 104 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9 (14.7 mg, 36.2 μmol, 92%, m / z = 407.1 [M + H] + ).

[1596] 1 H-NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.03 (s, 1H), 8.07 (s, 1H), 4.14 (d,J= 10.5 Hz, 1H), 4.07 (dd,J= 11.1, 2.0 Hz, 1H), 3.72 (dt,J= 9.7, 4.5 Hz, 1H), 3.64 - 3.49 (m, 4H), 3.38 (t,J= 7.8 Hz, 1H), 2.23 (s, 1H), 1.81 - 1.70 (m, 1H), 1.67 - 1.34 (m, 6H), 1.03 (dd,J=5.4, 3.9 Hz, 1H), 0.95 (t,J= 7.4 Hz, 3H), 0.81 (dd,J= 7.8, 3.9 Hz, 1H), 0.66 (dd,J= 7.9, 4.7 Hz, 1H), 0.24 (t,J= 4.3 Hz, 1H).

[1597]

[1598] [Example 105]

[1599] Preparation of N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}2-(2-pyridyl)cyclopropanecarboxamide (NRX02154)

[1600]

[1601]

[1602] 105-1 Step 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[1603] The target compound was obtained by the same method as in Example 104, Step 1, except that 2-(2-pyridyl)cyclopropenecarboxylic acid was used instead of 6-oxa-1-spiro[2.5]othanecarboxylic acid (30 mg, 55.2 μmol, 44%).

[1604]

[1605] 105-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}2-(2-pyridyl)cyclopropanecarboxamide (NRX02154)

[1606] The target compound of Example 105 was obtained (18.5 mg, 44.7 μmol, 81%) by performing the same method as in Step 2 of Example 104 above.

[1607] 1H-NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.16 (s, 1H), 8.44 - 8.38 (m, 1H), 8.06 (d,J= 2.0 Hz, 1H), 7.64 (td,J= 7.7, 1.8 Hz, 1H), 7.38 (dq,J= 7.8, 1.1 Hz, 1H), 7.15 (ddd,J= 7.5, 4.8, 1.2 Hz, 1H), 4.10 (t,J= 10.4 Hz, 1H), 3.97 (d,J= 11.1 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.56 (d,J= 10.5 Hz, 1H), 2.54 - 2.49 (m, 1H), 1.73 (dq,J= 14.6, 7.3 Hz, 1H), 1.51 - 1.30 (m, 4H), 0.94 (t,J= 7.4 Hz, 3H), 0.65 (dt,J= 7.9, 4.1 Hz, 1H), 0.20 (q,J= 4.7 Hz, 1H).

[1608]

[1609] [실시예 106]

[1610] N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-1-spiro[2.2]pentanecarboxamide의 제조(NRX02156)

[1611]

[1612]

[1613] 106-1 단계 1: N-(5-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)spiro[2.2]pentane-1-carboxamide

[1614] The compound was obtained by the same method as in Example 104, Step 1, except that 1-spiro[2.2]pentenecarboxylic acid was used instead of 6-oxa-1-spiro[2.5]otenecarboxylic acid (27 mg, 55.2 μmol, 44%).

[1615]

[1616] 106-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}-1-spiro[2.2]pentanecarboxamide (NRX02156)

[1617] The target compound of Example 106 was obtained by performing the same method as in Step 2 of Example 104 above (14.4 mg, 39.7 μmol, 72%).

[1618] 1 H-NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.89 (s, 1H), 8.06 (s, 1H), 4.14 (d,J= 10.5 Hz, 1H), 4.06 (dd,J= 11.1, 1.7 Hz, 1H), 3.71 (dt,J= 10.9, 4.0 Hz, 1H), 3.61 - 3.53 (m, 1H), 2.59 (s, 1H), 1.75 (dq,J= 14.6, 7.3 Hz, 1H), 1.48 (dt,J= 8.0, 4.0 Hz, 1H), 1.44 - 1.31 (m, 2H), 1.24 (dd,J= 7.5, 3.2 Hz, 1H), 0.95 (t,J= 7.4 Hz, 3H), 0.89 - 0.74 (m, 3H), 0.73 - 0.62 (m, 2H), 0.23 (t,J= 4.3 Hz, 1H).

[1619]

[1620] [Manufacturing Example 28]

[1621] Preparation of 6-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-9H-purin-2-amine (138)

[1622]

[1623] 500 mg (2.34 mmol) of 6-bromo-7H-purin-2-amine was added to 379 mg (2.57 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 488 μl (3.5 mmol) of triethylamine, and 11.5 ml of ethanol, and stirred at 80°C for 4 hours. After concentrating the reaction solution under reduced pressure, the mixture was purified by reverse phase column chromatography (C 18 resin, water: acetonitrile = 9: 1 to 1: 9) was used to separate the target compound (138) of the above manufacturing example 28 (527 mg, 2.16 mmol, 92%, m / z = 245.1 [M + H] + ).

[1624]

[1625] [Example 107]

[1626] Preparation of N-{6-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-2-purinyl}-1-spiro[2.2]pentanecarboxamide (NRX02162)

[1627]

[1628] Compound (138) (50.0 mg, 0.205 mmol) obtained in the above Preparation Example 28 was dissolved in dimethylformamide (0.6 mL), and then 1-spiro[2.2]pentanecarboxylic acid (60.0 mg, 0.535 mmol), HATU (233 mg, 0.614 mmol), and triethylamine (104 mg, 1.02 mmol) were added. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 107 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9 (15.6 mg, 46.1 μmol, 22.5%, m / z = 339.1 [M+ H] + ).

[1629] 1 H-NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.79 (s, 1H), 7.89 (s, 1H), 4.54 (s, 1H), 4.02 (s, 1H), 3.85 - 3.38 (m, 1H), 2.61 (s, 1H), 1.71 (dq,J= 14.6, 7.3 Hz, 1H), 1.45 (dd,J= 14.8, 8.0 Hz, 2H), 1.34 (t,J= 3.8 Hz, 1H), 1.22 (dd,J= 7.5, 3.3 Hz, 1H), 0.93 (t,J= 7.4 Hz, 3H), 0.88 - 0.73 (m, 4H), 0.72 - 0.66 (m, 1H), 0.63 (dd,J= 8.0, 4.6 Hz, 1H), 0.23 (t,J= 4.3 Hz, 1H).

[1630]

[1631] [Example 108]

[1632] N-{6-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-2-purinyl}2-(2-pyridyl) cyclopropane carboxamide (NRX02163)

[1633]

[1634] The same procedure as Example 107 was followed except that 2-(2-pyridyl)cyclopropanecarboxylic acid was used instead of 1-spiro[2.2]pentanecarboxylic acid, to obtain the desired target compound (11 mg, 28.2 μmol, 14%).

[1635] 1H-NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.06 (s, 1H), 8.41 (d,J= 4.5 Hz, 1H), 7.90 (s, 1H), 7.64 (td,J= 7.6, 1.8 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.15 (ddd,J= 7.5, 4.8, 1.1 Hz, 1H), 4.57 (s, 1H), 3.96 (s, 1H), 3.78 (s, 1H), 3.59 (s, 1H), 1.68 (s, 1H), 1.48 - 1.40 (m, 4H), 0.91 (t,J= 7.3 Hz, 3H), 0.62 (dd,J= 7.9, 4.6 Hz, 1H), 0.19 (s, 1H).

[1636]

[1637] [Example 109]

[1638] N-{6-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-2-purinyl}cyclopropanecarboxamide (NRX02164)

[1639]

[1640] Cyclopropenecarbonyl chloride (23.5 mg, 225 μmol) was added to the target compound (138) (50 mg, 0.205 mmol) obtained in the above Preparation Example 28 and pyridine (1.0 mL). The reaction solution was stirred at 60°C for 16 hours. After the reaction solution was concentrated under reduced pressure, it was purified by reverse phase column chromatography (C 18 The target compound of Example 109 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (14.1 mg, 45.1 μmol, 22%, m / z = 313.1 [M + H] + ).

[1641] 1H-NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 9.98 (s, 1H), 7.90 (s, 1H), 4.59 (s, 1H), 4.03 (s, 1H), 3.55 (d,J= 55.5 Hz, 1H), 2.22 (s, 1H), 1.71 (dq,J= 14.6, 7.3 Hz, 1H), 1.45 (dd,J= 14.1, 7.3 Hz, 2H), 0.93 (t,J= 7.4 Hz, 3H), 0.79 - 0.67 (m, 4H), 0.71 - 0.59 (m, 1H), 0.23 (t,J= 4.4 Hz, 1H).

[1642]

[1643] [Example 110]

[1644] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaindene (NRX02172)

[1645]

[1646] 4-Chloro-1H-1,5,7-triazaindene (20 mg, 0.130 mmol), 1-ethyl-3-azabicyclo[3.1.0]hexane (23.1 mg, 0.156 mmol), and potassium carbonate (124 mg, 0.391 mmol) were dissolved in 1,4-dioxane (0.651 mL). The reaction solution was stirred at 100°C for 16 hours. After concentrating the reaction solution under reduced pressure, the residue was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 110 (20.5 mg, 89.8 μmol, 69%, m / z = 229.1 [M + H] + ).

[1647] 1H-NMR (400 MHz, CDCl3-d) δ 9.60 (s, 1H), 8.27 (s, 1H), 6.99 (dd,J= 3.8, 1.7 Hz, 1H), 6.54 (dd,J= 3.7, 1.4 Hz, 1H), 4.10 (dd,J= 20.6, 10.3 Hz, 2H), 3.85 (s, 1H), 3.64 (s, 1H), 1.77 (dq,J= 14.6, 7.4 Hz, 1H), 1.55 - 1.42 (m, 2H), 1.02 (t,J= 7.5 Hz, 3H), 0.73 (ddt,J=8.1, 4.8, 1.0 Hz, 1H), 0.41 (t,J= 4.4 Hz, 1H).

[1648]

[1649] [Example 111]

[1650] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-methoxy-1H-1,5,7-triazaindene-3-carbonitrile (NRX02174)

[1651]

[1652]

[1653] 111-1 Step 1: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[1654] Compound (5) (50 mg, 0.120 mmol) of the above Preparation Example 1 and 25% w / w sodium methoxide (1.2 mL, 5.98 mmol) were stirred at 70°C for 16 hours. After quenching the reaction with ammonium chloride (30 mL), the mixture was extracted with ethyl acetate (250 mL x 3). The organic layer was washed with brine, and the remaining water was removed using sodium sulfate. The mixture was concentrated under reduced pressure to obtain the desired target compound (44.5 mg, crude, m / z = 414.1 [M+ H] + ).

[1655]

[1656] 111-2 Step 2: 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-methoxy-1H-1,5,7-triazaindene-3-carbonitrile (NRX02174)

[1657] 4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (44.5 mg, 0.108 mmol) was dissolved in tetrahydrofuran (1.0 mL), and 1 M tetra-n-butylammonium fluoride (1.08 mL, 1.08 mmol) was added. The reaction solution was stirred at 90°C for 16 h. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 111 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (26.8 mg, 94.6 μmol, 88%, m / z = 284.1 [M + H] + ).

[1658] 1 H-NMR (400 MHz, CDCl3-d) δ 11.18 (s, 1H), 7.54 (s, 1H), 4.27 (d,J= 10.8 Hz, 1H), 4.21 (d,J= 11.0 Hz, 1H), 3.95 (s, 2H), 3.72 (d,J= 10.9 Hz, 1H), 1.80 (dq,J= 14.6, 7.4 Hz, 1H), 1.56 - 1.42 (m, 2H), 0.74 (dd,J= 8.0, 5.0 Hz, 1H), 0.34 (t,J= 4.4 Hz, 1H).

[1659]

[1660] [Example 112]

[1661] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-methyl-1H-1,5,7-triazaindene (NRX02178)

[1662]

[1663] 50 mg (0.298 mmol) of 4-chloro-3-methyl-1H-1,5,7-triazaindene was added to 52.9 mg (0.358 mmol) of 1-ethyl-3-azabicyclo[3.1.0]hexane, 195 μl (1.40 mmol) of triethylamine, and 1.5 ml of ethanol, and stirred at 80°C for 18 hours. After concentrating the reaction solution under reduced pressure, the reaction solution was separated using column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the target compound of Example 112 (34.4 mg, 0.142 mmol, 48%, m / z = 243.1 [M + H] + ).

[1664] 1 H-NMR (400 MHz, CDCl3-d) δ 9.48 (s, 1H), 8.23 ​​(s, 1H), 6.84 (d,J= 1.9 Hz, 1H), 4.22 (d,J= 10.4 Hz, 1H), 4.12 (d,J= 10.5 Hz, 1H), 3.74 (dd,J= 10.5, 4.2 Hz, 1H), 3.53 (dd,J= 10.5, 1.2 Hz, 1H), 2.40 (d,J= 1.1 Hz, 3H), 1.79 (dq,J= 14.6, 7.4 Hz, 1H), 1.49 (dq,J= 14.7, 7.5 Hz, 1H), 1.40 (dt,J= 8.0, 4.0 Hz, 1H), 1.01 (t,J= 7.5 Hz, 3H), 0.63 (ddt,J= 8.0, 4.8, 1.0 Hz, 1H), 0.31 (t,J= 4.3 Hz, 1H).

[1665]

[1666] [Example 113]

[1667] Preparation of 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (NRX02179)

[1668]

[1669]

[1670] 113-1 Step 1: ethyl 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (142)

[1671]

[1672]

[1673] 1-Ethyl-3-azabicyclo[3.1.0]hexane hydrochloride (654 mg, 4.43 mmol) was dissolved in dimethylformamide (10 mL), and then triethylamine (1.1 g, 11.08 mmol) and ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1.0 g, 4.43 mmol) were added. The reaction solution was stirred at 80°C for 16 hours. After the reaction, the reaction solution was poured into water (120 mL) and extracted with ethyl acetate (60 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated compound was purified by column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the desired compound (900 mg, 67.61%, m / z 301.2 [M + H] + ).

[1674]

[1675] 113-2 Step 2: (4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (143)

[1676]

[1677] Ethyl 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (115 mg, 0.38 mmol) was dissolved in tetrahydrofuran (4 mL), and LAH (44 mg, 1.15 mmol) was added. The reaction solution was stirred at 50°C, and LAH (130 mg, 3.4 mmol) was added in three portions over 16 h. The reaction was quenched by adding sodium sulfate decahydrate (200 mg), filtered, and concentrated. The concentrate was purified by column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain the desired compound (45 mg, 45.5%, m / z = 259.1 [M + H] + ).

[1678]

[1679] 113-3 Step 3: 4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-5-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (NRX02179)

[1680]

[1681] (4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl l)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (30 mg, 0.12 mmol) was dissolved in methanol (4 mL), and sulfuric acid (50 μL, 98% wt.) was added at 0°C. The reaction solution was stirred at 50°C for 16 hours. After cooling to room temperature, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC (40% ACN in H2O (0.1% NH4HCO3)) to obtain the target compound of Example 113 (15.58 mg, 32.84%, m / z = 273.3 [M + H]+ ).

[1682] 1 H-NMR (400 MHz, DMSO-d6)δ11.62 (brs, 1H), 8.05 (s, 1H), 7.23 (s, 1H), 4.57 - 4.37 (m, 2H), 4.26 (d,J= 10.6 Hz, 1H), 4.17 (d,J= 10.8 Hz, 1H), 3.69 (dd,J= 10.9, 4.0 Hz, 1H), 3.53 (d,J= 10.7 Hz, 1H), 3.22 (s, 3H), 1.76 - 1.72 (m, 1H), 1.54 - 1.38 (m, 2H), 0.97 (t,J= 7.4 Hz, 3H), 0.70 - 0.55 (m, 1H), 0.18 - 0.17 (m, 1H).

[1683]

[1684] [실시예 114]

[1685] (1-methyl-3-methyl-4-pyrazolyl){4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}amine (NRX02181)

[1686]

[1687]

[1688]

[1689] 114-1 단계 1: 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (145)

[1690] 4,6-Dichloro-1H-1,5,7-triazaindene (5.32 mmol) was added to dimethylformamide containing sodium hydride (5.85 mmol) and stirred at room temperature for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (5.74 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. The reaction solution was washed with ethyl acetate and brine. The organic layer was removed with sodium sulfate and concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the desired compound (1.5 g, 4.71 mmol, 89%).

[1691]

[1692] 114-2 Step 2: 2-chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (146)

[1693] 2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.314 mmol) was added to ethanol containing 1-ethyl-3-azabicyclo[3.1.0]hexane (0.377 mmol) and triethylamine (0.943 mmol). The reaction solution was stirred at 90°C for 2 hours. The solvent of the reaction solution was concentrated under reduced pressure, and the desired compound was obtained by separation using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) (85 mg, 0.216 mmol, 69%, m / z = 394.1 [M + H] + ).

[1694]

[1695] 114-3 Step 3: N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (147)

[1696] 2-Chloro-4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.216 mmol), 1-methyl-3-methyl-4-pyrazoylamine (0.324 mmol), and potassium carbonate (0.649 mmol) were dissolved in 2-butanol (1.0 mL). Pd2(dba)3 (21.6 μmol) and XPhos (21.6 μmol) were added. The reaction solution was stirred at 100°C for 16 h. After completion of the reaction, the reaction solution was filtered through a Celite Pad. After concentrating the reaction solvent under reduced pressure, the residue was purified by column chromatography (SiO2, hexane: ethyl acetate = 5:1 to 1:1) to obtain the desired compound (47 mg, 100 μmol, 46%, m / z = 468.1 [M + H] + ).

[1697]

[1698] 114-4 Step 4: (1-methyl-3-methyl-4-pyrazolyl){4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazainden-6-yl}amine (NRX02181)

[1699] (1-Methyl-3-methyl-4-pyrazoyl){4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,5,7-triazaden-6-yl}amine (47 mg, 100 μmol) was dissolved in tetrahydrofuran (1.0 mL), and 1 M tetra-n-butylammonium fluoride (2.01 mL, 2.01 mmol) was added. The reaction solution was stirred at 90°C for 16 h. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 114 was obtained by separation using a resin, water: acetonitrile = 9: 1 to 1: 9) (15.0 mg, 44.5 μmol, 44%, m / z = 338.1 [M + H] + ).

[1700] 1 H-NMR (400 MHz, CDCl3-d) δ 8.48 (s, 1H), 7.69 (s, 1H), 6.74 (d,J= 3.6 Hz, 1H), 6.40 (d,J= 3.5 Hz, 1H), 4.06 (dd,J= 20.0, 10.7 Hz, 2H), 3.82 (s, 3H), 2.25 (s, 3H), 1.77 (dq,J= 14.6, 7.4 Hz, 1H), 1.57 - 1.47 (m, 2H), 1.24 (s, 1H), 1.01 (t,J= 7.4 Hz, 3H), 0.76 (dd,J=8.1, 4.9 Hz, 1H), 0.39 (t,J= 4.5 Hz, 1H).

[1701]

[1702] [Manufacturing Example 29]

[1703] Preparation of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile (150)

[1704]

[1705]

[1706] 29-1 Step 1: 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (149)

[1707]

[1708] 1-Methyl-1H-pyrrole-2-carbonitrile (800 mg, 7.54 mmol) was dissolved in dimethylformamide (20 mL), N-bromosuccinimide (1.3 g, 7.54 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (80 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine, the remaining water was removed using sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) to obtain the desired compound (149) (1.2 g, 86.04%, m / z = 185.0 [M + ] + ).

[1709]

[1710] 29-2 Step 2: 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile (150)

[1711]

[1712] Compound (149) (1.2 g, 6.49 mmol) obtained in the above Preparation Example 29 was dissolved in anhydrous 1,4-dioxane (20 mL), and then 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.3 g, 12.97 mmol), potassium acetate (1.6 g, 16.21 mmol), and Pd(dppf)Cl2 (712 mg, 0.97 mmol) were added. The reaction solution was stirred at 90°C for 4 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated mixture was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1) to obtain the target compound (150) (1.2 g, 79.72%) of Manufacturing Example 29.

[1713] 1 H-NMR (400 MHz, CDCl3-d) δ 7.18 (d,J= 1.4 Hz, 1H), 7.09 (d,J= 1.6 Hz, 1H), 3.77 (s, 3H), 1.30 (s, 12H).

[1714]

[1715] [Example 115]

[1716] Preparation of 4-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (NRX02140)

[1717]

[1718]

[1719] 115-1 Step 1:4-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (151)

[1720]

[1721] Compound (150) (335 mg, 1.44 mmol) of the above Preparation Example 29 was dissolved in dimethylformamide (5 mL), and then compound (54) (699 mg, 1.44 mmol) of the above Preparation Example 13, potassium carbonate (399 mg, 2.89 mmol), SPhos Pd G3 (225 mg, 0.20 mmol), and Pd(dppf)Cl2 (211 mg, 0.20 mmol) were added. The reaction solution was stirred at 80°C for 4 hours. The reaction solution was added to water (60 mL) and extracted with ethyl acetate (40 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and then concentrated under reduced pressure. The concentrated compound was separated using column chromatography (SiO2, hexane: ethyl acetate = 10:1 to 1:1) and prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the desired compound (151) (120 mg, 18%).

[1722] 1H-NMR (400 MHz, CDCl3-d) δ 8.42 (s, 1H), 7.05 (d,J= 5.0 Hz, 1H), 6.87 (d,J= 14.0 Hz, 2H), 5.62 (s, 2H), 3.89 (s, 5H), 3.66 - 3.54 (m, 2H), 3.41 (s, 1H), 3.18 (s, 1H), 1.79 - 1.68 (m, 1H), 1.39 - 1.29 (m, 2H), 1.00 - 0.94 (m, 2H), 0.92 - 0.88 (m, 3H), 0.55 (s, 1H), 0.28 (s, 1H), 0.01 (s, 9H).

[1723]

[1724] 115-2 Step 2: 4-(4-(1-ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (NRX02140)

[1725]

[1726] 4-(4-(1-Ethyl-3-azabicyclo[3.1.0]hexan-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (120 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction mixture, ammonia / methanol (7 M, 3 mL) was added, and the mixture was stirred for an additional 3 hours. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine, the remaining water was removed with sodium sulfate, and the mixture was concentrated under reduced pressure. The concentrated compound was separated using prep-HPLC (acetonitrile / water / 10 mM ammonium carbonate) to obtain the target compound of Example 115 (43.9 mg, 51%, m / z = 333.2 [M + H] +).

[1727] 1 H-NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.12 (s, 1H), 7.22 (d,J= 1.6 Hz, 1H), 7.11 (d,J= 2.4 Hz, 1H), 6.95 (d,J= 1.6 Hz, 1H), 3.79 (s, 3H), 3.71 (dd,J= 10.6, 3.7 Hz, 2H), 3.24 (dd,J= 10.8, 3.8 Hz, 1H), 2.96 (d,J= 10.4 Hz, 1H), 1.66 - 1.54 (m, 1H), 1.31 - 1.17 (m, 2H), 0.79 (t,J= 7.4 Hz, 3H), 0.45 - 0.38 (m, 1H), 0.25 (t,J= 4.0 Hz, 1H).

[1728] [Manufacturing Example 30]

[1729] Preparation of 6-amino-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (154)

[1730]

[1731]

[1732] 30-1 Step 1: 4-chloro-3-cyano-1H-pyrrolo[2,3-b]pyridine 7-oxide, methanesulfonic acid (153)

[1733] 4-Chloro-1H-1,7-diazaindene-3-carbonitrile (1.0 g, 5.63 mmol) was dissolved in dichloromethane (56 mL), and then meta-chloroperoxybenzoic acid (2.78 g, 11.3 mmol, purity 70%) was added at 0°C. After stirring at room temperature for 16 hours, methanesulfonic acid (812 mg, 8.45 mmol) was added and stirred for an additional 15 minutes. Diethyl ether was added, and the solid was filtered to obtain the desired compound (153) (1.8 g, 6.21 mmol, 110%).

[1734]

[1735] 30-2 Step 2: 6-amino-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (154)

[1736] Compound (153) (1.5 g, 5.18 mmol) obtained in Preparation Example 30 was dissolved in acetonitrile (11.3 mL), dimethyl sulfate (718 mg, 5.7 mmol) was added, and the mixture was stirred at 60°C for 16 hours. After cooling the reaction solution to room temperature, it was divided into three 15 mL vials. Ammonia (7 N in methanol, 5 mL) was added to each vial, and the mixture was stirred at 70°C for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated using column chromatography (SiO2, hexane: ethyl acetate = 1: 1) to obtain the desired compound (154) (31.7 mg, 0.165 mmol, 3%).

[1737]

[1738] [Example 116]

[1739] Preparation of 6-amino-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,7-diazaindene-3-carbonitrile (NRX02161)

[1740]

[1741] Compound (154) (28 mg, 0.145 mmol) from the above Preparation Example 30, 1-ethyl-3-azabicyclo[3.1.0]hexane (64.4 mg, 0.436 mmol) and triethylamine (0.101 mL, 0.727 mmol) were dissolved in n-butanol (0.485 mL), and stirred in a microwave reactor at 140°C for 4 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 116 was obtained (2 mg, 7.48 μmol, 5%) by separation using a solvent (resin, water: acetonitrile = 9:1 to 1:9).

[1742]

[1743] [Example 117]

[1744] Preparation of N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,7-diazainden-6-yl}cycloprop panecarboxamide (NRX02165)

[1745]

[1746]

[1747] 117-1 Step 1: N-(4-chloro-3-cyano-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide (155)

[1748] Compound (154) (20 mg, 0.104 mmol) from the above Preparation Example 30 was dissolved in anhydrous pyridine (0.5 mL), and cyclopropanecarbonyl chloride (11.9 mg, 0.114 mmol) was added, followed by stirring at room temperature for 2 hours. After concentrating the reaction solvent under reduced pressure, methanol was added, and the reaction solution was cooled, followed by the addition of 10% ammonium hydroxide. After concentrating the reaction solution under reduced pressure, the resultant was purified by reverse phase column chromatography (C 18 The desired compound was obtained by separation using a resin, water: acetonitrile = 9:1 to 1:9) (8 mg, 30.7 μmol, 30%).

[1749]

[1750] 117-2 Step 2: N-{3-cyano-4-(1-ethyl-3-azabicyclo[3.1.0]hex-3-yl)-1H-1,7-diazainden-6-yl}cycloprop panecarboxamide (NRX02165)

[1751] N-(4-chloro-3-cyano-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropanecarboxamide (8 mg, 30.7 μmol) was dissolved in n-butanol (0.5 mL), 1-ethyl-3-azabicyclo[3.1.0]hexane (22.7 mg, 0.153 mmol), triethylamine (31.1 mg, 0.307 mmol) were added, and the mixture was stirred at 140°C for 16 h. The reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (C 18 The target compound of Example 117 was obtained by separation using a solvent (resin, water: acetonitrile = 9:1 to 1:9) (4 mg, 11.9 μmol, 39%).

[1752]

[1753] [Example 1]

[1754] Compound screening against the LRRK2 kinase domain (ADP-glo)

[1755]

[1756] The degree of activity of the compound of the present invention according to the above examples to inhibit the LRRK2 kinase reaction is ADP-Glo TM Quantitative evaluation was performed using the Kinase Assay (Promega) method. The method analyzed kinase activity by measuring the degree of conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) through an enzymatic reaction as a luminescence value. An increase in the luminescence signal indicates an increase in the amount of ADP produced by the kinase reaction.

[1757] LRRK2 proteins were purified using two types of human LRRK2 (WT) (SignalChem, #L10-11G) and LRRK2 (G2019S) (SignalChem, #L10-12GG), and LRRKtide (SignalChem, #L10-58) was used as a substrate for phosphorylation. Ultra-Pure ATP (Promega, #V916A) was used as ATP, a mediator of the kinase reaction. ADP-Glo, which eliminates the remaining ATP at the same time as the enzyme reaction is completed TM Reagent (Promega, #V912B) was used, and Kinase Detection Buffer (Promega, #V913B) and Kinase Detection Substrate (Promega, #V914B) were mixed to convert ADP back to ATP and induce the luciferase / luciferin reaction.

[1758] The LRRK2 kinase inhibition ability of the compound of the present invention was performed according to the following method. The composition of the assay buffer is 50 mM Tris pH 7.4, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35, 2.5 mM DTT, and the reactions of all reagents between experiments were performed in the assay buffer. In the kinase reaction and the entire assay, each reagent was performed in a volume ratio of compound: enzyme: substrate / ATP = 2:1:2 and enzyme reaction solution: ADP-GloTM Reagent: Kinase Detection Solution = 2:2:1, respectively. The compounds were first analyzed for activity at two final concentrations of 100 and 10 nM by serial dilution from 0.5 mM DMSO stock, and among them, superior substances were selected compared to the reference compound, and the degree of enzyme reaction inhibition was measured at ten final concentrations of 10,000, 2,000, 400, 80, 16, 3.2, 0.640, 0.128, 0.0256, and 0.00512 nM.

[1759] In the experiment, the compound and each human LRRK2, LRRK2 (22.2 nM) and LRRK2 (G2019S) (15 nM) were first reacted at room temperature for 20 minutes, and then the substrate (200,000, 150,000 nM) and each ATP (12.5, 35 μM) were mixed and added according to the LRRK2 form, and the wild type was reacted for 2 hours and the mutant type for 1 hour. The detection reaction was performed using ADP-Glo TM After waiting 40 minutes after reagent treatment, Kinase Detection Solution was added and left for 30 minutes.

[1760] After completion of all assay reactions, the degree of LRRK2 kinase inhibition potency of the compounds was measured by luminescence (Gain: 150, Integration Time: 1 sec. Read Height: 1 mm) using Synergy NEO2 Multi-mode Reader (BioTek). From the luminescence values ​​measured at 10 concentrations of substances that showed higher activity at 2 concentrations than the reference compound, IC50, which inhibits enzyme activity by 50%, was calculated using GraphPad Prism (ver. 9.0) software. 50 (nM) values ​​were derived. As shown in Table 3, it was confirmed that the compounds of the present invention can excellently inhibit the LRRK2 kinase reaction.

[1761]

[1762] [Table 3]

[1763]

[1764]

[1765]

[1766]

[1767]

[1768] [Example 2]

[1769] Validation of intracellular activity of compounds targeting the LRRK2 kinase domain (NanoBRET)

[1770]

[1771] To quantitatively measure the interaction with LRRK2 protein in living cells, NanoBRET assay (Promega) was performed. After transducing LRRK2 target kinase fused to NanoLuc luciferase protein into cells, the binding affinity of test compounds to the selected kinase protein was measured by competitive displacement with a fluorescent NanoBRET kinase-ligand tracer. TMMeasured in energy.

[1772] HEK 293 cells were transfected with a plasmid expressing the NanoLuc-LRRK2 fusion protein, seeded in 96-well plates at 20,000 cells / well, and cultured in a humidified incubator at 37°C and 5% CO2. After 24 h, the cells were treated with NanoBRET tracer (0.0083 μM). Then, increasing doses (from 1 nM to 10 μM) of the compounds of the present invention were treated with the tracer and competitive inhibitor for 2 h. Subsequently, 50 μl of a 3x substrate + inhibitor solution was added. The plates were then analyzed using a Biotek Synergy NEO2 plate reader equipped with a NanoBRET filter (donor emission wavelength 450 nm and acceptor emission wavelength 600 nm). The BRET ratio was calculated as the ratio of the donor emission wavelength to the acceptor emission wavelength, and the BRET ratio was multiplied by 1,000 to express the value in milliBRET units (mBU). Based on this value, the degree to which the compound of the present invention inhibits the interaction between the wild-type LRRK2 protein and the G2019S mutant LRRK2 protein in cells and the tracer is shown in FIGS. 1 and 2 using GraphPad Prism (ver. 9.0) software.

[1773] IC that inhibits the interaction between LRRK2 protein and tracer by 50% 50 (nM) was derived and shown in Table 4 below.

[1774] IC 50 (nM) was calculated for experimental values ​​that were confirmed at 1 point (10 μM) or 2 points (0.1, 10 μM or 1, 10 μM) as an initial screening and had binding affinity similar to or activity equivalent to that of the reference substance.

[1775]

[1776] [Table 4]

[1777]

[1778]

[1779] As shown in Table 4 above, it was confirmed that the compound of the present invention excellently inhibits the activity of wild-type LRRK2 protein and G2019S mutant LRRK2 protein in cells.

[1780]

[1781] [Example 3]

[1782] Intracellular activity validation of compounds against the LRRK2 kinase domain (AlphaLISA)

[1783]

[1784] The compound of the present invention is T-REx TM We quantitatively evaluated the level of LRRK2 protein binding and phosphorylation inhibition in 293 LRRK2 wild-type and G2019S cell lines and HEK293 cell lines overexpressing LRRK2 wild-type and G2019S. AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen), an immunoassay method utilizing luminescent oxygen radicals, was used.

[1785] The LRRK2 protein was used as a substrate for reaction with the above compound (LRRK2 inhibitor), and a receptor bead conjugated with an antibody capable of recognizing and reacting with the phosphate group of the substrate was used.

[1786] Streptavidin-coated donor beads were used to enable binding to the LRRK2 substrate.

[1787] AlphaLISA ® SureFire ® Ultra TMwas purchased from PerkinElmer, and quantitative analysis was performed using a bright white 384-well proxiplate (#6008280; Perkin Elmer) using the following procedure.

[1788] T-REx TM 293 LRRK2 wild-type and G2019S cells were seeded at 20,000 cells / well in 96-well plates and cultured overnight in a humidified incubator at 37°C and 5% CO2. The following day, the growth medium was removed, and 100 μl of fresh DMEM containing 1 μg / ml of tetracycline was added. LRRK2 wild-type and G2019S overexpressing HEK293 cell lines were also tested under the same conditions, but 100 μl of fresh DMEM containing 1 μg / ml of tetracycline was not added. After 48 hours, they were treated with increasing doses of the compounds of the present invention. The cells were incubated in an incubator for 2 hours. The cells were harvested, lysed, and transferred to 10 μl 384-well plates.

[1789] After adding 5 μl of biotinylated acceptor beads, the mixture was left at room temperature for 1 hour. After the reaction was completed, 5 μl of donor beads were added and left at room temperature for 1 hour. As donor beads are highly sensitive to light, this process was performed in the dark.

[1790] After all reactions were completed, the LRRK2 phosphorylation inhibitory effect of the compound was detected and analyzed using the AlphaScreen signal (Excitation 680 nm, Emission 615 nm) using Synergy NEO2 Multi-mode Plate Reader (BioTek), and the obtained results were nonlinear regression fitted using GraphPad Prism (Ver. 9.0) as shown in Figure 3, and IC 50The values ​​were derived and shown in Table 5 below.

[1791]

[1792] [Table 5]

[1793]

[1794] As shown in Table 5 above, it was confirmed that the compound of the present invention binds to the wild-type LRRK2 protein and G2019S mutant LRRK2 protein in cells and excellently inhibits phosphorylation.

[1795]

[1796] [Example 4]

[1797] Intracellular activity of compounds against the LRRK2 kinase domain (Western Blot)

[1798]

[1799] T-REx TM293 LRRK2 wild-type cells were seeded in 96-well plates at 20,000 cells / well and cultured overnight in a humidified incubator at 37°C and 5% CO2. The following day, the growth medium was removed, and 100 μl of fresh DMEM medium containing 1 μg / ml tetracycline was added. After 48 hours, 100 μl of the compound of the present invention was treated (final concentrations of 0.1 μM and 10 μM). The cells were incubated in an incubator for 2 hours. The cells were harvested and lysed, and equal amounts of protein (20 μg) were subjected to 8-12% SDS PAGE to separate them by size. The cells were then transferred to PVDF membranes and blocked with 10% SKIM MILK for 1 hour. The primary antibody [p-LRRK2, ab133450, Abcam; LRRK2, ab133474, Abcam; p-Rab10, ab230261, Abcam; Rab10, ab237703, Abcam] was diluted 1:1,000 in 5% BSA solution and reacted for 16 hours at 4°C. The membrane was washed with Tris-buffered saline (TBS) buffer containing 0.1% Tween 20 (TBS-T). This was repeated three times. After reacting the membrane with horseradish peroxidase-labeled secondary antibody for 1 hour at room temperature, the washing was repeated. The ECL kit (1705062, Bio-rad) was used. Visualization was performed as in Figure 4.

[1800] As shown in Fig. 4, it was confirmed that the compounds of the present invention dose-dependently inhibited phosphorylation of LRRK2 and phosphorylation of Rab10 protein, a substrate of LRRK2, better than the comparative groups GNE-0877 (DNL-201) and PF-06447475.

[1801]

[1802] [Example 5]

[1803] Confirmation of compound cytotoxicity against LRRK2 kinase domain (cell viability assay)

[1804]

[1805] To determine the cytotoxicity of the compound, T-Rex TM 293 LRRK2 wild-type cells were seeded in 96-well plates at 20,000 cells / well and cultured overnight in a humidified incubator at 37°C and 5% CO2. The following day, the growth medium was removed, and 100 μl of fresh DMEM medium containing 1 μg / ml of tetracycline was added. After 24 hours, the compounds of the present invention were treated at different concentrations (from 1 nM to 10 μM). After 24 hours, 100 μl of CellTiter-Glo (G9241, Promega) was treated, and the luminescence value was measured using a Synergy NEO2 Multi-mode Plate Reader (BioTek). The obtained results were used to derive the % viability using GraphPad Prism (Ver. 9.0).

[1806] As shown in Figure 5, it was confirmed that the LRRK2 inhibitor of the present invention did not inhibit cell survival. The same result was confirmed in U2OS, a cell line with low LRRK2 expression.

[1807]

[1808] [Example 6]

[1809] Confirmation of antagonist binding to A2AR GPCR (G-protein coupled receptor) protein (Cell viability assay)

[1810]

[1811] To confirm the antagonistic binding of the compound to the Adenosine A2A receptor (A2AR), three experiments were commissioned to Eurofins (https: / www.eurofinsdiscovery.com / ) and the results of the binding were obtained as shown in Table 6 below.

[1812]

[1813] [Table 6]

[1814]

[1815] In vitropharmacology: binding assay experiments, compounds were tested at a concentration of 1.0E-06 M. Competitive binding with ligands known as radioisotopes was measured, and compound binding was calculated as % inhibition of binding of ligands specific for each target. In vitropharmacology: Adenosine Binding Assays, IC was determined using radioisotopes. 50 To confirm this, binding was measured for compounds at various concentrations. The service name gpcrSCAN is a test method that monitors GPCR activity through second messenger signaling in real time and confirms whether the compound binds as an agonist or antagonist.

[1816] As shown in Table 6, it was confirmed that the novel LRRK2 inhibitor of the present invention binds as an antagonist to A2AR GPCR.

[1817]

[1818] [Example 7]

[1819] Molecular calculations analysis of the kinase type I and type II inhibition activities of structural isomers.

[1820]

[1821] For protein model building, the 3D structure of the LRRK2 protein was generated from the cryo-EM resolution structures of 8FO7 and 8U8A reported in the Protein Data Bank (PDB). The two 3D structures were used as templates, and the missing loop regions in the 3D structures were modeled using the full FASTA sequences of the corresponding proteins. An accurate 3D protein structure model was constructed based on target-template alignment using homology modeling. The resulting 3D protein structure model reflected the coordinates of the template and the compound binding to it. The optimal 3D protein structure was secured through repeated insertion and deletion of additional protein residues and modeling using a fragment library. Furthermore, the process of restructuring side chains was repeated to ensure accuracy.

[1822] For molecular docking calculations, initial protein-ligand structures were generated using Schrödinger's Glide docking software. The docking grid included the space occupied by the bound compounds within the two proteins and a 10 Å buffer zone in each dimension. Atomic charges were adjusted to a factor of 0.8, and charges below a threshold of 0.15 were cut off. The docking settings used extra precision, enforced the planarity of conjugated ð-bonds, and considered hydrogen bond interactions. The final docking score included a strain correction term, and molecular docking between the protein and compound was performed iteratively without additional structural constraints.

[1823] Molecular dynamics simulations used parameters that included protein geometry and interaction information, excluding GTP ligands present in regions other than the protein site being analyzed. After establishing the system and parameters, the protein and ligand were solvated in TIP3P water and placed in a cubic box with 10 Å padding, and the system was equilibrated with counterions to compensate for charge. Geometry optimization was then performed using a conjugate gradient algorithm for 20,000 cycles (20 ps). Unconstrained equilibration was then performed for 80 ps under periodic boundary conditions at constant temperature and volume (NVT ensemble) using the Particle Mesh Ewald (PME) method, with a PME cutoff distance of 10 Å. In addition, simulations were performed in the unconstrained NPT ensemble for 20 ns, using a rigid TIP3P water model. All molecular dynamics simulations were performed using the SHAKE algorithm with a particle mesh Ewald grid spacing of 1.0. Temperature and pressure were controlled using the Langevin dynamics parameters and the modified Nose-Hoover method. All simulations were performed at 300 K and 1 bar. If reasonable root mean square deviation (RMSD) convergence was not observed within a 20 ns run, an additional 50 ns run was performed. For free ligands in water, a 5 ns NPT simulation was performed instead of the standard 20 ns simulation. Pairwise interaction energies between the ligand and its surroundings were extracted from the simulation trajectories. The average van der Waals (vdW) and electric interaction energies were approximated using a linear interaction energy formalism to derive the Gibbs ligand binding energy.For the approximate Gibbs energy, the electrical interaction energy scaling factor β was set to 0.43. Post-analysis of the simulation trajectories was performed using the MDAnalysis package.

[1824]

[1825] Based on the results of molecular docking and molecular dynamics simulations, it was predicted that the two ligands would likely enter the binding pocket of the LRRK2 protein (PDB ID: 8U8A). When both NRX02104 and NRX02105 entered the binding pocket, the binding affinities were calculated to be -13.79 kcal / mol and -12.63 kcal / mol, respectively. In contrast, under pure structural isomer conditions, both NRX02104 or both NRX02105 ligands bound to the protein with affinities of -12.63 and -10.94 kcal / mol, respectively.

[1826] Molecular docking and molecular dynamics simulations were performed under various ligand binding conditions. Specifically, the cases where a single ligand occupies the binding pocket and the cases where two ligands, representing regioisomeric pure or racemic conditions, are present in the binding pocket were analyzed. Subsequently, the Gibbs free energy profile was constructed using the linear interaction energy approximation. The results predicted that NRX02104 would bind to the preferred site, releasing a free energy of -8.66 kcal / mol. As shown in the contact profile, binding at this site was confirmed to be mainly determined by hydrogen bonding interactions with the Lys1906 residue and hydrophobic interactions with the Phe1890 residue. Subsequently, another NRX02104 bound to the adjacent vacant space, releasing an additional -4.07 kcal / mol, bringing the system to state A in Figure 6, which takes the system from the initial condition to -12.73 kcal / mol. However, the binding of NRX02105 is stronger in the adjacent void space than NRX02104, and the former shifts the system by -13.79 kcal / mol from the initial condition, which is predicted as state B in Figure 6. Therefore, the equilibrium was predicted to be dominated by state B, more specifically, by the form in which both ligands bind to the protein in this structure. On the other hand, under the condition of pure regioisomer of NRX02104, the equilibrium was predicted to be as state A in Figure 6. Similarly, under the condition of pure regioisomer of NRX02105, the equilibrium was predicted to be as state C in Figure 6 with an energy value of -10.94 kcal / mol. Finally, under the racemic condition, some forms such as state D in Figure 6 may appear, and the Gibbs energy was predicted to be more than 1 kcal / mol greater than that of B.

[1827] These computational results are consistent with experimental data showing that the racemic mixture of NRX02104 and NRX02105 exhibits higher affinity for proteins than either of the individual conformational isomers. Furthermore, it is predicted that the racemic mixture is more likely to act as a type I as well as type II kinase inhibitor than the individual conformations.

Claims

1. A compound of the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, are not independently present or are single bonds, X1 to X4 are each independently C or N, R1 and R2 are each independently hydrogen, alkyl, -O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocycloalkyl, -alkyl-aryl or -alkyl-heteroaryl, or R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together, R3 is absent, hydrogen, halo, cyano, alkyl, -alkyl-O-alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R4 is hydrogen, halo, cyano, -NH2, -alkyl, -alkyl-O-alkyl, -O-alkyl, -N(R 4A )(R 4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R 4A Inland R 4D are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl, R5 is hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R6 is absent, hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, The cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with one or more selected from the group consisting of halo, NH2, cyano, haloalkyl, alkyl, alkenyl, alkynyl, -alkynyl-alkyl, -O-alkyl, -alkyl-CN, -alkyl-OH, -alkyl-O-alkyl, -alkyl-NH2, -alkyl-N(alkyl)(alkyl), -alkyl-cycloalkyl, NH2, -N(alkyl)(alkyl), -C(=O)-NH2, -C(=O)-heteroaryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted or unsubstituted with alkyl or -OH, and wherein the alkyl may be substituted or unsubstituted with halo.

2. In paragraph 1, X1 to X4 are each independently C or N, R1 and R2 are each independently hydrogen, -C 1-6 Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-aryl or -C 1-6 Alkyl-heteroaryl, or R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R4 is hydrogen, halo, cyano, -NH2, -C1-6 alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R 4A Inland R 4D are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl, R5 is hydrogen, cyano, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R6 is absent, hydrogen, cyano, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, The above cycloalkyl, heterocycloalkyl, aryl or heteroaryl is halo, NH2, cyano, cycloalkyl, haloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -O-C1-6 alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 which may be substituted with one or more selected from the group consisting of alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, and heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, wherein the -C 1-6 A compound of formula 1, wherein alkyl may be substituted or unsubstituted with halo, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, X1 to X4 are each independently C or N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are 3- to 10-membered heteromonocycloalkyl or 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, A 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together is selected from the group consisting of halo, NH2, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 It may be substituted with one or more selected from the group consisting of alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, and heteroaryl, wherein the heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, wherein the -C 1-6 Alkyl may be substituted or unsubstituted with halo, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl is cyano, -C 1-6 It may be substituted with one or more selected from the group consisting of alkyl and heterocycloalkyl, wherein the -C 1-6 Alkyl may be substituted or unsubstituted with halo, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A Inland R 4C are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R5 is hydrogen, cyano, or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

4. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, R 1A Inland R 1S are each independently hydrogen, halo, NH2, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, -C(=O)-heteroaryl, heterocycloalkyl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl or -OH, and the -C 1-6 Alkyl may be substituted or unsubstituted with halo, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano, R 3A Inland R 3F are each independently hydrogen, cyano, -C 1-6 Alkyl or heterocycloalkyl, where -C 1-6 Alkyl may be substituted or unsubstituted with halo, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A Inland R 4C are each independently hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R5 is hydrogen, cyano, or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

5. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-heterocycloalkyl, or wherein heterocycloalkyl is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH, R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, heterocycloalkyl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl, R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-heteroaryl, wherein said heteroaryl may be substituted or unsubstituted with -OH, R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano, R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl, R 3D is hydrogen, -C 1-6 Alkyl or heterocycloalkyl, where -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, heteroaryl or -aryl-C(=O)-heterocycloalkyl, wherein aryl or heteroaryl may be unsubstituted or substituted with halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl or heteroaryl, wherein said heteroaryl may be substituted or unsubstituted with -C1-6 alkyl, R5 is hydrogen, cyano, or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

6. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH, R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl, R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH, R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano, R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl, R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl, R5 is hydrogen or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

7. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano, R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl, R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl, R5 is hydrogen or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

8. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH, R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl, R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH, R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 alkyl, or , R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 Alkyl, -N(R 4A )(R 4B ), or -NHC(=O)(R 4C ) and, R 4A and R 4B are each independently hydrogen, -C1-6 alkyl, pyrazole or -aryl-C(=O)-morpholine, wherein aryl may be unsubstituted or substituted with -O-C1-6 alkyl, and pyrazole may be unsubstituted or substituted with halo, -C1-6 alkyl, -C1-6 alkyl-CN, or -C1-6 alkyl-OH, R 4C is hydrogen, -C1-6 alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-pyridine, pyrazole or furan, wherein said pyridine, pyrazole or furan may be substituted or unsubstituted with -C1-6 alkyl, R5 is hydrogen or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

9. In paragraph 1, X1 and X4 are each independently C or N, X2 and X3 are N, R1 and R2 are each independently hydrogen or -C 1-6 Alkyl-piperidine, or where piperidine is -C 1-6 It may be substituted or unsubstituted with alkyl, R1 and R2 are a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together, and a 3- to 10-membered heteromonocycloalkyl or a 3- to 10-membered spiro or fused heterobicycloalkyl formed by connecting R1 and R2 together or And, , R 1A and R 1B are each independently hydrogen, cyano, or -C 1-6 Alkyl-OH, R 1C and R 1D are each independently hydrogen, halo, cyano, cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 2-6 alkynyl-C 1-6 Alkyl, -C 1-6 Alkyl-CN, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 Alkyl-cycloalkyl, -C(=O)-NH2, piperidine or isoxazole, wherein said piperidine or isoxazole is -C 1-6 It may be substituted or unsubstituted with alkyl, and the above -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 1E and R 1F are each independently hydrogen, halo, cyano, or -C 1-6 It is alkyl, R 1G and R 1H are each independently hydrogen, -C 1-6 It is alkyl, -C 1-6 Alkyl-NH2, or -C 1-6 Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), R 1I Inland R 1L are each independently hydrogen, halo, NH2 or -C 1-6 It's alkyl R 1M is hydrogen, -C(=O)-NH2, or -C(=O)-pyridine, wherein the pyridine may be substituted or unsubstituted with -OH, R 1N Inland R 1S are each independently hydrogen, halo, or -C 1-6 It is alkyl, R3 is absent, hydrogen, halo, cyano, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, aryl, or and wherein the aryl may be substituted or unsubstituted with cyano, R 3A Inland R 3C are each independently hydrogen, cyano, or -C 1-6 It is alkyl, R 3D is hydrogen, -C 1-6 Alkyl or morpholine, where -C 1-6 Alkyl may be substituted or unsubstituted with halo, R 3E and R 3F are each independently hydrogen or -C 1-6 It is alkyl, R4 is hydrogen, halo, -NH2, -C1-6 alkyl, -OC 1-6 alkyl, or And R5 is hydrogen or -C1-6 alkyl, A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R6 is absent, hydrogen, aryl or heteroaryl.

10. In paragraph 1, a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

11. In paragraph 10, a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

12. In paragraph 10, the following compound or a pharmaceutically acceptable salt thereof:

13. A method for producing a compound described in claim 1 or a pharmaceutically acceptable salt thereof, comprising a step of reacting a compound of the following chemical formula 2 and a compound of the following chemical formula 3: [Chemical Formula 2] [Chemical Formula 3] In the above formula, are not independently present or are single bonds, X1 to X4 are each independently C or N, Y is a halogen, R1 and R2 are each independently hydrogen, alkyl, -O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, -alkyl-heterocycloalkyl, -alkyl-aryl or -alkyl-heteroaryl, or R1 and R2 are heterocycloalkyl formed by connecting R1 and R2 together, R3 is absent, hydrogen, halo, cyano, alkyl, -alkyl-O-alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R4 is hydrogen, halo, cyano, -NH2, -alkyl, -alkyl-O-alkyl, -O-alkyl, -N(R 4A )(R 4B ), -N(R 4D )C(=O)(R 4C ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R 4A Inland R 4D are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, -cycloalkyl-heteroaryl, heteroaryl, aryl or -aryl-C(=O)-heterocycloalkyl, R5 is hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R6 is absent, hydrogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, The cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with one or more selected from the group consisting of halo, NH2, cyano, haloalkyl, alkyl, alkenyl, alkynyl, -alkynyl-alkyl, -O-alkyl, -alkyl-CN, -alkyl-OH, -alkyl-O-alkyl, -alkyl-NH2, -alkyl-N(alkyl)(alkyl), -alkyl-cycloalkyl, NH2, -N(alkyl)(alkyl), -C(=O)-NH2, -C(=O)-heteroaryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted or unsubstituted with alkyl or -OH, and wherein the alkyl may be substituted or unsubstituted with halo.

14. A pharmaceutical composition for preventing or treating a disease mediated by or related to LRRK2, comprising a compound according to paragraph 1 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition according to claim 14, wherein the disease mediated by or related to LRRK2 is Parkinson's disease.