KR101927375B1

KR101927375B1 - Novel heterocyclic compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient

Info

Publication number: KR101927375B1
Application number: KR1020170051186A
Authority: KR
Inventors: 박성준; 허정녕; 김광록; 김성수; 임환정; 이혁; 장성연; 김범태; 윤은영; 임병호
Original assignee: 한국화학연구원
Priority date: 2016-04-20
Filing date: 2017-04-20
Publication date: 2018-12-11
Also published as: WO2017183927A1; KR20170120521A

Abstract

The present invention relates to a novel heterocyclic compound, a process for producing the same, and a pharmaceutical composition for preventing or treating diseases associated with NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) can be inhibited with a concentration of nano-mol units, and the NAE (NEDD8-Activating Enzyme) or SAE Activating enzyme-related diseases, for example, can be useful as pharmaceutical compositions for the prevention or treatment of cancer.

Description

[0001] The present invention relates to a novel heterocyclic compound, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. ingredient}

The present invention relates to a novel heterocyclic compound, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Post-translational modification of proteins by ubiquitin-like molecules (ubl) is an important intracellular regulatory process that plays an important role in regulating many biological processes, including cell division, cell signaling, and immune response. Ubl is a small protein covalently linked to the lysine on the target protein via an isopeptide bond with the C-terminal glycine of ubl. Ubiquitin-like molecules can alter the molecular surface of a target protein and affect properties such as protein-protein interactions, enzyme activity, stability, and intracellular localization of the target.

Ubiquitin and other ubl is activated by a specific E1 enzyme that catalyzes the formation of an acyl-adenylate intermediate with the C-terminal glycine of ubl. The activated ubl molecule is then transferred to the catalytic cysteine residue in the E1 enzyme through the formation of the thioester binding intermediate. The E1-ubl intermediate and E2 are associated to generate thioester exchange, where ubl is delivered to the active site cysteine of E2. Subsequently, ubl is conjugated to the target protein, either directly or with E3 ligase, via isopeptide bond formation with the amino group of the lysine side chain in the target protein.

The biological outcome of the ubl transformation depends on the target. The result of the modification of ubiquitination is the degradation of the poly-ubiquitinated protein by the 26S proteasome. The ubiquitin is expressed through its enzyme cascade containing its ubiquitous E1 activating enzyme, Uba1 (ubiquitin activating enzyme, UAE), the family-derived conjugating enzyme of E2 and the ubiquitin ligase from either the E3 ring or the HECT class Protein.

Currently known, the target specificity is determined by a specific combination of 40 or more E2 proteins and 100 or more E3 proteins, respectively. In addition to ubiquitin, it is believed that there are 10 ubiquitin-like proteins, each of which is activated by a specific E1 activating enzyme and processed through a similar but distinct downlink pathway. UD1 (APPBP1-Uba3), ISG15 (UBE1L), and SUMO family (Aos1-Uba2) are examples of ubl with E1 activating enzymes identified.

Among them, NEDD8 is activated by heterodimeric NEDD8-activating enzyme (APPBP1-Uba3) (NAE) and delivered to a single E2 (Ubc12), eventually ligated to cullin protein. The action of neddylation induces the activation of the culrin-type ubiquitin ligases involved in ubiquitination and consequently changes in cell signaling proteins and many cell cycles, including p27 and I-κB.

Meanwhile, SUMO has an activation mechanism through SAE (SUMO Activating Enzyme) enzyme depending on ATP, SUMO is moved from E1 to the cysteine residue of E2 (SUMO Conjugating Enzyme, Ubc9), SUMO protein is transferred to lysine side chain Through conjugation with an E3 ligase directly to the target protein, and then binding to the target protein through binding of the epsilon amino group to the target protein, SUMO binds to the target protein via binding of SUMO to the target protein Position, function, substrate protein complex formation and stability.

Therefore, since SUMO binding is initiated by SAE enzyme, it can inhibit or regulate cell metabolism, cell regulation, transcription regulation, conservation of genetic information, chromosome fraction, and the like. In particular, since the gene expression and growth regulatory pathways of cancer cells are regulated through SUMO binding, the development of drugs for cancer or tumor treatment targeting SAE enzymes makes it possible to inhibit and kill cancer and tumor cells.

Recently, it has been confirmed that multiple myelopathy and breast cancer are associated with the expression of SAE deformation, and the correlation between SAE inhibition and cancer has been confirmed (Non-Patent Document 1). Thus, SAE enzyme- It has become more apparent that it can be usefully used as a means of treatment. It has also been found that SAE inhibitors can be effective in the treatment of diseases other than tumors and can be used for the treatment of neuropathic diseases, inflammation, viral infections, etc. However, Research and effort are required.

Thus, targeting of E1 activating enzymes provides a unique opportunity to interfere with a variety of biochemical pathways that are crucial to maintaining cell signaling and cell division integrity. The E1 activating enzyme acts in the first step of the ub junction pathway, and the inhibition of the E1 activating enzyme specifically regulates the downward biological consequences of the ubl transformation. The inhibition of this activating enzyme and the consequent suppression of the downward effect of the resulting ubil junctions represent a way of interfering with the integrity of some aspects of cell division, cell signaling and cell physiology important for disease mechanisms. Thus, E1 enzymes such as UAE, NAE and SAE, which are modulators of various cellular actions, are potentially important therapeutic targets for identifying novel approaches to the treatment of diseases and disorders.

An important specific pathway regulated through E1 activating enzyme activity is the ubiquitin-proteasome pathway (UPP), which regulates UPP at different stages in the ubiquitinated cascade. The UAE activates ubiquitin in the first step of the cascade, while NAE activates the coryneform ligase through activation of NEDD8 and ultimately ultimately delivers ubiquitin to specific target proteins.

Thus, the functional UPP pathway described above is required for maintenance of normal cells, and UPP plays a pivotal role in many important regulatory protein changes involved in transcription, cell cycle progression, and apoptosis, both of which are critical for disease states, including tumor cells do. For example, cell proliferation is particularly sensitive to the inhibition of UPP, and the role of the UPP pathway in carcinogenesis is proteasome inhibition, which can be a potential method of chemotherapy. For example, modulation of the UPP pathway from the inhibition of 26S proteasome by VELCADE (bortezomib) has been shown to be an effective treatment in certain cancers, and in the treatment of multiple myeloma and mantle cell lymphoma subjects It has been approved.

Examples of proteins that down-regulate NAE and UAE activity whose levels are regulated by culinic ubiquitin ligase include inhibitors of CDK inhibitors, p27Kip1 and NFkB, IkB. The inhibition of the degradation of p27 is expected to block the cell cycle through the G1 phase and the S phase of the cell cycle, and degradation of IκB may be caused by nuclear localization of NF-κB, transcription of various NF-κB- And to prevent resistance to standard cytotoxic drugs. In addition, NF-κB plays an important role in the expression of several proinflammatory mediators, suggesting the role of the inhibitor in inflammatory diseases.

Moreover, inhibition of UPP through inhibition of NAE and UAE activity may be useful in the treatment of inflammatory diseases including, for example, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis and reperfusion injury; For example, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases including tricyclic cirrhosis; Neuropathic pain; Ischemic diseases such as stroke, infarction, kidney disease; And cachexia. &Lt; / RTI >

Specifically, in the relationship between NAE and cancer disease, inhibition of NEDD8-activating enzyme (NAE) has been shown to induce cancer cell death and inhibit tumor growth in a xenograft model (Non-Patent Document 2 (Patent Document 1). However, the supply of a novel NAE inhibitor has not been so far available and has not yet been approved as a therapeutic agent, There is a constant demand for.

On the other hand, as in the case of NAE described above, it was confirmed that multiple myelopathy, breast cancer and the like were associated with SAE modification expression as a target for SAE, and SAE activity inhibition was correlated with cancer, Lt; RTI ID = 0.0 > proliferative < / RTI > It has also been found that SAE inhibitors can be effective in the treatment of diseases other than tumors and can be used for the treatment of neuropathic diseases, inflammation, viral infections, etc. However, Research and effort are required.

Accordingly, the present inventors have made efforts to develop an effective cancer therapeutic agent from a novel compound exhibiting inhibitory activity against NAE and SAE, and have found that the novel heterocyclic compound according to the present invention inhibits NAE (NEDD8-Activating Enzyme) and SAE (Sumo Activating Enzyme ) Can be excellently inhibited in units of nano-moles, and the cancer cell proliferation can be remarkably inhibited from the inhibition. Thus, the present invention has been completed.

U.S. Patent Application No. 11 / 346,469 (Publication Nos. 2006/0189636 and 7,951,810)

Driscoll et al. Blood. 2010 ;. 115 (14): 2827-2834. T.A. Soucy et al., Nature, 2009, 458, 732-737

It is an object of the present invention to provide a novel heterocyclic compound.

Another object of the present invention is to provide a process for producing the heterocyclic compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases containing the above heterocyclic compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the above heterocyclic compound as an active ingredient.

It is still another object of the present invention to provide a health functional food composition for preventing or ameliorating NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases containing the above heterocyclic compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² are in a -H, -OH, halogen, amine, nitro independently, cyano, a straight or branched C _1-10 alkyl, or C _1-10 straight or branched chain alkoxy group and;

R ³ is selected from -H, -OH, halogen, amine, nitro, cyano, substituted or unsubstituted C _1-10 linear or branched alkyl, substituted or unsubstituted C _1-10 straight or branched alkoxy , Unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 cycloalkyl-C _1-10 alkyl, heterocycloalkyl of unsubstituted or substituted 3 to 10 heterocyclic, unsubstituted or substituted the 3-10 aryl -C _1-10 alkyl, N, O in each ring-heterocycloalkyl -C _1-10 alkyl, aryl unsubstituted or substituted C _6-10, an unsubstituted or substituted C _6-10 and S or an unsubstituted or substituted heteroaryl of 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, S and S, or a 5- to 10-membered heterocyclic ring containing at least one heteroatom selected from the group consisting of N, Unsubstituted or substituted heteroaryl-C _1-10 alkyl,

Wherein the C-C single bond of the substituted alkyl and substituted alkoxy may each independently be substituted with one or more double bonds (C = C) or triple bonds (C = C)

Alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl, and substituted heteroaryl, wherein said alkyl, said substituted alkyl, said substituted alkoxy, said substituted cycloalkyl, substituted heteroaryl-alkyl are each independently selected from _{-OH, -SCF 3, -SF 5,} -SO 2 -C 1-10 alkyl, -NH-SO ₂ -C _1-10 alkyl, -SO ₂ -NH-C _1-10 alkyl, - (C = O) -OC 1-10 alkyl, halogen, amine, nitro, cyano, oxo (oxo), with an unsubstituted or substituted by one or more halogens or one or more -OH-substituted C _{1- 10} linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C _1-10 is substituted C _2-10 carbonyl (alkynyl ), made of a tree of a straight or branched C _1-10 alkylsilyl (trialkylsilyl) aryl-cycloalkyl, C _6-10 of _3-10 C, N, O and S Heteroaryl of 5 to 10 ring heteroatoms containing at least one heteroatom selected from N, O and S, and unsubstituted or substituted heterocycloalkyl of 3 to 8-membered rings containing at least one heteroatom selected from the group consisting of N, O and S Alkyl substituted with one or more substituents selected from the group consisting of alkyl; Phenyl which is unsubstituted or substituted by one or more halogens or heteroaryl of unsubstituted 5- to 6-membered rings containing one or more N can be fused,

Wherein said substituted heterocycloalkyl may be substituted with one or more -OH;

Is unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl of 6-ring containing 1 to 2 N, or pentagonal ring containing at least one heteroatom selected from the group consisting of N, O and S Unsubstituted or substituted heteroaryl,

Here, the substituted phenyl and substituted heteroaryl are independently -H, -OH, a halogen, -BnO, amine, nitro, cyano, alkyl of straight or branched C _1-10, C _1-10 and A straight chain or branched alkoxy group may be substituted; And

X is CH or N;

The present invention also relates to a method for preventing or treating NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases containing the compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition is provided.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for preventing or ameliorating NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases containing the compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutically acceptable salt thereof.

The heterocyclic compound according to the present invention can effectively inhibit NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) at a concentration of nano-mol unit, and can be used as a NAE (NEDD8-Activating Enzyme) or For example, SAE (Sumo Activating Enzyme) -related diseases, for example, as a pharmaceutical composition for preventing or treating cancer.

Hereinafter, the present invention will be described in detail as follows. It is to be understood, however, that the following description is presented to assist the understanding of the present invention, and the scope and spirit of the present invention is not limited to the following description.

[Chemical Formula 1]

In Formula 1,

X is CH or N;

Preferably,

Each of R ¹ and R ² is independently -H, -OH, or halogen.

Preferably,

R ³ is selected from the group consisting of -H, -OH, halogen, amine, nitro, cyano, substituted or unsubstituted C _1-10 straight or branched alkyl, substituted or unsubstituted C _1-10 straight or branched Unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 cycloalkyl-C _1-2 alkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted each ring substituted with 3-9 heterocycloalkyl -C _1-2 alkyl, unsubstituted or substituted C _6-10 aryl of, unsubstituted or substituted C _6-10 aryl -C _1-2 alkyl, N, O And S, unsubstituted or substituted heteroaryl of 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and 5 or more heteroatoms selected from the group consisting of N, O and S and to 10, each ring unsubstituted or substituted heteroaryl, -C _1-2 alkyl,

Alkyl, substituted heterocycloalkyl, substituted heterocycloalkyl-alkyl, substituted aryl, substituted aryl-alkyl, substituted heteroaryl, and substituted heteroaryl, wherein said alkyl, said substituted alkyl, said substituted alkoxy, said substituted cycloalkyl, substituted heteroaryl-alkyl are each independently selected from _{-OH, -SCF 3, -SF 5,} -SO 2 -C 1- 2 alkyl, -NH-SO ₂ -C _1- ₂ alkyl, -SO ₂ -NH-C _1-2 alkyl, - (C = O) with -OC _1-2 alkyl, halogen, amine, nitro, cyano, oxo (oxo), with an unsubstituted or substituted by one or more halogens or one or more -OH-substituted C _{1- 10} linear or branched alkyl, an alkynyl of straight or branched unsubstituted or at least one halogen is alkoxy, unsubstituted or substituted by one or more halogens of the linear or branched substituted C _1-10 is substituted C _2-10 carbonyl (alkynyl ), A straight or branched trialkylsilyl of C _1-10 , a C _3-10 cycloalkyl, a C _6-10 aryl, a group consisting of N, O and S Heteroaryl of 5 to 10 ring heteroatoms containing at least one heteroatom selected from N, O and S, and unsubstituted or substituted heterocycloalkyl of 3 to 8-membered rings containing at least one heteroatom selected from the group consisting of N, O and S Alkyl substituted with one or more substituents selected from the group consisting of alkyl; Phenyl which is unsubstituted or substituted by one or more halogens or heteroaryl of unsubstituted 5- to 6-membered rings containing one or more N can be fused,

Here again, the substituted heterocycloalkyl may be substituted with one or more -OH.

Preferably,

remind

Is unsubstituted phenyl, or -CH _3, -F or hexagonal ring beach comprising a phenyl or a N atom substituted with one or more substituents selected from the group consisting of -BnOr unsubstituted heteroaryl.

More preferably,

R ³ is

,

,

,

,

,

,

,

,

,

or

to be.

Most preferably,

The compound represented by the formula (1) is any one selected from the following group of compounds.

(3-bromobenzyl) -lH-indole-3-carbonyl) pyrimidin-4-yl) amino) - 2,3-dihydrooxycyclopentyl) methyl sulfamate;

(2R, 3R, 4R) -4 - ((5- (1- (3-bromobenzyl) -1 H- indazole-3-carbonyl) pyrimidin- -2,3-dihydroxycyclopentyl) methyl sulfamate;

(3-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydro Lt; / RTI > cyclopentyl) methyl sulfamate;

(4-chlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl sulfamate;

(5) (1- (3-fluorobenzyl) -1 H-indole-3-carbonyl) pyrimidin-4-yl) amino) - 2,3-dihydroxycyclopentyl) methyl sulfamate;

(6) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3- (trifluoromethyl) benzyl) ) Pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;

(7) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3-methoxybenzyl) -lH-indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;

(8) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-Chloro-4-fluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(9) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2,5- dichlorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- -2,3-dihydroxycyclopentyl) methyl sulfamate;

(10) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3,4- difluorobenzyl) -1 H- indole- 3-carbonyl) pyrimidin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(11) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2,4- difluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(12) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3-fluorobenzyl) 4-yl) amino) cyclopentyl) methyl sulfamate;

(13) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-cyanobenzyl) -1 H- indole-3-carbonyl) pyrimidin- 2,3-dihydroxycyclopentyl) methyl sulfamate;

(14) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2-fluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- 2,3-dihydroxycyclopentyl) methyl sulfamate;

(15) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3,5- bis (trifluoromethyl) benzyl) -1 H- indole- 3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(16) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((trifluoromethyl) thio) benzyl) -1 H- indole- 3-carbonyl) pyrimidin- -Yl) amino) cyclopentyl) methyl sulfamate;

(17) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (1, 1'- biphenyl) -4-ylmethyl) -1 H- indole-3-carbonyl) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(18) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- -Carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;

(19) ((1R, 2R, 3S, 4R) -2,3-Dihydroxy-4 - ((5- (1- (5- (trifluoromethyl) furan- 1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;

(20) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (5-methylisooxazol- 3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;

(21) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-bromobenzyl) ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(22) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-bromobenzyl) -5-fluoro-1H-indole-3-carbonyl) pyrimidin- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(23) ((1R, 2R, 3S, 4R) -4 - ((5- (5- (Benzyloxy) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(24) (lR, 2R, 3S, 4R) -4 - ((5- (l- (3- bromobenzyl) - lH- pyrrolo [2,3- b] pyridine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(25) Synthesis of methyl 3 - ((3- (4 - ((1R, 2S, 3R, 4R) -2,3-dihydroxy- 4- ((sulfamoyloxy) methyl) cyclopentyl) amino) pyrimidine -5-carbonyl) -5-fluoro-1 H-indol-1-yl) methyl) benzoate;

(26) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (naphthalen- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(27) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- 1- (3- methylbenzyl) -1 H- indole- 3- carbonyl) pyridin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(28) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(29) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (4-fluoro-3-methoxybenzyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(30) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

Amino) -2-hydrocyclo-pentyl) methyl (2-methylpiperazin-1 -yl) Sulfamate;

(32) ((1R, 2R, 3R, 4R) -4 - ((5- (l- benzyl- lH- indole- 3-carbonyl) pyrimidin- 4- yl) amino) -Hydrocyclopentyl) methyl sulfamate;

(33) ((1R, 2R, 3S, 4R) -4 - ((5- (1- ) -2,3-dihydrocyclopentyl) methyl sulfamate;

(34) ((1R, 2R, 3S, 4S) -4 - ((5- (1- -Yl) amino) -2,3-dihydrocyclopentyl) methyl sulfamate;

(35) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (2-methoxyethyl) -1 H- indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;

(36) ((1R, 2R, 3S, 4S) -2,3-dihydroxy- Amino) cyclopentyl) methyl sulfamate;

(37) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (cyclohexylmethyl) -1 H- indole- 3-carbonyl) pyrimidin- 3-dihydroxycyclopentyl) methyl sulfamate;

(38-) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (morpholinoethyl) -1 H- indole- 3-carbonyl) pyrimidin- -Yl) amino) cyclopentyl) methyl sulfamate;

(39) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3- morpholinobenzyl) -lH-indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;

(40) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (1- (1H-pyrazol-1-yl) pyridin- -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(41) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (6- (Bromobenzofuran-3- yl) methyl) -5- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(42) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(43) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (3- (methylsulfonamido) benzyl) -1 H- indole-3-carbonyl) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;

(44) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (4- (N-methylsulfamoyl) benzyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate; And

(45) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- Carbonyl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclopentyl) methyl sulfamate.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

The present invention also relates to a process for preparing a compound represented by the following formula 1,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2);

Preparing a compound represented by the formula (7) from the compound represented by the formula (6) prepared in the step (2) (step 3);

Reacting the compound represented by the formula (7) prepared in the step 3 with a compound represented by the formula (8) to prepare a compound represented by the formula (9) (step 4);

Reacting a compound represented by the formula (9) prepared in the step 4 with a compound represented by the formula (10) to prepare a compound represented by the formula (11) (step 5); And

A step of preparing a compound represented by the general formula (1) from the compound represented by the general formula (11) prepared in the step (5); and a process for producing the compound represented by the general formula (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ ,

And X is as defined in Formula 1 above; And

The PT is -Boc.

Hereinafter, the method for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing a compound represented by the general formula (1) of the present invention, the step (1) is a step of reacting a compound represented by the general formula (2) with a compound represented by the general formula to be.

The solvent used in this step may be dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Amide (DMF) can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at a boiling point of the solvent at -10 to 10 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours , Step 1 is most preferably carried out in the same manner as in step 1 of Example 1, which is not limited to the production method of the present invention.

In the process for preparing a compound represented by the general formula (1) according to the present invention, in the above step 2, the compound represented by the general formula (4) and the compound represented by the general formula (5) Is prepared.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at a boiling point of the solvent at -10 to 10 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours , But the step 2 is most preferably carried out in the same manner as in the step 2 of Example 1, which is not limited to the production method of the present invention.

In the method for preparing the compound represented by the formula (1) of the reaction formula 1 according to the present invention, the above step 3 is a step for preparing the compound represented by the formula (7) from the compound represented by the formula (6) prepared in the above step 2.

The solvent used in this step may be dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours, , But step 2 may most preferably be carried out as in step 3 of Example 1, below.

In the process for preparing a compound represented by the general formula (1) according to the present invention, in the above step 4, the compound represented by the general formula (7) and the compound represented by the general formula (8) Is prepared.

At this time, the solvent which can be used in the above step may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, t-BuOH, n-BuOH, tetrahydrofuran, Methylene chloride, toluene, acetonitrile and the like can be used, and n-butanol (n-BuOH) can be preferably used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 90 to 120 ° C., and the reaction time is not particularly limited, but it is preferable to carry out the reaction for 0.5 to 20 hours, , But step 2 may most preferably be carried out as in step 4 of Example 1, below.

In step (5), the compound represented by formula (9) and the compound represented by formula (10) prepared in step (4) are reacted to produce a compound represented by formula (11) Is prepared.

The solvent used in this step may be dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Amides can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited. However, the reaction is preferably carried out for 0.5 to 40 hours, , But step 2 may be most preferably carried out as in step 5 of Example 1, below.

In step (6), the compound of formula (1) is prepared from the compound of formula (11) prepared in step (5).

The solvent used in this step may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Furan can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours, , Step 2 is most preferably carried out as in step 6 of Example 1, below.

Further, the present invention relates to a process for the preparation of

Preparing a compound represented by the formula (4 ') from the compound represented by the formula (2) (step 1);

Reacting the compound represented by the formula (4 ') and the compound represented by the formula (5) prepared in the step (1) to prepare a compound represented by the formula (6') (step 2);

Preparing a compound represented by the formula (7 ') from the compound represented by the formula (6') prepared in the step (2) (step 3);

Reacting a compound represented by the formula (7 ') prepared in the above step 3 with a compound represented by the formula (8) to prepare a compound represented by the formula (9') (step 4);

Preparing a compound represented by the formula (12) from the compound represented by the formula (9 ') prepared in the step (4) (step 5);

Preparing a compound represented by the formula (13) from the compound represented by the formula (12) prepared in the step 5 (step 6);

Reacting the compound represented by the formula (13) prepared in the step 6 with a compound represented by the formula (3) to prepare a compound represented by the formula (14) (step 7); And

A step of preparing a compound represented by the formula (1) from the compound represented by the formula (14) prepared in the step (7).

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ , R ² , R ³ ,

And X are as defined in Chemical Formula 1 of claim 1; And

The PT, PT ¹ and PT ² are each independently a protecting group.

Hereinafter, the process for preparing the compound represented by the formula (1) of the reaction scheme 2 according to the present invention will be described in detail.

In the process for preparing a compound represented by the general formula (1) of the reaction formula (2) according to the present invention, the above step (1) is a step for preparing a compound represented by the general formula (4 ') from the compound represented by the general formula (2).

In this case, Step 1 of Scheme 2 can be understood as a step of introducing a protecting group (-PT ¹ ) to the N-position of the compound.

Here, the protecting group (-PT ¹ ) introduced is not particularly limited, but is preferably -Boc as long as it does not interfere with performing the method of the present invention. The protecting group (-PT ¹ ) of Step 1 is included in the present invention as long as it can be easily modified or modified by a person skilled in the art, that is, it does not hinder the performance of the production method. The protecting group introduced in Step 1 is subsequently removed in Step 6 of Scheme 2 and the step of introducing a substituent of -R ³ to the N-position in Step 7. In Reaction Scheme 1, a substituent of -R ³ is directly introduced at the N-position without introducing a protecting group, which is different from Reaction Scheme 2. This can be changed or modified according to the desired yield depending on the desired yield Indicates that the compound represented by formula (1) of the present invention can be prepared. Accordingly, it will be appreciated that those skilled in the art can easily modify or modify the respective steps of the reaction schemes 1 and 2 described above and the preparation methods of the following example compounds in consideration of the conditions such as target compounds and yield I can understand. Therefore, it should be understood that any method that can produce the compound represented by the formula (1) proposed by the present invention is included in the present invention even if it can be changed or modified.

Meanwhile, in carrying out Step 1 of Scheme 2, the compound represented by Formula 2, (Boc) ₂ O, DMAP, and TEA may be reacted in DMF in one embodiment.

The solvent used in step 1 of Scheme 2 is preferably DMF, but the solvents that can be used in the above step include dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF ), Methylene chloride, toluene, acetonitrile and the like can be used.

Although there is no particular restriction on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but it is preferable to carry out the reaction for 0.5 to 20 hours.

In Step 2, the compound represented by Formula 4 'prepared in Step 1 is reacted with the compound represented by Formula 5 to obtain a compound represented by Formula 6' in Reaction Formula 2 according to the present invention. Is prepared.

The solvent used in this step may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Furan (THF) can be used.

Although there is no particular limitation on the reaction temperature in the above step, the reaction can be carried out preferably at a temperature of -80 to 10 ° C. The reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours. For example, by reacting a compound represented by formula (4 '), n-BuLi, and a compound represented by formula (5) in THF.

In the method for preparing the compound represented by the formula (1) of the reaction formula 2 according to the present invention, the above step 3 is a step for preparing the compound represented by the formula (7 ') from the compound represented by the formula (6') prepared in the above step (2).

At this time, this step can be understood as an oxidation step, and any oxidation step in which the compound represented by the formula (7 ') is prepared is included in the production method of the present invention without limitation.

The solvent used in the above step may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, methylene chloride toluene, acetonitrile, Methylene chloride can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours, , But the step 2 may be carried out, for example, by reacting the compound represented by the formula 6 ', MnO ₂ with methylene chloride.

In step 4, the compound represented by formula (7 ') and the compound represented by formula (8) are reacted to produce a compound represented by formula (9) according to the present invention, Is a step of preparing a compound represented by the formula

In this case, the -O-PT group of the compound represented by the general formula (8 ') may be protected with a separate protecting group when one of R 1 and R 2 is -OH group or a substituent to which a protecting group can be introduced, The -PT group of the -O-PT group may be a protecting group simultaneously protecting one substituent of R1 and R2. For example, when one of R1 and R2 is an -OH group, the PT (protecting group) may be a protecting group protected by only one PT (protecting group), such as -O-PT-O-.

The solvent used in the above step may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, t-BuOH, n-BuOH, tetrahydrofuran, Methylene chloride, toluene, acetonitrile and the like can be used, and n-butanol (n-BuOH) can be preferably used.

Although there is no particular restriction on the reaction temperature in the above step, it is preferable to carry out the reaction at a temperature of 50 to 120 ° C, and the reaction time is not particularly limited. However, the reaction is preferably performed for 0.5 to 20 hours, For example, by reacting a compound represented by the formula (7 '), a compound represented by the formula (8), and DIPEA in n-butanol.

In step (5), the compound represented by formula (12) is prepared from the compound represented by formula (9 ') prepared in step (4) in the process for preparing the compound represented by formula (1) according to the present invention.

In this case, the step can be understood by introducing a protecting group (-PT ²⁾ -OH groups of the cyclopentyl portion -CH ₂ -OH, wherein, the protecting group (-PT ^2), but can be used without particular limitation, for example Lt; / RTI > may be TBS (tert-butyldimethylsilyl). In addition, a protecting group equivalent to this can be used, and a compound represented by the formula (12) can be prepared. If the protecting group is a range that does not hinder the final production of the compound represented by the formula (1) .

The solvent used in step 5 may include dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Chloride can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited. However, the reaction is preferably carried out for 0.5 to 40 hours, For example, by reacting a compound represented by the formula (9 '), TBSCl, and imidazole in methylene chloride.

In step (6), the compound represented by formula (13) is prepared from the compound represented by formula (12) prepared in step (5).

In this case, step 6 may be understood as a step of removing the protective group (PT ¹ ) of the indole N-position introduced in step 1 above.

The solvent used in this step may be dimethylformamide (DMF), H ₂ O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene or acetonitrile Isopropanol can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 50 to 90 ° C, and the reaction time is not particularly limited. However, the reaction is preferably carried out for 0.5 to 20 hours, For example, by reacting a compound represented by the general formula (12), K ₃ PO ₄ in isopropanol.

In step (7), the compound represented by formula (13) prepared in step (6) is reacted with a compound represented by formula (3) to obtain a compound represented by formula (14) &Lt; / RTI > compound.

In this case, step 7 can be understood as a step of introducing a -R ³ substituent and can be understood to be carried out in the same manner as in step 1 of the above reaction scheme 1.

Examples of the solvent that can be used in the above step include dimethylformamide (DMF), H ₂ O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile DMF can be used.

Although there is no particular limitation on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 20 hours, For example, by reacting a compound represented by the formula (13), a compound represented by the formula (3), and Cs ₂ CO ₃ in DMF.

In step (8), the compound represented by formula (1) is prepared from the compound represented by formula (14) prepared in step (7).

At this time, the step 8 is a step of removing all the protecting groups of the cyclopropyl moiety. Especially, the substitution of -O-SO ₂ -NH ₂ is introduced by introducing NH ₂ SO ₂ Cl into the -OH moiety at the portion protected with TBS. .

The solvent used in the above step is not particularly limited, but DMF is preferably used. DMF, H ₂ O, methanol, ethanol, propanol, isopropanol, tetrahydrofuran (THF), methylene chloride, Toluene, acetonitrile and the like can be used.

Although there is no particular restriction on the reaction temperature in the above step, it is preferable to carry out the reaction at 0 to 30 ° C, and the reaction time is not particularly limited, but it is preferable to carry out the reaction over 0.5 to 20 hours or 1 to 3 days For example, the step 8 can be carried out in three steps. First, the compound represented by the formula (14), TASF, is reacted in DMF, and then NH ₂ SO ₂ Cl in DMF, overnight or overnight, and finally reacting with TfOH: H ₂ O (9: 1) in methanol overnight.

Further, as described in the above Reaction Formula 1 and Reaction Formula 2, the above-described production process of the present invention can be carried out by modifying or modifying each step, such as by taking each step in consideration of the desired compound, It will be readily understood that included in the present invention are those that can be changed or modified in the manufacturing method of the invention.

Accordingly, it should be understood by those skilled in the art that the preparation methods described herein are to be understood as a preferred embodiment, and that the compounds of the present invention can be prepared by conducting the following examples as preferred embodiments thereof. You will understand.

Herein, the disease associated with NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) has been correlated with NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) For example, NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related diseases are cancer, inflammatory, cardiovascular disease, neurological diseases, Neurodegenerative diseases, and the like.

The cancer may be selected from the group consisting of a cancer selected from the group consisting of a cancer selected from the group consisting of a caudal myxoma, an intrahepatic bile duct cancer, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a glioblastoma, a oral cancer, a larynx cancer, a bacterial sarcoma, an acute lymphocytic leukemia, Cholangiocarcinoma, cholangiocarcinoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Barter's bulge, ovarian cancer, ovarian cancer, ovarian cancer cell, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, Cancer, bladder cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Malignant melanoma, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovarian cancer, vulvar cancer, ureter cancer, urethral cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, Cancer of the uterus, uterine cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, uterine cancer, breast cancer, sarcoma, penile cancer, Cancer of the lungs, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, neuroendocrine tumor, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, Skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma.

Preferably, the cancer is at least one selected from breast cancer, colon cancer, colon cancer, lung cancer, prostate cancer, esophageal cancer, bladder cancer, and head and neck cancer.

Furthermore, preferably said cancer is acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML); Acute lymphocytic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Valgendrogmaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocytic lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And bone marrow proliferative syndrome.

Herein, NAE-related diseases include, but are not limited to, all diseases that can be manifested from a non-normal activity such as abnormality, deformation, overexpression of NAE, and the like. Particularly, an example of NAE-related diseases is cancer. The compounds of the present invention, its stereoisomers and acceptable salts thereof, when caused by abnormal activity of NAE in association with cell proliferation of cancer cells, Moles, and can be effectively used for improving, preventing or treating diseases mentioned above as NAE-related diseases.

Here, the compound, its stereoisomer or pharmaceutically acceptable salt thereof may be characterized by inhibiting NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) to prevent or treat cancer, Myelodysplastic syndrome, glioblastoma, oral cancer, oral cancer, mycotic sarcoma, acute myelogenous leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian cancer, ovarian cancer, Cholangiocarcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, bladder cancer, bladder cancer, ovarian cancer, ovarian cancer cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, , Peritoneal cancer, pituitary cancer, adrenal cancer, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, Neuroblastoma, neuroblastoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovarian cancer, vulvar cancer, ureter Cancer, uterine cancer, primary undetermined cancer, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, pregnancy cannabis disease, cervical cancer, endometrial cancer, uterine sarcoma, Cancer, metastatic cancer, metastatic brain cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, neuroendocrine cancer, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, Squamous cell carcinoma, squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma.

As used herein, the term " cancer " is used to establish unregulated or aberrantly regulated cell proliferation, reduced cellular differentiation, impaired ability to invade surrounding tissues, and / &Lt; RTI ID = 0.0 > and / or < / RTI > The term " cancer " includes, but is not limited to, solid tumors and blood mediated tumors (hematologic malignant tumors). The term " cancer " includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term " cancer " further includes primary and metastatic cancers.

The solid tumor may be pancreatic cancer; Invasive bladder cancer containing bladder cancer; Colorectal cancer; Breast cancer including thyroid cancer, stomach cancer, metastatic breast cancer; Prostate cancer, including androgen-dependent and androgen-independent prostate cancer; Kidney cancer, including, for example, metastatic renal cell carcinoma; Liver cancer including hepatocellular carcinoma and intrahepatic bile duct; Lung and bronchial carcinoma, including non-small cell lung cancer (NSCLC), squamous cell lung cancer, bronchoalveolar alveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); Ovarian cancer, including, for example, advanced epithelial or primary peritoneal cancer; Cervical cancer; For example, uterine cancer including uterine body and cervix; Endometrial cancer; Gastric cancer; Esophagus cancer; For example, head and neck cancer including squamous cell carcinoma of the head and neck, nasopharyngeal cancer, oral cavity and pharynx; Melanoma; Neuroendocrine carcinoma, including metastatic neuroendocrine tumors; For example, brain tumors including glioma / glioblastomas, inverse dysplastic glomerulonephrosis, adult glioblastoma multiforme, and adult retroformed astrocytoma; Metastatic neuroendocrine tumors; Bone cancer; And neuroendocrine involvement including soft tissue sarcoma.

The hematological malignancies include acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML), including accelerated CML and CML aspirate (CML-BP); Acute lymphocytic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma (including diffuse large B-cell lymphoma (DLBCL)); T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Valgendrogmaglobulinemia; (Including anemia of intractable anemia (RAE), hyperammonemia (RAEB), and transformation with accompanying RAEB (RAEB-T)) with mastitis formation syndrome (MDS) ; Small lymphocytic lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome.

Herein, the disease associated with NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) includes cancer, inflammatory, cardiovascular disease, neurodegenerative diseases, etc. And preferably cancer.

On the other hand, the cancer can be diagnosed as a malignant myxoma, intrahepatic bile duct cancer, hepatoblastoma, hepatoma, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cancer, bacterial sarcoma, acute lymphoblastic leukemia, The present invention relates to a method of treating a cancer selected from the group consisting of cancer, ovarian cancer, ovarian cancer, ovarian cancer cell line, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Papillary carcinoma, papillary cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, stomach cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Neuroblastoma, neuroblastoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, ureter cancer Cancer, uterine cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic breast cancer, breast cancer, sarcoma, penile cancer, pancreatic cancer, uterine cancer, uterine cancer, endometrial cancer, uterine cancer, Cancer of the lungs, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acne vulgaris, pancreatic cancer, salivary gland cancer, Kaposi sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, Cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma.

In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof may be administered orally or parenterally in various formulations at the time of clinical administration. May be prepared by using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, etc. which are usually used.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition containing the compound represented by Formula 1 as an active ingredient can be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

Examples of formulations are as follows.

&Lt; Formulation Example 1 > Preparation of powders

The derivative represented by the formula (1): 2 g

Lactose: 1 g

The above components were mixed and packed in airtight bags to prepare powders.

&Lt; Formulation Example 2 > Preparation of tablet

A derivative represented by the formula (1): 100 mg

Corn starch: 100 mg

Lactose: 100 mg

Magnesium stearate: 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; Formulation Example 3 > Preparation of capsules

A derivative represented by the formula (1): 100 mg

Corn starch: 100 mg

Lactose: 100 mg

Magnesium stearate: 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

&Lt; Formulation Example 4 > Preparation of injection

A derivative represented by the formula (1): 100 mg

Mannitol: 180 mg

Na ₂ HPO ₄ .2H ₂ O: 26 mg

Distilled water: 2974 mg

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

It should be understood by those skilled in the art that the formulations described above are only for the ordinary formulation examples, and that the formulations of the present invention are not limited thereto.

Further, the dose of the compound of the present invention represented by the formula (1) or a pharmaceutically acceptable salt thereof of the present invention to the human body may be varied depending on the age, weight, sex, dosage form, health condition and disease severity of the subject, The dosage is generally 0.1-1000 mg / day, preferably 1-500 mg / day, based on an adult subject of 70 kg, and may be divided once or several times a day at regular intervals according to the judgment of a doctor or pharmacist .

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of diseases caused by the urotensin-II receptor and its activity have.

Furthermore, the present invention relates to a method for the treatment of NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) comprising the step of administering to said subject a therapeutically effective amount of said compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ) Associated diseases.

At this time, the NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) -related disease is prevented or prevented from inhibiting NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) Refers to a disease that can be treated, and is preferably cancer. Further, the arm includes all of the arms as described above.

The therapeutically effective amount refers to an amount sufficient to improve the symptoms or the condition of the subject when administered into the body, depending on the administration method. In addition, the amount may vary depending on the body weight, age, sex, condition, and family history of the subject to be administered. In the present invention, the treatment method can set different doses depending on different conditions.

The " effective amount " is an amount effective to treat proliferative, inflammatory, infectious, neurological, or cardiovascular disorders, or an amount effective to treat cancer. In another embodiment, an " effective amount " of the compound is an amount that inhibits the binding of NAE or SAE.

The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective in treating the disease. The exact amount required will vary by subject depending upon the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression " dosage unit form " means a physically discrete unit of formulation suitable for the subject to be treated, as used herein. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors including:

The severity of the disease and disorder to be treated; The activity of the specific compound employed; Specific composition; Age, weight, general health, gender and diet of the subject; The time of administration, the route of administration, and the rate of excretion of the particular compound employed; Duration of treatment; Drugs used in conjunction with or concurrently with the particular compound employed, and factors well known in the medical arts, for example.

The term " subject ", as used herein, means an animal, such as a mammal, such as a human.

The pharmaceutical compositions of the present invention can be administered orally, rectally, parenterally, intracavally, intravaginally, intraperitoneally, topically (including powders, ointments, lotions, ointments, or drops) to humans and other animals, depending on the severity of the infection to be treated , By mouth, by oral or nasal spray, and the like. In certain embodiments, a compound of the invention is administered in an amount of from about 0.01 mg / kg to about 50 mg / kg, such as from about 1 mg / kg to about 25 mg / kg body weight of a subject, / Day < / RTI > at a dosage level of < RTI ID = 0.0 >

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents of the following examples commonly used in the art: water or other solvents, solubilizing agents, and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example cottonseed, peanut, corn, germ, olive, castor, and pine oil), glycerol, Fatty acid esters of furfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or lipid productive suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterilized, fixed oils are conventionally used as a solvent or dispersion medium. For this purpose, any blend stationary oil may be utilized, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by incorporation of the active agent in the form of sterile solid compositions that are filtered or dissolved prior to use in a sterile water or other sterile injectable medium prior to use, have.

In order to sustain the effect of the compounds of the invention, slow absorption of the compound from subcutaneous or intramuscular injection is often desired. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound depends on the crystal size and its dissolution rate which may depend on the crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. The injectable depot form is made by forming a microencapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal administration are, for example, suppositories which may be prepared by admixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycols or suppository waxes, But is liquid at body temperature and therefore melts in the rectum or in the vagina to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such a solid dosage form, the active compound is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) filler or extenders such as starch, lactose Such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as sucrose, glucose, mannitol and silicic acid, E) a solution retarder such as paraffin, f) an absorption accelerator such as a quaternary ammonium compound, g) a wetting agent such as, for example, a wetting agent such as, for example, an agar-agar, a dextrose or tapioca starch, an alginic acid, C) c) an absorbent such as kaolin and bentonite clay, and i) a lubricant, for example, cetyl alcohol and glycerol monostearate, For talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like. Tablets, dragees, capsules, pellets, and granules in solid dosage form can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation arts. May optionally contain opacifying agents and may also be a composition that releases only the active ingredient (s), e.g., in a particular part of the intestinal tract, optionally in a delayed manner. Examples of embolic compositions that may be used include polymeric substrons and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more excipients and one or more excipients as described above. Tablets, dragees, capsules, pellets, and granules in solid dosage forms may be prepared with coatings and shells such as enteric coatings, release modifying coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain additional substances other than inert diluents, such as tabletting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as in normal practice. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. May optionally contain opacifying agents and may also be a composition that releases only the active ingredient (s), e.g., in a particular part of the intestinal tract, optionally in a delayed manner. Examples of embolic compositions that may be used include polymeric substrons and waxes.

The topical or transdermal dosage forms of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with the pharmaceutically acceptable carrier and any necessary preservatives or buffers under sterile conditions, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches with the added benefit of providing controlled cleavage of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The speed can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

In some embodiments, a compound of the invention or a pharmaceutical composition thereof is administered with an anti-cancer agent. As used herein, the term " anti-cancer agent " refers to any agent that is administered to a subject having cancer to treat cancer. Combination therapy includes administration of a therapeutic agent either concurrently or sequentially. Alternatively, the therapeutic agent can be combined into one composition to be administered to a subject.

In one embodiment, the compounds of the invention are used in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is selected from other SAE inhibitors. In another embodiment, a compound of the invention is administered with a therapeutic agent selected from the group consisting of a cytotoxic drug, radiation therapy, and immunotherapy. In some embodiments, the compounds of the invention may be used in conjunction with chemotherapeutic regimens for the treatment of relapsed / challenged non-Hodgkin lymphoma, including DLBCL and CLL. Chemotherapeutic regimens include, but are not limited to, the following: R-ICE (rituximab, ifosfamide, carboplatin and etoposide), R-DHAP (rituximab, dexamethasone, Rabbin and cisplatin), and R-GDP (rituximab, gemcitabine, cisplatin and dexamethasone). It is understood that other combinations can be embodied within the scope of the present invention.

Additional agents may be administered separately from the concomitant therapy provided as part of a multiple dose regimen. Alternatively, formulations may be part of a single dosage form mixed with a compound of the present invention. If administered as part of a combination therapy, the two therapeutic agents may be administered simultaneously, sequentially, or intermittently. Combination therapies may be used for any of the therapeutic indications described herein. In some embodiments, the combination therapy is for treating a proliferative disorder (e.g., cancer) in the subject. In some embodiments, the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myelogenous leukemia or acute lymphoblastic leukemia.

Another aspect of the present invention relates to inhibiting SAE activity in a biological sample or a subject comprising administering a compound represented by formula 1 or a composition comprising said compound or contacting said biological sample with said compound . The term " biological sample ", as used herein, generally encompasses in vivo, in vitro, and in vitro materials, and also includes, but is not limited to, cell cultures or extracts thereof; A biopsied material obtained from a mammal or an extract thereof; And includes blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Yet another aspect of the present invention is to provide a kit comprising a separate container in a single package, wherein the compound or pharmaceutical composition and / or its salts disclosed herein are useful for the treatment of one or more disorders in which SAE plays a role, And one or more pharmaceutically acceptable carriers for use in the treatment of diseases.

The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to the present invention inhibits the activity of NAE (NEDD8-Activating Enzyme) or SAE (Sumo Activating Enzyme) and inhibits NAE (NEDD8-Activating Enzyme) or SAE Activating Enzyme-Related Disease, the present invention has been confirmed through experiments.

Experiments were conducted on human breast cancer cells (HCT-116, THP-1) purchased from ATCC in order to evaluate inhibition of cancer cell growth of the heterocyclic compound according to the present invention. As a result, -45 compound was found to inhibit cancer cell growth with excellent micromolar or nanomolar unit concentration against human breast cancer cells (HCT-116, THP-1), and thus the heterocyclic compound according to the present invention inhibits cancer Or as an active ingredient of a pharmaceutical composition for treatment (see Experimental Example 1).

As a result of conducting an experiment to evaluate the inhibitory activity of the heterocyclic compound according to the present invention on SAE and NAE, the compounds of Examples 1-45 according to the present invention were found to have excellent SAE And NAE, and it was confirmed that it can be effectively used as a pharmaceutical composition for prevention and treatment of cancer containing the same (see Experimental Example 2 and Experimental Example 3).

Hereinafter, the present invention has been described in detail by way of examples and experimental examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Example 1> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydrooxycyclopentyl) methyl sulfamate

Step 1: Synthesis of l- (2-bromobenzyl) -lH-indole-3-carbaldehyde

3-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous DMF (2 ml), and then the solution was cooled to 5 캜 with ice water under nitrogen gas, Cs ₂ CO ₃ (1.1 g, 3.4 mmol). 3-Bromobenzyl bromide (2.1 g, 8.6 mmol) was slowly added dropwise at the same temperature, followed by stirring at room temperature for 2 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: n-hexane = 1: 5) to obtain a white solid (1.0 g, 94%).

^{1 H NMR (300 MHz, CDCl} 3) δ 9.89 (s, 1H), 8.26-8.29 (m, 1H), 7.66 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.22-7.28 ( m, 3H), 7.07-7.17 (m, 1H), 6.99 (d, J = 7.4 Hz, 1H), 5.20 (s, 2H).

Step 2: (1- (3- Bromobenzyl ) -LH-indol-3-yl) (4- Chloropyrimidine -5-yl) methanol

4-Chloro-5-iodopyrimidine (1.27 mmol, 306 mg) was added to a 50 ml two-necked round bottom flask, dissolved in THF (2.0 ml) and stirred at -78 ° C. Add n-BuLi (1.6 mmol, 0.64 ml) dropwise and react for 30 minutes. L- (2-bromobenzyl) -1H-indole-3-carbaldehyde (0.8 mmol, 250 mg) dissolved in THF (3.0 ml) was added slowly and reacted at 0 ° C for 2 hours. After completion of the reaction, the reaction mixture was quenched using saturated NH ₄ Cl, extracted with EA / H ₂ O, and dried using MgSO ₄ . The product was separated and purified by silica gel column chromatography under 30% EA / Hex to obtain a yellow solid (204.4 mg, 60%).

^{1 H NMR (300 MHz, CDCl} 3) δ 9.15 (s, 1H), 8.92 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.24 (M, 3H), 6.95 (d, J = 6.1 Hz, 2H), 6.40 (s, 1H), 5.24 (s, 2H).

Step 3: (1- (3- Bromobenzyl ) -LH-indol-3-yl) (4- Chloropyrimidine -5 days) Methanone Produce

In 20ml vial (1- (3-Bromo-benzyl) -1H- indol-3-yl) (4-Chloro-5-yl) methanol (0.47 mmol, 200 mg), MnO 2 (4.7 mmol, 404.7 mg ) And CH ₂ Cl ₂ (5.0 ml) were added and reacted at room temperature for 12 hours. After completion of the reaction, the reaction solution was filtered with celite, washed several times with MC, and then concentrated. The product was separated and purified by silica gel column chromatography under 30% EA / Hex to obtain a yellow solid (124.1 mg, 62%).

^{1 H NMR (300 MHz, CDCl} 3) δ 9.10 (s, 1H), 8.78 (s, 1H), 8.40 (d, 1H, J = 7.0 Hz), 7.48-7.29 (m, 6H), 7.20 (t, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.7 Hz), 5.32 (s, 2H).

Step 4: (4- ((3aR, 4R, 6R, 6aS) -6- (hydroxymethyl-2,2-dimethyltetra Dihydro-4H- cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrimidin-5-yl) methanone

(3aS, 4R, 6R, 6aR) -7-methoxy-7- (l- (3- bromobenzyl) D] [1,3] dioxol-4-yl) methanol (23 mg, 0.12 mmol) was dissolved in anhydrous n-BuOH (0.5 ml) , And DIPEA (0.04 ml, 0.2 mmol) was added dropwise. The reaction mixture was stirred at 105 < 0 > C for 2.5 hours. After completion of the reaction was confirmed by TLC, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: n-hexane = 1: 1) to obtain a white solid (41 mg, 70%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.96 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 2.9 Hz, 2H), 8.23-8.27 (m, 1H), 7.61 (s, 1H) , 7.41-7.44 (m, 1 H), 7.29-7.33 (m, 4H), 7.18 (t, J = 7.8 Hz, 1 H), 7.02 (d, J = 7.7 Hz, (Dd, J = 6.2, 2.5 Hz, 1H), 4.55 (dd, J = 6.2, 2.3 Hz, 1H), 3.82 , 3.74 (dd, J = 10.2, 5.5 Hz, IH), 2.54-2.64 (m, IH), 2.40-2.44 (m, IH), 1.61-1.69 (s, 3 H).

Step 5: ((3aS, 4R, 6R, 6aR) -6- (5- (1- (3-Bromobenzyl) -lH- indole- 3- carbonyl) pyrimidin- Preparation of 2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate

(4-fluorophenyl) -1H-indol-3-yl) Yl) methanone (40 mg, 0.07 mmol) and sulfamoyl chloride (60 mg, 0.5 mmol) were dissolved in anhydrous DMF (0.5 ml), and reacted at room temperature for 20 hours. After completion of the reaction was confirmed by TLC, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give a white solid (31 mg, 68%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.73 (s, 1H), 8.70 (s, 1H), 8.59-8.66 (m, 1H), 8.19-8.23 (m, 1H), 7.66 (s, 1H), (M, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.31-7.36 2H), 1.70-1.79 (m, 1H), 1.52 (m, 2H), 5.35 (s, 2H), 4.56-4.68 s, 3H), 1.30 (s, 3H).

Step 6: (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydrooxycyclopentyl) methyl Sulfamate Produce

((3aS, 4R, 6R, 6aR) -6- (5- (1- (3-Bromobenzyl) -1 H- indole-3-carbonyl) pyrimidin- 4-yl) methyl sulfamate (31 mg, 0.05 mmol) was dissolved in THF (0.5 ml), and a solution of concentrated HCl (0.15 ml, 1.4 mmol) was slowly added dropwise. It was stirred for 2 hours the reaction mixture at room temperature, and after confirming that the reaction was completed by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent removed under reduced pressure. The reaction mixture was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give a white solid (5 mg, 18%).

^{1 H NMR (300 MHz, CD} 3 OD) δ 8.69 (s, 1H), 8.59 (s, 1H), 8.24-8.28 (m, 1H), 8.09 (s, 1H), 7.44-7.47 (m, 4H) , 7.30-7.33 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 5.53 (s, 2H), 4.54-4.59 2H), 3.94-4.00 (m, 2H), 2.49-2.56 (m, 1H), 2.36-2. 45 (m, 1H), 1.36-1.46 (m, 1H).

< Example 2> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -1H- Indazole -3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated except that 1H-indazole-3-carbaldehyde was used instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to prepare the desired compound LC / MS < / RTI > M + H: 616.1).

^{1 H NMR (300 MHz, DMSO} ) δ 9.49 (s, 1H), 9.07 (d, J = 7.5 Hz, 1H), 8.66 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.93 ( 1H), 3.98-4.33 (m, 2H), 5.90 (s, 2H), 4.40-4.63 2H), 3.72-3.90 (m, 2H), 2.16-2.43 (m, 2H), 1.16-1.26 (m, 1H).

< Example 3> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- benzyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The objective compound was prepared (LC / MS M + H: 538.2) by following the procedure of Example 1, except that benzyl bromide was used in place of 3-bromobenzyl bromide used in Step 1 of Example 1 above.

^{1 H NMR (300 MHz, MeOD} ) δ 8.63 (s, 1H), 8.57 (s, 1H), 8.23 (dd, J = 5.9, 3.1 Hz, 1H), 8.00 (s, 1H), 7.43 (dd, J (M, 2H), 3.87 (m, 2H), 4.87 (s, 2H) 4.05 (m, 2H), 2.29-2.64 (m, 2H), 1.35-1.43 (m, 1H).

< Example 4> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Chlorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The objective compound was prepared in the same manner as in Example 1 except that 3-chlorobenzyl bromide was used instead of 3-bromobenzyl bromide used in the step 1 of Example 1 (LC / MS M + H: 572.1).

^{1 H NMR (300 MHz, DMSO} ) δ 8.73 (s, 1H), 8.64 (s, 1H), 8.39 - 8.48 (m, 2H), 8.20 - 8.27 (m, 1H), 7.53 - 7.63 (m, 1H) , 7.46 (s, 1 H), 7.34-7.37 (m, 2H), 7.26-7.32 (m, 3H), 5.58 (m, 2H), 3.94-3.85 (m, 2H), 2.15-2.39 (m, 2H), 1.05-1.29 (m, 2H).

< Example 5> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Fluorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The objective compound was prepared in the same manner as in Example 1 except that 3-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in step 1 of Example 1 (LC / MS M + H : 556.2).

^{1 H NMR (300 MHz, DMSO} ) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.16 - 8.30 (m, 1H), 7.53 - 7.64 (d, J = 5.9 Hz, IH), 4.73 (s, IH), 7.38-7.31 (m, 2H) 2H), 3.92-4.04 (m, 1H), 3.67-3.88 (m, 2H), 2.19-2.36 (m, 2H), 1.07-1.30 (m, 1H).

< Example 6> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1- (3- ( Trifluoro ) benzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

The objective compound was prepared in the same manner as in Example 1 except that 3-trifluoromethylbenzyl bromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H 606.2).

^{1 H NMR (300 MHz, DMSO} ) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.52 - 8.38 (m, 2H), 8.21 - 8.27 (m, 1H), 7.83 (s, 1H), 7.28 2H), 2.15-2.38 (m, 2H), 3.96-4.02 (m, 1H), 3.69-3.85 (m, 2H) , 1.07-1.30 (s, 1H).

< Example 7> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy Preparation of 4 - ((5- (1- (3-methoxybenzyl) -1 H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

The objective compound was prepared in the same manner as in Example 1 except that 3-methoxybenzyl bromide was used in place of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H : 568.2).

< Example 8> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Chloro -4- Fluorobenzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The target compound was prepared in the same manner as in Example 1 except that 3-chloro-4-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in step 1 of Example 1 (LC / MS M + H: 590.1).

< Example 9> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (2,5- Dichlorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The objective compound was prepared in the same manner as in Example 1 except that 2,5-dichlorobenzyl bromide was used instead of 3-bromobenzyl bromide used in step 1 of Example 1 (LC / MS M + H: 606.1).

< Example 10> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3,4- Difluorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

(LC / MS M + H: 574.2) was obtained in the same manner as in Example 1, except that 3,4-difluorobenzyl bromide was used.

¹ H NMR (300 MHz, DMSO)? 8.75 (s, IH), 8.64 (s, IH), 8.43 (s, IH), 8.14-8.28 (d, J = 9.3, 6.0 Hz, 2H), 3.92-4.04 (m, 2H), 4.88 ), 3.72-3.80 (m, 2H), 2.10-2.42 (m, 2H), 1.14-1.24 (m, 2H).

< Example 11> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (2,4- Difluorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

The target compound was prepared (LC / MS M + H: 574.2) by following the procedure of Example 1 while using 2,4-difluorobenzyl bromide.

< Example 12> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1- (3- Iodobenzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

The objective compound was prepared in the same manner as in Example 1 except that 3-iodobenzyl bromide was used instead of 3-bromobenzyl bromide used in step 1 of Example 1 (LC / MS M + H : 664.1).

¹ H NMR (300 MHz, MeOD)? 8.67 (s, IH), 8.58 (s, IH), 8.22-8.27 1H), 7.49 (m, 1H), 7.27-7.33 (m, 2H), 7.19 (d, J = 7.5 Hz, 2H), 2.46-2.56 (m, 1H), 2.34-2.42 (m, 1H), 1.34-1.44 (m, 1H) ).

< Example 13> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Cyanobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

The target compound was prepared (LC / MS M + H: 563.2) by following the procedure of Example 1 while using 3-cyanobenzyl bromide.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.78 (s, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H), 8.29 - 8.23 (m, 1H), 7.70 - 7.58 (m 2H), 4.99 (s, 2H), 3.99 (t, J = 6.0, 2H), 7.50-7.41 (m, 2H), 7.27-7.38 1H), 1.41 (d, J = 2.9 Hz, 2H), 2.53 (s,

< Example 14> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (2- Fluorobenzyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The objective compound was prepared in the same manner as in Example 1 except that 2-fluorobenzyl bromide was used instead of 3-bromobenzyl bromide used in the step 1 of Example 1 (LC / MS M + H : 556.2).

¹ H NMR (300 MHz, MeOD)? 8.62 (s, IH), 8.56 (s, IH), 8.21 - 8.24 2H), 3.61 (d, J = 5.5 Hz, 2H), 7.37 (m, 3H), 7.07-7.22 , 2H), 2.40-2.56 (m, 2H), 2.12-2.21 (m, 2H), 1.32-1.41 (m, 1H).

< Example 15> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3,5- Bis (trifluoromethyl) benzyl ) -1H-indole-3-carbonyl) pyrimidin-4- yl) amino) -2,3-dihydroxycyclopentyl) Mate Produce

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

The objective compound was prepared (LC / MS M + H: 674.1) by following the procedure of Example 1, except that 4-trifluoromethylthiobenzyl bromide was used.

¹ H NMR (300 MHz, MeOD)? 8.70 (s, IH), 8.58 (s, IH), 8.25-8.28 2H), 7.42-7.45 (m, 1H), 7.30-7.35 (m, 2H), 5.73 (s, 2H), 4.53-4.62 (m, 2H), 2.47-2.59 (m, 1H), 2.38-2.42 (m, 1H), 1.35-1.45 (m, 1H).

< Example 16> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4-( (Trifluoromethyl) thio ) Benzyl) -lH-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl Sulfamate Produce

The objective compound was prepared in the same manner as in Example 1 except that 3,5-ditrifluoromethylbenzylbromide was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS M + H: 638.1).

< Example 17> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1 - ([1,1'- Biphenyl ]-4- Yl methyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

The objective compound was prepared (LC / MS M + H: 614.20) by following the procedure of Example 1 while using 4- (bromomethyl) -1,1'-biphenyl.

< Example 18 (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1 - ((6- Methyl pyridine Yl) methyl) -lH-indole-3-carbonyl) pyrimidin-4- yl) amino) cyclopentyl) methyl Sulfamate Produce

Instead of 3-bromobenzyl bromide used in step 1 of Example 1

The objective compound was prepared (LC / MS M + H: 553.2) by following the procedure of Example 1 while using 2- (bromomethyl) -6-methylpyridine.

< Example 19 (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1 - ((5- ( Trifluoromethyl ) Furan-2-yl) methyl) -1H-indole-3-carbonyl) pyrimidin-4- yl) amino) cyclopentyl) methyl sulfamate

The procedure of Example 1 was repeated except that 2- (bromomethyl) -5- (trifluoromethyl) furan was used instead of 3-bromobenzyl bromide used in Step 1 of Example 1 to obtain the target compound The compound was prepared (LC / MS M + H: 596.1).

^{1 H NMR (300 MHz, MeOD} ) δ 8.64 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.60 (d, J = 7.4 2H), 4.60 (d, J = 2.8 Hz, 2H), 6.30 (s, ), 4.18-4.30 (m, 2H), 4.07 (d, J = 5.5 Hz, 1H), 2.40-2.52 (m, 2H), 1.38-1.43 (m, 1H).

< Example 20> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1 - ((5- Methyl isoxazole Yl) methyl) -1H-indole-3-carbonyl) pyrimidin-4- yl) amino) cyclopentyl) methyl Sulfamate Produce

The target compound was prepared by following the procedure of Example 1 while using 3- (bromomethyl) -5-methylisoxazole instead of 3-bromobenzyl bromide used in Step 1 of Example 1 (LC / MS < / RTI > M + H: 543.2).

< Example 21> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -5- methyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

1H-indole-3-carbaldehyde was used in place of 1H-indole-3-carbaldehyde used in Step 1 of Example 1 to obtain the desired compound (LC / MS M + H: 630.1).

^{1 H NMR (300 MHz, MeOD} ) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.46 (s, 2H), 7.32 - 7.21 (m, 4H), 7.07 - 7.16 (m, 3H), 5.54 (s, 2H), 4.62 (s, IH), 4.23 (s, 2H), 3.98 (s, 2H), 2.48 s, 1 H), 1.41 (s, 1 H).

< Example 22> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -5- Fluoro Indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 634.1).

¹ H NMR (300 MHz, MeOD)? 8.57 (s, IH), 8.47 (s, IH), 8.04 (s, IH), 7.82 (dd, J = 9.6,2.5 Hz, 1H), 7.26-7.37 (M, 2H), 7.08-7.17 (m, 2H), 6.96 (td, J = 9.0,2.6 Hz, 1H) ), 3.84-3.86 (m, 2H), 2.35-2.47 (m, 1H), 2.24-2.33 (m, 1H), 1.27-1.33 (m, 1H).

< Example 23> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- ( Benzyloxy ) -1- (3- Bromobenzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated except that 5- (benzyloxy) -1H-indole-3-carbaldehyde was used in place of the 1H-indole-3-carbaldehyde used in the step 1 of Example 1, The compound was prepared (LC / MS M + H: 722.1).

< Example 24> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (3- Bromobenzyl ) -1H- Pyrrolo [2,3-b] pyridine Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated, except that 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde was used instead of 1H-indole-3-carbaldehyde used in Step 1 of Example 1 To give the desired compound (LC / MS M + H: 617.1).

^{1 H NMR (300 MHz, MeOD} ) δ 8.69 (s, 1H), 8.56 - 8.61 (m, 2H), 8.43 (dd, J = 4.8, 1.5 Hz, 1H), 8.25 (s, 1H), 7.51 (s 1H), 7.41-7.45 (m, 1H), 7.36 (dd, J = 7.9,4.8Hz, 1H), 7.20-7.29 ), 4.17-4.22 (m, 2H), 3.91-3.98 (m, 2H), 2.46-2.58 (m, 1H), 2.34-2.43 (m, 1H), 1.36-1.43 (m, 1H).

< Example 25> methyl Amino) pyrimidine-5-carbo (2-amino-4-methylpiperazin-1- Yl) -5-fluoro-1H-indol-1-yl) methyl) benzoate

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 614.2).

^{1 H NMR (300 MHz, CDCl3} ) δ 8.73 (s, 1H), 8.60 - 8.67 (m, 2H), 7.97 (d, J = 7.2 Hz, 2H), 7.85 - 7.92 (m, 1H), 7.71 (s 1H), 3.95 (s, 1 H), 3.45 (s, 3H) ), 3.88 (s, 3H), 3.65 (s, IH), 2.49 (s, 2H), 1.46-1.55 (m, IH).

< Example 26 (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (naphthalene-2- Yl methyl ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 606.2).

¹ H NMR (300 MHz, CDCl ₃ )? 8.76 (s, 1 H), 8.58 - 8.67 (m, 2H), 7.91-7.98 ), 7.47-7.52 (m, 2H), 7.19-7.55 (m, 2H), 7.02-7.09 (m, ), 4.07 (s, IH), 3.96 (s, IH), 3.65 (s, IH), 2.51 (s, 2H), 1.25 (s, 2H).

< Example 27> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (3- Methylbenzyl ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 570.2).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.72 (s, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.61 (s, 1H), 7.91 (dd, J = 9.8, 1.8 Hz, 1H) , 7.67 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00-7.04 2H), 2.30 (s, 3H), 1.34 (s, 2H), 4.28 (s, (s, 1 H).

< Example 28> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (4- Fluoro -3- Methylbenzyl ) -1H-indole-3-carbonyl) pyridin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfame Manufacturing

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 588.2).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H) 2H), 4.25 (s, 3H), 4.05 (s, 1H), 7.18 (dd, J = 9.0, 4.0 Hz, 1H), 6.88-7.02 ), 3.94 (s, 1H), 2.46 (s, 2H), 2.18 (s, 3H), 1.74 (s,

< Example 29> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (4- Fluoro -3-methoxybenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 604.2).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.74 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.3, 2.5 Hz, 1H) , 7.66 (s, 1H), 7.22-7.29 (m, 1H), 7.00-7.11 (m, 2H), 6.76 (dd, J = 7.6,1.8 Hz, 1H) (s, 2H), 4.30 (s, 2H), 4.06 (s, IH), 3.93-4.00 (m, IH), 3.82 (s, 3H), 2.51

< Example (5-fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) -1 H-indole-3-carbo Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

The procedure of Example 1 was repeated except for using 5-fluoro-1H-indole-3-carbaldehyde instead of 1H-indole-3-carbaldehyde used in step 1 of Example 1 to obtain the title compound (LC / MS M + H: 682.1).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.77 (s, 1H), 8.69 (d, J = 4.1 Hz, 1H), 8.63 (s, 1H), 7.92 (dd, J = 9.2, 2.7 Hz, 1H) , 7.74 (s, 1H), 7.71 (s, 2H), 7.15-7.23 (m, 3H), 7.10-7.03 1H), 3.96 (s, 1H), 3.65 (s, 1H), 2.50 (s, 2H), 1.47

< Example 31> (( 1R, 2S, 4R ) -4 - ((5- (1- benzyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2-hydrocyclopentyl) methyl Sulfamate Produce

Step 1: (l- benzyl -1H-indol-3-yl) (4 - ((( 1R, 3R, 4S ) -3- ( Hydroxymethyl )-4-(( Triisoprose filly ) Oxy) cyclopentyl) amino) pyrimidin-5-yl) methanone

(4-chloropyrimidin-5-yl) methanone (70 mg, 0.22 mmol) was dissolved in anhydrous n-BuOH and added to a 25 mL round- mg, 0.49 mmol) and 2,2,2-trifluoroacetyl aldehyde ((lR, 2S, 4R) -4-amino- 2- ((triisopropylsilyl) oxy) cyclopentyl) methanol mmol) was added dropwise. The reaction mixture was stirred at 105 ° C for 3.5 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid (20 mg, 18%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.67 (s, 1H), 8.63 (s, 1H), 7.60 (s, 1H), 7.38 - 7.26 (m, 7H), 7.16 - 7.13 (m, 2H), J = 5.9 Hz, 1H), 2.52-2.48 (m, 1H), 2.25-2.16 (m, 2H) (m, 2H), 1.92-1.83 (m, 2H), 1.37-1.23 (m, 2H), 1.05 (s, 20H).

Step 2: (( 1R, 2S, 4R ) -4 - ((5- (1- benzyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2-hydrocyclopentyl) methyl sulfamate

To a 25 mL round bottom flask was added (l- benzyl-lH-indol-3-yl) (4 - ((lR, 3R, 4S) -3- (hydroxymethyl) -4 - ((triisopropylphenyl) oxy ) Cyclopentyl) amino) pyrimidin-5-yl) methanone (20 mg, 0.03 mmol) and sulfamoyl chloride (19 mg, 0.16 mmol) were dissolved in anhydrous DMF and reacted at room temperature for 20 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (CH2Cl2: MeOH = 10: 1) to give a pale yellow solid (13 mg, 75%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.74 (s, 1H), 8.66 (s, 1H), 8.60 (d, J = 6.91 Hz, 1H), 8.23 (d, J = 7.54, 1H), 7.64 ( (s, 2H), 5.41 (s, 2H), 4.79 (q, J = 6.91 Hz, 1H), 4.44 2H), 4.30 (d, J = 10.06,5.66 Hz, 1H), 2.62-2.54 (m, 1H), 2.35 , 2H).

< Example 32> (( 1R, 2R, 3R, 4R ) -4 - ((5- (1- benzyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -3-fluoro-2-hydrocyclopentyl) methyl sulfamate

Step 1: (l- benzyl -1H-indol-3-yl) (4 - ((( 1R, 2R, 3R, 4R )-2- Fluoro -3- Hydroxy -4- (hydroxymethyl) cyclopentyl) amino) pyrimidin-5-yl) methanone

(1R, 2R, 3R, 5R) -3- (4-chloropyrimidin-5-yl) methanone was used in the place of (1-benzyl- Amino-2-fluoro-5- (hydroxymethyl) cyclopenten-l-ol hydrochloride was used as starting material.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.79 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 25.2 Hz, 2H), 8.33 - 8.23 (m, 1H), 7.61 (s, 1H) , 7.29-7.01 (m, 10H), 5.38-5.19 (m, 2H), 4.30-4.10 (m, 1H), 3.78 (dd, J = 10.5,5.4 Hz, - 2.28 (m, 1H), 2.21-2.01 (m, 1H), 1.50 (q, J = 10.9 Hz, 1H).

Step 2: (l-Benzyl lH-indol-3-yl) (4 - (((1R, 2R, 3R, 4R) -3 - ((tert- butyldimethylsilyl) oxy) -4- -Butyldimethylsilyl) oxy) methyl) 2-fluorocyclopentyl) amino) pyrimidin-5-yl) methanone

((1R, 2R, 3R, 4R) -2-fluoro-3-hydroxy-4- (hydroxymethyl) cyclopentyl) amino) (20 mg, 0.04 mmol) and imidazole (14 mg, 0.21 mmol) were dissolved in anhydrous DMF, TBSCl (19 mg, 0.13 mmol) was added thereto, and the mixture was stirred for 20 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid (20 mg, 75%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.73 (d, J = 8.06 Hz, 1H), 8.67 (2, 1H), 8.59 (s, 1H), 8.33 - 8.20 (m, 1H), 7.55 (s, 2H), 4.88-4.68 (m, 2H), 4.09 (ddd, J = 21.7, 5.1, 1.5Hz, 1H), 7.35-7.18 (m, 6H), 7.14-7.03 1H, J = 2.2Hz, 1H), 3.67-3.49 (m, 2H), 2.33-2.24 (mH), 2.09-1.95 0.06 (d, J = 1.4 Hz, 12H).

Step 3: (l- benzyl-lH-indol-3-yl) (4 - (((lR, 2R, 3R, 4R) -3 - ((tert- butyldimethylsilyl) oxy) 4- (hydroxymethyl) cyclopentyl) amino) pyrimidin-5-yl) methanone

(Tert-butyldimethylsilyl) oxy) -4- (tert-butyldimethylsilyloxy) -4-hydroxy- Yl) methanone (10 mg, 0.01 mmol) was dissolved in ethanol. The reaction vessel was cooled to 0 占 폚 and 1% HCl And the mixture was stirred at room temperature for 17 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (CH2Cl2: MeOH = 10: 1) to give a white solid compound (10 mg, 60%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.73 (d, J = 7.7 Hz, 1H), 8.61 (s, 1H), 8.53 (s, 1H), 8.24 - 8.14 (m, 1H), 7.48 (s, 2H), 5.25 (s, 2H), 4.87-4.79 (m, 1H), 4.09-3.93 (m, 1H), 3.67 1H), 3.50 (m, 2H), 2.34-2.24 (m, 1H), 2.07-1.96 (m, 1H), 1.49-1.26 .

Step 4: (( 1R, 2R, 3R, 4R ) -4 - ((5- (1- benzyl -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -3-fluoro-2-hydrocyclopentyl) methyl Sulfamate Produce

(4-chloropyrimidin-5-yl) methanone was used instead of (l-benzyl-lH-indol-3-yl) 4- (hydroxymethyl) cyclopentyl) amino) pyrimidine-2-carboxylic acid ethyl ester was used in place of 4- ((4R) 5-yl) < / RTI > methanone was used as starting material.

^{1 H NMR (300 MHz, MeOD} ) δ 8.74 (d, J = 5.31, 1H), 8.64 (d, J = 6.87, 1H), 8.26 (q, J = 3.12, 1H), 8.07 (d, J = 2.50 , 7.48 (m, 1H), 7.38-7.26 (6H, m), 5.54 (s, 2H), 4.33-4.10 (m, 4H), 2.56-2.48 , 1.00 (4H, m), 0.97-0.90 (m, 2H).

< Example 33 > (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- (2- Butin -1-yl) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydrocyclopentyl) methyl Sulfamate Produce

Step 1: (3 - ((3aS, 4R, 6R, 6aR) -6 - (((Tartaric acid tert- 4-yl) amino) pyrazin-2-yl) -methanone as a colorless amorphous solid. Produce

(3S, 4R, 6R, 6aR) -6 - (((tert-butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydro-4H-cyclopenta-4H- [d (5-fluoro-lH-indol-3-yl) methanone (20 mg, 0.04 mmol) was dissolved in anhydrous DMF after that, it puts the _{Cs 2 CO 3 (23 mg,} 0.07 mmol). 1-Bromo-2-butyne (7.6 mg, 0.05 mmol) was slowly added dropwise thereto, followed by stirring for 4 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid (26 mg, 92%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.72 (t, J = 10.4 Hz, 3H), 8.07 - 7.94 (m, 1H), 7.77 (s, 1H), 7.41 (dd, J = 8.9, 4.2 Hz, 2H), 4.73 (m, 2H), 3.73 (q, J = 2.5 Hz, 2H) J = 2.4 Hz, 3H), 1.71 (d, J = 12.8 Hz, 2H), 2.97 (s, , 1H), 1.33 (s, 3H), 1.27 (t, J = 7.1 Hz, OH), 0.92 (s, 9H), 0.09 (d, J = 1.5 Hz, 6H).

Step 2: (3 - ((3aS, 4R, 6R, 6aR) -6-Hydroxymethyl-pyrrolidin- Preparation of 2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) amino) pyrazin-

(3 - ((3aS, 4R, 6R, 6aR) -6 - (((Tart-butyldiglycidyl) -1- 4-yl) amino) pyrazin-2-yl) methanone (26 mg, 0.04 mmol) is dissolved in anhydrous DMF, and the reaction vessel is cooled to 0 ° C with ice water. TBAF (57 mg, 0.21 mmol) was slowly added dropwise, followed by stirring at 0 ° C for 1 hour. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid (20 mg, 97%).

1H NMR (300 MHz, CDCl3)? 8.89 (d, J = 7.9 Hz, 1H), 8.71 (d, J = 3.7 Hz, 2H), 8.07-7.91 (d, J = 8.9,4.2 Hz, 1H), 7.13 (t, J = 9.0 Hz, 1H), 4.88 (q, J = 2.5 Hz, 2H), 4.84-4.71 2H), 2.90 (s, 2H), 2.70-2.54 (m, 2H), 3.86 (dd, J = 10.2,4.9 Hz, 1H), 3.78 (dd, J = 10.2,5.4 Hz, (m, 1H), 2.45 (t, J = 5.4 Hz, IH), 2.28 (s, IH), 1.87 (t, J = 2.4 Hz, 3H), 1.76 13.7 Hz, 1H), 1.33 (s, 3H), 1.31-1.24 (m, 1H).

Step 3: ((3aR, 4R, 6R, 6aS) -6- (3- (1- (2-Butyne-1-yl) 5-fluoro-lH-indole-3-carbonyl) pyrazin- ) Amino) -2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl sulfamate

(1- (2-butyn-1-yl) -methanone was used in place of (l-benzyl-lH-indol-3-yl) (3aS, 4R, 6R, 6aR) -6-hydroxymethyl-2,2-dimethyltetrahydro-4H-cyclopenta [d ] [1,3] dioxol-4-yl) amino) pyrazin-2-yl) methanone was used.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.72 (d, J = 5.1 Hz, 4H), 8.60 (d, J = 7.1 Hz, 2H), 8.01 (s, 4H), 7.93 - 7.76 (m, 4H) (D, J = 9.0, 4.2 Hz, 2H), 7.11 (t, J = 9.0 Hz, 2H), 5.91 4H), 2.96 (s, 14H), 2.88 (s, 14H), 2.66 (d, J = 11.2 Hz, 4H), 2.05 (d, J = 7.6 Hz, 2H), 1.86 (t, J = 2.4 Hz, 6H), 1.82-1.66 (m, 3H), 1.28 (d, J = 15.9 Hz, 8H), 0.88 (t, J = 6.4 Hz, 1H).

Step 4: (( 1R, 2R, 3S, 4R ) -4 - ((3- (1- (2- Butin -1 day) 5- Fluoro -1H-indole-3- Carbonyl ) Pyrazin-2-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

((3aR, 4R, 6R, 6aS) -6- (3- (1- (2-butyn- D] [1,3] dioxol-4-yl) methyl sulfamate (19 mg, 0.03 mmol) was dissolved in MeOH, Lt; 0 > C. 1 ml of TfOH: H 2 O = 1: 9 was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 18 hours. The reaction was terminated using NaHCO3, extracted with ethyl acetate, and dried over MgSO4. The reaction mixture was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) to give a yellow solid (13 mg, 73%).

^{1 H NMR (300 MHz, MeOD} ) δ 8.67 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 9.95 Hz, 1H), 7.62 (q, J = 8.93 (D, J = 5.36 Hz, 2H), 4.02 (s, 2H), 4.58 1H), 3.97 (m, 2H), 2.59-2.42 (m, 2H), 1.83 (s, 3H), 1.48-1.38 (m,

< Example 34> (( 1R, 2R, 3S, 4S ) -4 - ((5- (1 - ((E) -2- Beaten -1-yl) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydrocyclopentyl) methyl Sulfamate Produce

The procedure of Example 33 was repeated except that (E) -1-2-bromobutene was used in place of 1-bromo-2-butyne used in the step 1 of Example 33 to obtain the desired compound Respectively.

(LC / MS M + H: 502.2);

^{1 H NMR (300 MHz, MeOD} ) δ 8.65 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 9.64 Hz, 1H), 7.56 - 7.48 (m, 1H J = 5.78 Hz, 2H), 4.58 (q, J = 8.26 Hz, 1H), 4.22 (d, J = 4.96 (d, J = 5.98 Hz, 2H), 3.96 (q, J = 4.96 Hz, 2H), 2.59-2.37 1.45-1.35 (m, 1H).

< Example 35> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1- (2- Methoxyethyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

Bromo-2-butyne used in Step 1 of Example 33 was replaced by the procedure of Example 33, except that 1-bromo-2-methoxyethane was used instead of 1- Respectively.

(LC / MS < / RTI > M + H: 506.2);

^{1 H NMR (300 MHz, MeOD} ) δ 8.54 (d, J = 6.3 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 9.7, 2.6 Hz, 1H), 7.49 (dd, J = 9.0 J = 5.0 Hz, 2H), 4.15-3.93 (m, 2H), 3.86 (m, 2H) (d, J = 4.8 Hz, 2H), 3.65 (t, J = 5.0 Hz, 2H), 2.41 (m, 2H), 2.06 (s, 3H), 1.39-1.21 (m, 1H).

< Example 36> (( 1R, 2R, 3S, 4S ) -2,3- Dihydroxy -4 - ((5- (1- Isobutyl -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

step 1: 1 -(2- Butin -1-yl) -1H-indole-3- Cavaldehyde's Produce

Was dissolved 1H- indol-3-hydroxy to Cavalli (500 mg, 3.1 mmol) in anhydrous DMF solvent, were added to Cs ₂ _{CO 3 (1.1 g, 3.41 mmol} ). 1-Bromo-2-methylpropane (1.06 g, 6.2 mmol) was slowly added dropwise, followed by stirring for 4 hours. The reaction was terminated by TLC, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (EA: HEX = 1: 1) to give a white solid compound (380 mg, 57%).

^{1 H NMR (300 MHz, MeOD} ) δ 10.02 (s, 1H), 8.33 (dd, J = 7.0, 3.8 Hz, 1H), 7.69 (s, 1H), 7.45 - 7.25 (m, 3H), 3.98 (d J = 7.3 Hz, 2H), 2.33-2.24 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H).

Step 2: ((4- Chloropyrimidine Yl) (1- Isobutyl -1H-indol-3-yl) methanol

4-Chloro-5-iodopyrimidine (350 mg, 1.49 mmol) was added to a 50 ml two-neck round bottom flask and dissolved in THF (3.0 ml) and stirred at -78 ° C. To this, n-BuLi (95 mg, 1.49 mmol) was slowly added dropwise and allowed to react for 30 minutes. 1- (2-butyn-1-yl) -1H-indole-3-carbaldehyde (150 mg, 0.74 mmol) dissolved in THF (3.0 ml) was added slowly and reacted at 0 ° C for 2 hours. After completion of the reaction, the reaction was terminated using saturated NH ₄ Cl, extracted with EA, and dried using MgSO ₄ . The reaction mixture was separated and purified by flash column chromatography (EA: HEX = 1: 1) to give the product as a yellow solid (80 mg, 34%).

^{1 H NMR (300 MHz, MeOD} ) δ 9.14 (s, 1H), 8.87 (s, 1H), 7.69 (dd, J = 8.0, 1.0 Hz, 1H), 7.40 - 7.08 (m, 4H), 6.89 (s (D, J = 3.4 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H), 3.87 (d, J = 6.7, Hz, 6H).

Step 3: (4- Chloropyrimidine Yl) (1- Isobutyl -1 H-indol-3-yl) Methanone Produce

(80 mg, 0.24 mmol), MnO ₂ (215 mg, 2.47 mmol) and CH ₂ ( ₂ -chloropyrimidin-5-yl) . the addition of Cl ₂ (5.0ml) and reacted at room temperature for 12 hours after the completion of the reaction, given by filtration through celite, washed several times with MC, and concentrated by silica gel column chromatography. (EA: Hex = 1: 1) Separation and purification as a condition gave a yellow solid (75 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ )? 9.11 (s, IH), 8.78 (s, IH), 8.46-8.34 (m, IH), 7.49-7. Hz, 2H), 2.35-2.08 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H).

Step 4: (4 - (((3aS, 4S, 6R, 6aR) -6- (Hydroxymethyl) -2,2- dimethyltetrahydro- 4H- cyclopenta [d] Yl) amino) pyrimidin-5-yl) (1-isobutyl-1H-indol-3-yl)

(3aR, 4R, 6R, 6aS) -6 (4-chloropyrimidin-5-yl) methanone was used in the place of (1-benzyl- -Amino-2,2-dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methanol was used as the starting material.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.88 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 7.2 Hz, 2H), 8.35 - 8.21 (m, 1H), 7.46 - 7.25 (m, (M, 2H), 2.64 - 2.54 (m, 2H), 4.75 (dd, J = 7.8, 5.3 Hz, 1H), 4.63-4.54 (s, 3H), 1.31 (s, 3H), 0.95 (d, 1H), 2.45-2.39 (m, J = 6.6 Hz, 6H).

Step 5: ((3aR, 4R, 6S, 6aS) -6- (5- (1- (2-Butyl-1 H- indole- 3-carbonyl) pyrimidin- -Dimethyltetrahydro-4H-cyclopenta [d] [1,3] dioxol-4-yl) methyl Sulfamate Produce

((4 - (((3aS, 4S, 6R, 6S) -7-methoxy-5- (4-chloropyrimidin- D] [1,3] dioxol-4-yl) amino) pyrimidin-5-yl) (1 (R) -6- (hydroxymethyl) -2,2- dimethyltetrahydro-4H-cyclopenta [ -Isobutyl-1H-indol-3-yl) methanone was used as the starting material.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.67 (d, J = 6.21 Hz, 1H), 8.21 (d, J = 10. 5 Hz, 1H), 7.6 (s, 1H), 7.47 - 7.27 (m, J = 7.4 Hz, 2H), 2.72-2.59 (m, 2H), 6.30 (s, 2H), 4.74-4.54 ), 1.53 (s, 3H), 1.31 (s, 3H), 0.97 (d, J = 6.6, Hz, 6H).

Step 6: (( 1R, 2R, 3S, 4S ) -2,3- Dihydroxy -4 - ((5- (1- Isobutyl -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl Sulfamate Produce

((3aR, 4R, 6S, 6aS) -6- (5- (1- (2-Butyl-1 H- indole- 3-carbonyl) pyrimidin- D] [1,3] dioxol-4-yl) methyl sulfamate (22 mg, 0.04 mmol) was dissolved in MeOH and the reaction vessel was cooled to 0 占 폚 using ice water. TfOH: H2O = 1:. after dropping a 9 to 1ml and extracted and then at 0 ℃ stirred for 30 minutes and the mixture was stirred at room temperature for 18 hours after completion of the reaction by using the NaHCO ₃ with ethyl acetate, using MgSO ₄ and dried over silica gel column chromatography to give to give the compound of yellow solid (18 mg, 82%) in _{(CH 2 Cl 2: 1:} MeOH = 10).

(LC / MS < / RTI > M + H: 504.2);

¹ H NMR (300 MHz, MeOD)? 8.61 (d, J = 10.8 Hz, 2H), 8.30-8.18 (m, 1H), 7.92 (m, 2H), 4.57 (td, J = 8.1, 5.7 Hz, 1H), 4.29-4.15 (m, 2H), 4.20-4.04 (m, 1H), 2.46-2.34 (m, 1H), 2.40-2.16 (m, 1H), 2.03 ).

< Example 37> (( 1R, 2R, 3S, 4R ) -4 - ((5- (1- ( Cyclohexylmethyl ) -1H-indole-3- Carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 36 was repeated except that 1-bromo-2-methylpropane (mg, mmol) used in the step 1 of Example 36 was replaced by bromomethyl) cyclohexane, Lt; / RTI >

(LC / MS < / RTI > M + H: 544.2);

^{1 H NMR (300 MHz, MeOD} ) δ 8.46 (t, J = 6.9 Hz, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.39 (t, J = 7.0 (M, 3H), 3.84 (td, 1H), 7.16 (dt, J = 17.9, 7.4 Hz, 2H), 4.48-4.35 2H), 1.90 (s, 2H), 1.84-1.69 (m, 1H), 1.55-1.61 (m, 6H), 1.21-0.91 m, 8H).

< Example 38> ( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1- ( Morpholinoethyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

The procedure of Example 36 was repeated except for using 4- (2-chloroethyl) morpholine instead of 1-bromo-2-methylpropane used in Step 1 of Example 36 to obtain the desired compound Respectively.

(LC / MS < / RTI > M + H: 561.2);

¹ H NMR (300 MHz, MeOD)? 8.68 (s, IH), 8.60 (s, IH), 8.28-8.19 2H), 7.39-7.27 (m, 2H), 4.63-4.49 (m, 1H), 4.41 (t, J = 4.7 Hz, 4H), 2.83 (t, J = 6.2 Hz, 2H), 2.54 (q, J = 4.4 Hz, 4H), 2.52-2.32 (m, 1H), 1.45-1.35 , 1H).

< Example 39> (( 1R, 2R, 3S, 4R ) -2,3- Dihydroxy -4 - ((5- (1- (3- Morpholino benzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate

The procedure of Example 33 was repeated, except that 4- (3- (chloromethyl) phenyl) morpholine was used in place of 1-bromo-2-butyne used in Step 1 of Example 33, .

(LC / MS < / RTI > M + H: 623.2)

^{1 H NMR (300 MHz, MeOD} ) δ 8.66 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J = 9.7, 2.6 Hz, 1H), 7.47 (dd, J J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 6.1 Hz, 2H), 6.73 (dd, J = 9.0, 7.5 Hz, 1H) (d, J = 7.5 Hz, 1H), 5.45 (s, 2H), 4.57 (q, J = 8.0 Hz, 1H), 4.29-4.12 (m, 2H), 4.03-3.86 3.75 (m, 4H), 3.23-2.98 (m, 4H), 2.61-2.32 (m, 2H), 1.45-1.37 (m, 1H).

< Example Yl) methyl) -5-fluoro-pyridin-2-yl] - (4- Indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The title compound was obtained as a yellow amorphous solid in the same manner as in Example 33 (1) except for using 5- (chloromethyl) -2- (1H-pyrazol-1-yl) pyridine in place of 1-bromo- The target compound was prepared.

(LC / MS < / RTI > M + H: 623.2);

1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.70-7.26 (s, 1H) 2H), 4.50-4.38 (m, 3H), 3.98 (m, 1H), 7.20-7.17 2H), 2.96-2.88 (m, 2H), 2.33 (m, 1H), 1.56-1.20 (m, 2H), 1.19-1.06 (m, 3H), 1.00 (s, 1H).

< Example Fluoro-1H-indole-3-carbo (4-methylpiperazin-1 -yl) Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl Sulfamate Produce

The procedure of Example 33 was repeated, except that 6-bromo-3- (chloromethyl) benzofuran was used in place of 1-bromo-2-butyne used in Step 1 of Example 33 to obtain the desired compound .

(LC / MS < / RTI > M + H: 674.1);

¹ H NMR (300 MHz, CDCl ₃ + MeOD)? 8.80 (br s, 1 H), 8.67 (br s, 1 H), 8.18 2H), 4.65 - 4.58 (m, 3H), 4.25 (br s, 2H) 2.56-2.48 (m, 2H), 1.86-1.57 (m, 1H), 1.27-1.22 (4H, m), 0.97-0.90 (m, 2H).

< Example 4 - ((5- (5-fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) -lH-indole-3-carbonyl ) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

Example 33 was repeated except for using 4- (chloromethyl) -1- (methylsulfonyl) -2-nitrobenzene in place of 1-bromo-2-butyne used in Step 1 of Example 33. The objective compound was prepared by carrying out the same procedure (LC / MS M + H: 679.1).

< Example 43> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (3- ( Methylsulfonamido ) benzyl ) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

The procedure of Example 33 was repeated except that N- (3- (chloromethyl) phenyl) methanesulfonamide was used instead of 1-bromo-2-butyne used in the Step 1 of Example 33 to obtain The compound was prepared (LC / MS M + H: 649.1).

< Example 44> (( 1R, 2R, 3S, 4R ) -4 - ((5- (5- Fluoro -1- (4- (N- Methylsulfamoyl ) Ben Indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate

The procedure of Example 33 was repeated, except that 4- (chloromethyl) -N-methylbenzenesulfonamide was used in place of 1-bromo-2-butyne used in Step 1 of Example 33 to obtain the desired compound (LC / MS M + H: 649.1).

< Example (5-fluoro-1- (2-methyl-3- (trifluoromethyl) benzyl) -lH-indole-3-carbo Yl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclopentyl) methyl Sulfamate

The procedure of Example 33 was repeated except for using 1- (chloromethyl) -2-methyl-3- (trifluoromethyl) benzene in place of 1-bromo-2-butyne used in Step 1 of Example 33. The target compound was prepared.

^{1 H NMR (300 MHz, MeOD} ) δ 8.78 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.04 (dd, J = 9.5, 2.6 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.0, 4.2 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.12 2H, J = 7.8 Hz, 2H), 5.68 (s, 2H), 4.27-4.15 (m, 2H), 4.15-3.96 1.59-1.44 (m, 1H).

The chemical structures of the compounds prepared in Examples 1-45 are summarized in Table 1 below.

Example constitutional formula Example constitutional formula One

24

2

25

3

26

4

27

5

28

6

29

7

30

8

31

9

32

10

33

11

34

12

35

13

36

14

37

15

38

16

39

17

40

18

41

19

42

20

43

21

44

22

45

23

< Experimental Example 1> Cell growth inhibition experiment

In order to evaluate the inhibition of cancer cell growth of the heterocyclic compound according to the present invention, experiments were conducted as follows.

Specifically, human-derived breast cancer cells (HCT-116, THP-1) purchased from ATCC were cultured in RPMI medium containing 10% fetal bovine serum. The cultured breast cancer cells were separated from the cells by 2% trypsin into individual cells, and then the number of cells per 1 ml was measured with a cell counting device. Cells were seeded at 3,000 cells / well / 100 ul in clear 96 wells and incubated for 18 hours to stabilize. The compound of the present invention dissolved in DMSO was treated with 20 uM, 10 uM, 5 uM, 2.5 uM, 1.25 uM, 0.625 uM and 0.3125 uM. At this time, the concentration of DMSO did not exceed 0.1% of the cell culture medium. Samples treated with DMSO at the same ratio were used as a control. The cells of the Example were treated for 48 hours and after 48 hours the cells were dissolved in DMSO at concentrations of 20 mM, 10 mM, 5 mM, 2.5 mM, 1.25 mM, 0.625 mM and 0.3125 mM Compounds were diluted 1000-fold in culture medium and injected in 200 μl aliquots into wells. Additional cultures were performed for 24 hours and cell growth was measured. Cell growth was measured using a cell count kit-8 (Dojindo, CK04-13). 10 μl of CCK-8 solution was added to the cells, reacted at 37 ° C for 2 hours, and the absorbance at 450 nm was measured using an absorptometer. At this time, the formula for cell growth inhibition is as follows.

(%) Inhibition = 100 - (absorbance of treated group of Example compound / absorbance of control group) X 100

The experimental values obtained through the above experiment are shown in Table 2 below.

Example LD ₅₀ (μM) HCT116 THP1 One 0.934 0.223 3 0.2277 <0.03 4 0.7897 0.6002 5 0.4557 <0.03 6 1.237 1.284 7 0.4306 <0.03 8 1.801 1.426 9 0.6429 0.6619 10 2.276 1.808 11 1.481 1.557 12 0.587 0.163 13 15.131 13.171 14 3.121 1.002 15 4.121 2.781 18 0.4134 0.0553 19 2.014 0.813 22 1.009 0.896 24 2.014 0.813

As shown in the results of Table 2 and the results of this Experimental Example, the compounds of Examples 1-45 according to the present invention all have a unit concentration of micromole or nano moles with respect to human breast cancer cells (HCT-116, THP-1) , And it is confirmed that it inhibits cancer cell growth.

Therefore, the heterocyclic compound according to the present invention is found to be capable of inhibiting the growth of cancer cells, and thus can be usefully used as a pharmaceutical composition for improving, preventing or treating cancer, or as a health functional food composition.

< Experimental Example 2> SAE (Sumo Activating Enzyme) inhibitory activity

In order to evaluate the SAE inhibitory activity of the heterocyclic compound according to the present invention, the following experiment was conducted.

In vivo humoral analysis kit (SA-001) and sumo-1 His-tag (Enzo, BML-UW9195) were used. The negative control was adjusted to 2 μl of Reagent A, 1 μg of sumo-1 His-tag and 1 μl of Reagent C to a total of 20 μl of DW. Positive controls and samples were adjusted to a total of 19 μl with 2 μl of Reagent A, 1 μg of sumo-1 His-tag, 1 μl of Reagent C and 1 μl of Reagent D with DW. For the positive control, 1 μl of DW and 1 μl of 20 x sample (diluted in DW) were added to the treated group and reacted at 37 ° C for 2 hours. After the reaction was terminated, anti-6HIS-Eu cryptate (cisbio, 61HI2KLA) and anti-GST-d2 (cisbio, 61GSTDLA) were used for detection by the HTRF method. A solution prepared by injecting 0.1% BSA and 0.5% Tween 20 in PBS was injected into wells and 0.2 μl of anti-6HIS-Eu and 0.2 μl of anti-GST-d2 were injected into 384 wells of white. The reaction solution was reacted for 1 hour at 37 ° C. After the reaction solution was injected in 3-well portions of 1 μl each, the HTRF was measured using an HRTRF measuring device I3 (molecular device) Respectively.

Example SAE
[IC ₅₀ (uM)] One 0.10 2 1.70 3 0.12 4 0.46 5 1.65 6 3.18 7 0.04 8 1.60 10 3.48 11 0.03 12 0.47 14 2.88 18 2.21 19 1.29 22 0.53 24 0.661 27 0.68 28 1.72 31 0.56 32 1.84 34 1.86 37 1.65 39 > 10 45 0.99

As a result of the results of Table 3 and the experimental example, it was confirmed that the compounds of Examples 1-45 according to the present invention can excellently inhibit SAE activity at a concentration of micromolar or nanomolar units.

Therefore, the heterocyclic compound according to the present invention can excellently inhibit the SAE activity at a concentration of micromolar or nanomolar unit, so that the compound of the present invention is useful as a pharmaceutical composition for the improvement, prevention or treatment of cancer, It can be usefully used as a food composition.

< Experimental Example 3> NAE ( NEDD8 -Activating Enzyme inhibitory activity

In order to evaluate the NAE inhibitory activity of the heterocyclic compound according to the present invention, the following experiment was conducted.

The NAE enzyme activity is measured using a time-resolved fluorescence energy transfer assay. First, 10 nM Ubc12 was added to 50 [mu] l enzyme reaction solution (50 mM HEPES (Sigma), pH 7.5, 0.05% BSA (Sigma), 5 mM MgCl2 (Sigma), 20 uM ATP (Sigma), 250 uM glutathione (Gibco), GST (Ubiquigent), 75 nM NEDD8-Flag (Boston Biochem) and 0.3 nM NAE enzyme (Enzo) were placed in a 384 well plate for 90 minutes at room temperature. , 0.53 nM antiGST-d2 antibody (Cisbio), 0.53 nM antiFLAG-cryptate antibody (Cisbio)), pH 7.5, 0.05% tween20 (Sigma), 20 mM EDTA For 2 hours and then measured with a fluorescence meter.

Example NAE
[IC ₅₀ (uM)] 3 0.005 4 0.019 5 0.091 6 0.012 7 0.022 9 0.037 10 0.02 11 0.008 22 0.0009 26 0.141 28 0.015 30 0.010 31 0.0006 39 0.013 45 0.112

As a result of the results of Table 4 and the experimental example, it was confirmed that the compounds of Examples 1-45 according to the present invention all exhibited excellent NAE activity at a concentration of micromolar or nanomolar units.

Therefore, the heterocyclic compound according to the present invention can excellently inhibit the NAE activity at a concentration of micromolar or nanomolar unit, and thus the compound of the present invention is useful as a pharmaceutical composition for improving, preventing or treating cancer, It can be usefully used as a food composition.

Claims

Claims 1. A compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ and R ² are independently -H, -OH, or -F;

R ³ is

,

,

,

,

,

,

,

,

,

or

ego;

It is substituted with an unsubstituted phenyl, or -CH _3, -F or -BnO phenyl, or pyridine, and; And

X is CH or N).

delete

The method according to claim 1,
The compound represented by Formula 1 is any one selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(3-bromobenzyl) -lH-indole-3-carbonyl) pyrimidin-4-yl) amino) - 2,3-dihydrooxycyclopentyl) methyl sulfamate;
(2R, 3R, 4R) -4 - ((5- (1- (3-bromobenzyl) -1 H- indazole-3-carbonyl) pyrimidin- -2,3-dihydroxycyclopentyl) methyl sulfamate;
(3-benzyl-1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydro Lt; / RTI > cyclopentyl) methyl sulfamate;
(4-chlorobenzyl) -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2 , 3-dihydroxycyclopentyl) methyl sulfamate;
(5) (1- (3-fluorobenzyl) -1 H-indole-3-carbonyl) pyrimidin-4-yl) amino) - 2,3-dihydroxycyclopentyl) methyl sulfamate;
(6) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3- (trifluoromethyl) benzyl) ) Pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(7) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3-methoxybenzyl) -lH-indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;
(8) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-Chloro-4-fluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(9) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2,5- dichlorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- -2,3-dihydroxycyclopentyl) methyl sulfamate;
(10) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3,4- difluorobenzyl) -1 H- indole- 3-carbonyl) pyrimidin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(11) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2,4- difluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(12) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (3-fluorobenzyl) 4-yl) amino) cyclopentyl) methyl sulfamate;
(13) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-cyanobenzyl) -1 H- indole-3-carbonyl) pyrimidin- 2,3-dihydroxycyclopentyl) methyl sulfamate;
(14) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (2-fluorobenzyl) -1 H- indole-3-carbonyl) pyrimidin- 2,3-dihydroxycyclopentyl) methyl sulfamate;
(15) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3,5- bis (trifluoromethyl) benzyl) -1 H- indole- 3-carbonyl) pyrimidine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(16) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((trifluoromethyl) thio) benzyl) -1 H- indole- 3-carbonyl) pyrimidin- -Yl) amino) cyclopentyl) methyl sulfamate;
(17) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (1, 1'- biphenyl) -4-ylmethyl) -1 H- indole-3-carbonyl) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(18) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- -Carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(19) ((1R, 2R, 3S, 4R) -2,3-Dihydroxy-4 - ((5- (1- (5- (trifluoromethyl) furan- 1H-indole-3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(20) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (5-methylisooxazol- 3-carbonyl) pyrimidin-4-yl) amino) cyclopentyl) methyl sulfamate;
(21) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-bromobenzyl) ) Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(22) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (3-bromobenzyl) -5-fluoro-1H-indole-3-carbonyl) pyrimidin- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(23) ((1R, 2R, 3S, 4R) -4 - ((5- (5- (Benzyloxy) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(24) (lR, 2R, 3S, 4R) -4 - ((5- (l- (3- bromobenzyl) - lH- pyrrolo [2,3- b] pyridine- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(25) Synthesis of methyl 3 - ((3- (4 - ((1R, 2S, 3R, 4R) -2,3-dihydroxy- 4- ((sulfamoyloxy) methyl) cyclopentyl) amino) pyrimidine -5-carbonyl) -5-fluoro-1 H-indol-1-yl) methyl) benzoate;
(26) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (naphthalen- Yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(27) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- 1- (3- methylbenzyl) -1 H- indole- 3- carbonyl) pyridin- Amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(28) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(29) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (4-fluoro-3-methoxybenzyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(30) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (4- (pentafluoro-16-sulfanyl) benzyl) Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
Amino) -2-hydrocyclo-pentyl) methyl (2-methylpiperazin-1 -yl) Sulfamate;
(32) ((1R, 2R, 3R, 4R) -4 - ((5- (l- benzyl- lH- indole- 3-carbonyl) pyrimidin- 4- yl) amino) -Hydrocyclopentyl) methyl sulfamate;
(33) ((1R, 2R, 3S, 4R) -4 - ((5- (1- ) -2,3-dihydrocyclopentyl) methyl sulfamate;
(34) ((1R, 2R, 3S, 4S) -4 - ((5- (1- -Yl) amino) -2,3-dihydrocyclopentyl) methyl sulfamate;
(35) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (2-methoxyethyl) -1 H- indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;
(36) ((1R, 2R, 3S, 4S) -2,3-dihydroxy- Amino) cyclopentyl) methyl sulfamate;
(37) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (cyclohexylmethyl) -1 H- indole- 3-carbonyl) pyrimidin- 3-dihydroxycyclopentyl) methyl sulfamate;
(38-) ((1R, 2R, 3S, 4R) -2,3-dihydroxy-4 - ((5- (1- (morpholinoethyl) -1 H- indole- 3-carbonyl) pyrimidin- -Yl) amino) cyclopentyl) methyl sulfamate;
(39) ((1R, 2R, 3S, 4R) -2,3-Dihydroxy-4 - ((5- (1- (4-morpholinobenzyl) -lH-indole-3-carbonyl) pyrimidine 4-yl) amino) cyclopentyl) methyl sulfamate;
(40) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (1- (1H-pyrazol-1-yl) pyridin- -1H-indole-3-carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(41) ((1R, 2R, 3S, 4R) -4 - ((5- (1- (6- (Bromobenzofuran-3- yl) methyl) -5- Carbonyl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(42) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro-1- (4- (methylsulfonyl) -3-nitrobenzyl) Yl) pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(43) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (3- (methylsulfonamido) benzyl) -1 H- indole-3-carbonyl) 4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate;
(44) ((1R, 2R, 3S, 4R) -4 - ((5- (5-Fluoro-1- (4- (N-methylsulfamoyl) benzyl) Pyrimidin-4-yl) amino) -2,3-dihydroxycyclopentyl) methyl sulfamate; And
(45) ((1R, 2R, 3S, 4R) -4 - ((5- (5- fluoro- Carbonyl) pyrimidin-4-yl) amino) -2,3, -dihydrocyclopentyl) methyl sulfamate.

Prevention of inflammatory, cardiovascular disease, or neurodegenerative diseases comprising the compound represented by the general formula (1) of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for preventing or treating cancer comprising the compound represented by the general formula (1) of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

8. The method of claim 7,
Wherein the cancer is selected from the group consisting of a malignant myxoma, an intrahepatic bile duct carcinoma, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a glioblastoma, a oral cancer, a laryngectomy, a fungal sarcoma, a basal cell carcinoma, an ovarian carcinoma, Pituitary adenoma, gallbladder carcinoma, bile duct carcinoma, colon cancer, retinoblastoma, choroidal melanoma, bladder cancer, bladder cancer, peritoneal cancer, pituitary cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, astrocytoma, small cell lung cancer, Neuroblastoma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, urethral cancer, urethra Cancer, uterine cancer, uterine sarcoma, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic cancer, metastatic cancer, breast cancer, sarcoma, pancreatic cancer, Brain cancer, mediastinal cancer, rectal cancer, Cancer of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, rhabdomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, squamous cell carcinoma, Laryngeal cancer, pleural cancer, thymus cancer, and head and neck cancer.

8. The method of claim 7,
Said cancer being selected from the group consisting of acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML); Acute lymphocytic leukemia (ALL); Chronic myelogenous leukemia; Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Valgendrogmaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocytic lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; Pediatric lymphoma; Childhood leukemia; Malignant lymphoma; Gastric lymphoma and myeloproliferative syndrome. &Lt; RTI ID = 0.0 > 8. < / RTI >

A pharmaceutical composition for treating cancer, inflammatory, cardiovascular disease, or neurodegenerative disease (hereinafter referred to as " cardiovascular disease ") comprising the compound represented by the general formula (1) of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, neurodegenerative diseases. < / RTI >