WO2022203466A1

WO2022203466A1 - Novel phenylaminopyrimidine compound having inhibitory activity against lrrk2 and use thereof

Info

Publication number: WO2022203466A1
Application number: PCT/KR2022/004259
Authority: WO
Inventors: 강은지; 신재홍; 김현진; 이재영; 조대현; 고은; 김승찬; 송상옥
Original assignee: 주식회사 스탠다임
Priority date: 2021-03-26
Filing date: 2022-03-25
Publication date: 2022-09-29
Also published as: KR20230117756A; KR102585194B1

Abstract

The present invention provides a pyrimidine compound of chemical formula 1, a pharmaceutical composition containing same for preventing or treating a LRRK2-mediated or related disease (for example, Parkinson's disease), and a method for treating and preventing disorders or diseases by using same. Having inhibitory activity against LRRK2, the pyrimidine compound according to the present invention can be advantageously used for preventing or treating LRRK2-related diseases (for example, Parkinson's disease).

Description

Novel phenylaminopyrimidine compounds having inhibitory activity against LRRK2 and uses thereof

The present invention relates to a phenylaminopyrimidine compound of Formula 1, a leucine-rich repeat kinase 2 (leucine-rich repeat kinase 2: LRRK2)-mediated or related disease or disorder comprising the same, a pharmaceutical composition for preventing or treating, and It relates to a method for treating and preventing a disease or disorder using the same.

Degenerative brain diseases, such as Parkinson's disease, affect millions of people. Parkinson's disease is caused by progressive deficits in midbrain dopamine neurons, impairing the patient's ability to direct and control movement.

Leucine-rich repeat kinase 2 (leucine-rich repeat kinase 2: LRRK2) is implicated in hereditary Parkinson's disease. For example, the LRRK2 Gly2019Ser mutation causes an increase in kinase activity, resulting in hereditary Parkinson's disease. In addition to Parkinson's disease, it has been reported to be associated with Alzheimer's disease, dyskinesia, central nervous system disorders, cancer, rheumatoid arthritis, and ankylosing spondylitis. In addition, it was known that LRRK2 is also associated with Crohn's disease through genomic association analysis (Teri A. Manolio, N Engl J Med 2010;363:166-176). As the relationship between LRRK2 and diseases is known, modulators or inhibitors of LRRK2 are being developed (eg, Patent Publication No. 2020-0085779 (July 15, 2020)).

Accordingly, it is an object of the present invention to provide a phenylaminopyrimidine compound of Formula 1 that exhibits excellent inhibitory activity against LRRK2, and uses the same to treat and prevent diseases mediated by or related to LRRK2, for example, neurodegenerative diseases. to achieve high efficacy.

It is an object of the present invention to provide a phenylaminopyrimidine compound of formula (1).

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2, which includes a phenylaminopyrimidine compound of Formula 1.

Another object of the present invention is to provide a method for preventing or treating a disease or disorder mediated by or related to LRRK2 using an LRRK2 inhibitor including a phenylaminopyrimidine compound of Formula 1.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.

One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1, R ¹ and R ² are each independently H, halogen, OH, CN, amino, nitro, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, or halogen It may be C _1-6 alkoxy substituted with .

In one embodiment, R ¹ and R ² can each independently be H, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with halogen. In one embodiment, one of R ¹ and R ² may be H, and the other may be halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with halogen. In one embodiment, R ¹ is H and R ² can be halogen, C _1-6 alkyl, or C _1-6 alkyl substituted with a halogen atom. For example, R ¹ may be H and R ² may be C _1-4 alkyl or C _1-4 alkyl substituted with halogen. In one embodiment, R ² is H and R ¹ can be halogen, C _1-6 alkyl, or C _1-6 alkyl substituted with a halogen atom. For example, R ² can be H and R ¹ can be halogen or C _1-4 alkyl.

In the above definitions of R ¹ and R ² , halogen may be F, Cl, Br or I. C _1-6 alkyl substituted with halogen or C _1-4 alkyl substituted with halogen may be substituted with 1, 2, 3 or more halogens (eg, F, Cl, Br, I), For example, it may be substituted with 2 or 3 or more halogens. For example, halogen-substituted C _1-6 alkyl may be C _1-4 perhaloalkyl containing a trihalomethyl group (-CX′ ₃ ; X′ is halogen). For example, the halogen-substituted C _1-6 alkyl or halogen-substituted C _1-4 alkyl may be one substituted with fluorine, for example, a plurality of fluorine-substituted C _1-4 alkyl, tri It may include C _1-4 alkyl or C _1-4 perfluoroalkyl including a fluoromethyl group (—CF ₃ ).

Alternatively, R ¹ and R ² together are a substituted or unsubstituted 4-7 membered saturated or partially unsaturated carbocyclyl ring, or a substituted or unsubstituted 4-7 membered carbocyclyl ring comprising 1 to 3 nitrogen atoms. It may form a membered heteroaryl or heterocyclyl ring. In one embodiment, R ¹ and R ² together represent a 5 or 6 membered saturated or partially unsaturated carbocyclyl ring, or a 5 or 6 membered heteroaryl or heterocyclyl ring containing 1 or 2 nitrogen atoms. can be formed For example, R ¹ and R ² together can form, but are not limited to, cyclopentenyl, pyrrolyl, imidazolyl or pyrazolyl.

The carbocyclyl ring, heteroaryl or heterocyclyl ring formed by R ¹ and R ² is C 1 -substituted with halogen, oxo, OH, CN, amino, nitro, C _1-6 alkyl, halogen or _hydroxy selected from the group consisting of ₆ alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _2-6 alkoxyalkyl, C _1-6 alkylamino and di-(C _1-6 alkyl)-amino may be optionally substituted with one or more substituents. For example, the carbocyclyl ring, heteroaryl or heterocyclyl ring formed by R ¹ and R ² is halogen, OH, CN, amino, C _1-4 alkyl, halogen-substituted C _1-4 alkyl or may be optionally substituted with a substituent selected from C _1-4 alkoxy.

In Formula 1, R ³ may be —NR ³¹ R ³² or substituted or unsubstituted C _3-8 cycloalkyl.

In one embodiment, R ³ can be substituted or unsubstituted C _3-6 cycloalkyl. For example, R ³ can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, R ³ is —NR ³¹ R ³² , any one of R ³¹ and R ³² is H, the other is optionally substituted or unsubstituted 3-12 membered containing 1 nitrogen or oxygen atom It may be a saturated or partially unsaturated carbocyclyl or heterocyclyl ring. For example, any one of R ³¹ and R ³² is H and the other is a substituted or unsubstituted 5-8 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ringyl optionally containing 1 oxygen atom. can The carbocyclyl or heterocyclyl ring may optionally be bridged or form a spiro ring.

For example, any one of R ³¹ and R ³² is H, and the other one is cyclohexyl, cycloheptyl, cyclooctyl, oxacyclohexyl, oxacycloheptyl, oxacyclooctyl, bicyclohexanyl, bicycloheptanyl. , bicyclooctanyl, oxabicyclohexanyl, oxabicycloheptanyl, oxabicyclooctanyl, spirohexanyl, spiroheptanyl, spirooctanyl, oxaspirohexanyl, oxaspiroheptanyl and oxaspirooctanyl It can be selected from the group consisting of. Without limitation, any one of R ³¹ and R ³² is H and the other is bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.1.1]heptanyl, bicyclo[2.1.1]heptanyl Cyclo[4.1.1]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, oxabicyclo[2.1.1]hexanyl, oxabicyclo[2.2.1]heptanyl , oxabicyclo[3.1.1]heptanyl, oxabicyclo[4.1.1]octanyl, oxabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, bicyclo[3.1. 0]hexanyl, bicyclo[2.2.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[5.1.0]octanyl, bicyclo[4.2. 0] octanyl, bicyclo [3.3.0] octanyl, oxabicyclo [3.1.0] hexanyl, oxabicyclo [2.2.0] hexanyl, oxabicyclo [4.1.0] heptanyl, oxabi Cyclo[3.2.0]heptanyl, oxabicyclo[5.1.0]octanyl, oxabicyclo[4.2.0]octanyl, oxabicyclo[3.3.0]octanyl, spiro[2.3]hexanyl, spiro [2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro[3.3]heptanyl , may be selected from the group consisting of oxaspiro [2.5] octanyl and oxaspiro [3.4] octanyl. For example, one of R ³¹ and R ³² may be H and the other may be bicyclo[2.2.1]heptanyl or oxabicyclo[2.2.1]heptanyl.

Alternatively, R ³ is —NR ³¹ R ³² and R ³¹ and R ³² together with the nitrogen atom to which they are attached are substituted or unsubstituted 3-10 membered monocyclic comprising 1 or 2 nitrogen atoms or a bicyclic heterocyclyl ring. For example, R ³¹ and R ³² together with the nitrogen atom to which they are attached may form a substituted or unsubstituted 3-8 membered heterocyclyl ring containing 1 or 2 nitrogen atoms. For example, R ³¹ and R ³² together with the nitrogen atom to which they are attached may form a substituted or unsubstituted 4-7 membered heterocyclyl ring containing 1 nitrogen atom. For example, R ³¹ and R ³² together can form, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl.

In the above definitions of R ³ , R ³¹ and R ³² , a substituted C _3-8 cycloalkyl or C _3-6 cycloalkyl, a substituted carbocyclyl ring or a substituted heterocyclyl ring is halogen, oxo, OH, CN , amino, nitro, C _1-6 alkyl, halogen or hydroxy substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _2-6 alkoxyalkyl, C ₁ may be optionally substituted with one or more substituents selected from the group consisting of _-6 alkylamino and di-(C _1-6 alkyl)-amino. For example, the substituted C _3-8 cycloalkyl or C _3-6 cycloalkyl, substituted carbocyclyl ring or substituted heterocyclyl ring is each independently halogen, OH, CN, amino, C _1-4 may be substituted with one or more substituents selected from the group consisting of alkyl, C _1-4 alkoxy, C _1-4 alkylamino and di-(C _1-4 alkyl)amino. For example, the substituted C _3-8 cycloalkyl or C _3-6 cycloalkyl, substituted carbocyclyl ring or substituted heterocyclyl ring is each independently halogen (eg, F, Cl, Br, I), OH, amino, C _1-4 alkoxy (eg methoxy, ethoxy) and C _1-4 alkylamino (eg methylamino, ethylamino) or It may be substituted with two substituents.

In Formula 1, R ⁴ may be ring X and R ⁵ may be H. In this case, ring X may be -NR ^X1 R ^X2 or substituted or unsubstituted C _3-8 cycloalkyl.

In one embodiment, ring X can be substituted or unsubstituted C _3-6 cycloalkyl. For example, ring X can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, ring X is —NR ^X1 R ^X2 , R ^X1 and R ^X2 together with the nitrogen atom to which they are attached are substituted or unsubstituted 3-10 membered monocytic containing 1 or 2 nitrogen atoms It may form a cyclic or bicyclic heterocyclyl ring. For example, R ^X1 and R ^X2 may form a substituted or unsubstituted 3- to 7-membered heterocyclyl ring containing one or two nitrogen atoms together with the nitrogen atom to which they are attached. For example, R ^X1 and R ^X2 may form a substituted or unsubstituted 4- to 7-membered heterocyclyl ring including one nitrogen atom together with the nitrogen atom to which they are attached. For example, R ^X1 and R ^X2 together may form, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl.

wherein ring X is halogen, oxo, OH, CN, amino, nitro, C _1-6 alkyl, halogen or hydroxy substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy , C _2-6 alkoxyalkyl, C _1-6 alkylamino and di-(C _1-6 alkyl)-amino may be optionally substituted with one or more substituents selected from the group consisting of. In one embodiment, ring X is substituted with halogen, oxo, OH, C _1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _1-4 alkoxy and halogen It may be optionally substituted with one or more substituents selected from the group consisting of C _1-4 alkoxy. For example, ring X can be halogen (eg F, Cl, Br, I), oxo, OH, C _1-4 alkyl (eg methyl, ethyl) and halogen substituted C _1-4 alkyl (eg, CHF ₂ , CH ₂ F, CF ₃ , CH ₂ CF ₃ ) may be optionally substituted with one or two substituents selected from the group consisting of.

Alternatively, R ⁴ and R ⁵ may be joined together with the carbon atom of the benzene ring to which they are attached to a *—CO—NR ⁶ —CH ₂ — group to form a five membered lactam ring. In this case, * represents the position at which R ⁴ is bonded to the benzene ring. In this case, R ⁶ may be H, C _1-6 alkyl, or C _1-6 alkyl substituted with a halogen atom. For example, R ⁶ can be H or C _1-4 alkyl.

However, in Formula 1, R ³ is -NR ³¹ R ³² , R ³¹ and R ³² form a substituted or unsubstituted 3- to 10-membered heterocyclyl ring, R ⁴ is Ring X, and Ring X is When -NR ^X1 R ^X2 , if either of R ¹ and R ² is H, then the other of R ¹ and R ² is not C _1-6 alkyl substituted with halogen.

According to an embodiment of the present invention, R ¹ and R ² together are a substituted or unsubstituted 5- or 6-membered saturated or partially unsaturated carbocyclyl ring, or a substituted or unsubstituted 4-membered ring containing 1 nitrogen atom. to 7 membered heteroaryl or heterocyclyl ring; R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclyl ring containing 1 or 2 nitrogen atoms; R ⁴ is ring X, R ⁵ is H, wherein ring X is -NR ^X1 R ^X2 and R ^X1 and R ^X2 together with the nitrogen atom to which they are attached are substituted or unsubstituted 4 members containing one nitrogen atom to 7 membered heterocyclyl rings. In this case, the substituted rings may each independently be optionally substituted with a substituent selected from halogen, OH, C _1-6 alkyl, or C _1-6 alkyl substituted with halogen or hydroxy.

For example, R ¹ and R ² together form cyclopentenyl, pyrrolyl, imidazolyl or pyrazolyl; R ³¹ and R ³² together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl optionally substituted with halogen, OH, or C _1-4 alkyl substituted with halogen; ring X is —NR ^X1 R ^X2 , R ⁵ is H, and R ^X1 and R ^X2 taken together form halogen, C _1-4 alkyl substituted with halogen, or pyrrolidinyl or piperidinyl optionally substituted with OH can do.

According to an embodiment of the present invention, R ¹ and R ² are each independently H, halogen or C _1-6 alkyl; R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-7 membered heterocyclyl ring containing 1 nitrogen atom; R ⁴ is ring X, R ⁵ is H, wherein ring X is -NR ^X1 R ^X2 and R ^X1 and R ^X2 together with the nitrogen atom to which they are attached are substituted or unsubstituted 4 members containing one nitrogen atom to 7 membered heterocyclyl rings. The aforementioned R ³¹ , R ³² ,R ^X1 and R ^X2 _, And specific examples of substituents thereof may be equally applied to the present embodiment, if applicable.

According to one embodiment of the present invention, R^One and R²are each independently H, halogen or C_1-6 alkyl, for example R^One and R² one is H and the other is halogen or C_1-4 alkyl; R³¹ and R³² any one is H and the other is a substituted or unsubstituted 5-8 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring optionally containing 1 oxygen atom, wherein the carbocyclyl or heterocyclyl may optionally be bridged or form a spiro ring, for example R³¹ and R³² one is H and the other is oxabicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptanyl; R⁴is ring X and R⁵is H and ring X is -NR^X1R^X2and R^X1 and R^X2may be a substituted or unsubstituted 4-7 membered heterocyclyl ring containing 1 nitrogen atom together with the nitrogen atom to which they are attached. above R.³¹, R³²,R^X1 and R^X2 _, and specific examples of substituents thereof may be equally applied to the present embodiment, if applicable.

According to an embodiment of the present invention, any one of R ¹ and R ² is H, and the other is C _1-6 alkyl substituted with halogen (eg, C _1-4 alkyl substituted with fluoro, such as For example, when CF ₃ ), R ³ is —NR ³¹ R ³² or substituted or unsubstituted C _3-6 cycloalkyl, either of R ³¹ and R ³² is H and the other is optionally 1 oxygen. A substituted or unsubstituted 5- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring containing atoms, wherein the carbocyclyl or heterocyclyl ring may optionally be bridged or form a spiro ring, e.g. For example, one of R ³¹ and R ³² is H and the other is oxabicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptanyl; R ⁴ is ring X, R ⁵ is H, and ring X is —NR ^X1 R ^X2 or substituted or unsubstituted C _3-6 cycloalkyl, wherein R ^X1 and R ^X2 together with the nitrogen atom to which they are attached are 1 A substituted or unsubstituted 4- to 7-membered heterocyclyl ring containing two nitrogen atoms may be formed. The aforementioned R ³¹ , R ³² ,R ^X1 and R ^X2 _, And specific examples of substituents thereof may be equally applied to the present embodiment, if applicable.

According to an embodiment of the present invention, any one of R ¹ and R ² is H, and the other is C _1-6 alkyl substituted with halogen (eg, C _1-4 alkyl substituted with fluoro, such as For example, in the case of CF ₃ ), R ³ is —NR ³¹ R ³² , and R ³¹ and R ³² are substituted or unsubstituted 4-7 membered heterocycle containing 1 nitrogen atom together with the nitrogen atom to which they are attached. forming a reel ring; R ⁴ is ring X, R ⁵ is H, and ring X can be substituted or unsubstituted C _3-6 cycloalkyl. The aforementioned R ³¹ , R ³² ,R ^X1 and R ^X2 _, And specific examples of substituents thereof may be equally applied to the present embodiment, if applicable.

The reaction for preparing the compound of the present invention can be carried out in a suitable solvent which can be appropriately selected by a person skilled in the art of organic synthesis. Suitable solvents are those that are substantially unreactive with the starting materials (reactants), intermediates or objects at the temperature at which the reaction occurs. A person skilled in the art will be able to properly select a suitable solvent for a particular reaction step.

The compound of the present invention can be synthesized according to the synthesis procedure described in the following examples, and based on this, reactants and reaction conditions (eg, reaction solvent, reaction temperature, reaction time, reaction catalyst, etc.) according to the structure of the target compound, etc. With appropriate modifications, the target compound may be prepared.

Each reaction can be monitored by an appropriate method known in the art. For example, the synthesis of the target compound may be monitored by spectroscopic means, such as NMR (eg, ¹ H or ¹³ C), mass spectroscopy, or chromatography (HPLC or TLC).

In one embodiment, in the compound of Formula 1, R ¹ and R ⁵ are each H, and R ³ is -NHR ³¹ A compound of Formula 1 may be prepared according to Scheme A below.

[Scheme A]

In step 1, the aniline compound and the dichloropyrimidine compound are mixed in a suitable organic solvent such as dichloroethane (DCE), t-butanol (tBuOH), etc. optionally in the presence of a suitable catalyst such as ZnCl ₂ , triethylammonium (TEA), etc. can be reacted. In one embodiment, the reaction may be carried out at about -10 °C to about 25 °C, about -5 °C to about 10 °C, or about 0 °C for about 1 to 5 hours, or about 2 to 3 hours.

In step 2, the compound obtained in step 1 may be mixed with an appropriate amine compound (NH ₂ R ³¹ ) and an appropriate organic solvent, such as N,N-diisopropylethylamine (DIEA), acetonitrile (ACN), or the like. . In one embodiment, the reaction may be carried out at about 50 °C to about 1500 °C, about 80 °C to about 120 °C, or about 100 °C.

In one embodiment, in the compound of Formula 1, R ¹ and R ⁵ are each H and R ³ is C _3-8 cycloalkyl may be prepared according to Scheme B below.

[Scheme B]

In step 1, the chloropyrimidine compound and the carboxylic acid compound (R ³ COOH) are optionally mixed with a suitable catalyst such as (NH ₄ ) ₂ S ₂ O ₈ , AgNO ₃ in a suitable solvent such as a mixed solvent of ACN and H ₂ O. It can be reacted by mixing in the presence of such. In one embodiment, the reaction is at about 50 °C to about 120 °C, about 70 °C to about 100 °C, or about 80 °C for about 10 hours to about 20 hours, about 12 hours to about 18 hours, or about 16 hours. can be done

In step 2, the compound obtained in step 1 is mixed with an appropriate aniline compound and a suitable solvent such as butanol (BuOH), ACN, DIEA, optionally by dropwise addition of 1 drop of concentrated hydrochloric acid, to obtain the compound of formula 1. In one embodiment, the reaction is at about 50 °C to about 120 °C, about 70 °C to about 100 °C, or about 80 °C for about 30 minutes to about 15 hours, about 30 minutes to about 10 hours, about 1 hour to about This can be done for 12 hours.

In one embodiment, the compound of Formula 1 wherein R ³ is —NR ³¹ R ³² , R ⁴ is Ring X, and R ⁵ is H may be prepared according to Scheme C below.

[Scheme C]

In step 1, the dichloropyrimidine compound and the amine compound (NHR ³¹ R ³² ) are mixed with an appropriate organic solvent, such as DIEA (diisopropylethylamine), DCM (dichloromethane), DMF (dimethylformamide) and ACN (aceto The reaction may be carried out in one or more organic solvents selected from the group consisting of nitrile). For the reaction of step 1, for example, at a temperature of about -80 ° C. to about 80 ° C., for example, about 10 minutes to about 10 hours, preferably about 15 minutes to about 6 hours may be stirred and mixed.

In step 2 above, the compound obtained in step 1 may be reacted with aniline substituted with ring X by adding 1 drop of HCl optionally in a suitable solvent such as nBuOH. For the reaction of step 2, for example, at a temperature of about 50° C. to about 150° C., preferably about 80° C. to about 120° C., for example, about 30 minutes to about 10 hours, preferably about 1 hour to about 6 hours. It can be stirred and mixed.

Alternatively, a compound of Formula 1 wherein R ³ is —NR ³¹ R ³² , R ⁴ is Ring X and R ⁵ is H may be prepared according to Scheme D below.

[Scheme D]

In step 1, the dichloropyridine compound may be stirred and mixed in an appropriate organic solvent, such as dichloroethane (DCE) and t-BuOH, and ZnCl ₂ may be added thereto, followed by stirring and mixing with the ring X-substituted aniline compound.

In step 2, the compound obtained in step 1 is mixed with an appropriate amine compound (NHR ³¹ R ³² ) with an appropriate organic solvent such as DIEA (diisopropylethylamine), DCM (dichloromethane), DMF (dimethylformamide) and The reaction may be carried out in one or more organic solvents selected from the group consisting of ACN (acetonitrile). For the reaction of step 2, for example, at a temperature of about -80 ° C. to about 80 ° C., for example, about 10 minutes to about 10 hours, preferably about 15 minutes to about 6 hours may be stirred and mixed.

The preparation method of Chemical Formula 1 described above is exemplary, and may be modified by selecting an appropriate solvent, catalyst, reaction conditions, etc. depending on the type of starting material for obtaining the final compound, and these solvents, catalysts, reaction conditions, etc. It is well known to those skilled in the art.

In one embodiment, the compound of Formula 1 may be selected from the group consisting of:

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

; and

.

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The C _1-6 alkyl may be a C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ alkyl group. Non-limiting examples of the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl. have.

The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine.

The term “cycloalkyl” refers to a saturated monocyclic hydrocarbon group. The cycloalkyl may contain 3 to 12, such as 3 to 10, 3 to 8, or 3 to 6 carbon atoms. For example, C _3-8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "carbocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group. As used herein, the carbocyclyl is intended as a term inclusive of the cycloalkyl. The term "carbocyclyl" as used herein refers to a saturated or partially unsaturated carbocyclic ring having 3 to 20, 3 to 10, 3 to 8, 4 to 7, 5 to 8, 5 or 6 carbon atoms. can refer to The term carbocyclyl includes mono-, bi-, tri-, fused, bridged and spiro-ring systems and combinations thereof. In one embodiment, the bicyclic carbocyclyl may contain 6 to 12, 6 to 10, or 6 to 8 carbon atoms. In other embodiments, the spiro carbocyclyl may contain 5 to 12, 6 to 10, or 6 to 8 carbon atoms. Representative examples of monocyclic carbocyclyl may include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. Bicyclic carbocyclyl having 6 to 12 ring atoms is [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ] ring systems, for example, bridged bicyclic rings such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.2]nonanyl. Spiro carbocyclyls may include spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[4.5]decanyl, and the like.

The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. The heterocyclyl ring group may be a single ring group, a two ring group, or a three ring group. The two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group. Heterocyclyl ring groups are 3 to 20, 3 to 12, 3 to 10, 3 to 8, 3 to 7, 4 to 7, 5 to 7, 3 to 6, It may contain 4 to 6, or 5 to 6 ring atoms. The heteroatom may be any one or more selected from the group consisting of N, O and S. For example, the heteroatom can be 1 to 3 N, or 1 or 2 N, 1 N, or 1 O. The heteroatom may be one or two N. Non-limiting examples of monocyclic heterocyclyl rings include aziridine, azetidine, pyrrolidine, piperidine, azepane, and the like. Non-limiting examples of bridged or spiro heterocyclic rings include oxabicyclohexanyl, oxabicycloheptanyl, oxabicyclooctanyl, oxaspirohexanyl, oxaspiroheptanyl, oxaspirooctanyl, azabicyclohexane yl, azabicycloheptanyl, azabicyclooctanyl, azaspirohexanyl, azaspiroheptanyl, azaspirooctanyl, and the like.

The term "aryl" also includes groups in which an aromatic ring is fused to one or more carbon rings. The C ₆ -C ₃₀ aryl group may be, for example, a C ₆ to C ₁₅ , or a C ₆ to C ₁₀ aryl group. Non-limiting examples of aryl include phenyl, naphthyl, or tetrahydronaphthyl.

The term “heteroaryl” refers to a monocyclic or bicyclic aromatic compound containing one or more heteroatoms selected from the group consisting of N, O, P and S, the remaining ring atoms being carbon. The heteroaryl group may contain, for example, 1 to 3, 1 or 2 heteroatoms, and 4 to 10, 5 to 10, 4 to 7, 5 or 6 ring atoms. may include. The S or N may be oxidized to have several oxidation states. Non-limiting examples of "heteroaryl" include pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, or 1,2,3-oxadiazolyl, and the like.

The term "hydroxy" refers to a -OH functional group (hydroxyl group).

The term “alkoxy” refers to an alkyl bound to an oxygen atom. For example, the C ₁ to C ₂₀ alkoxy group may be, for example, C ₂ to C ₁₅ , C ₂ to C ₁₀ , or C ₂ to C ₅ alkoxy group. C _1-6 alkoxy may include methoxy, ethoxy, propoxy, and the like.

The term “amino” group refers to a —NH ₂ group.

The term “nitro” refers to —NO ₂ .

The term "cyano" refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom as -CN.

The term "oxo" refers to =O, and "substituted with oxo" means that the carbon atom has an =O substituent in the form -C(=O)-.

The term “substituted” of “substituted or unsubstituted” refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and “substituent” refers to an introduced atomic group . When the term “substituted” or “substituted” is used herein without limitation of the substituent, the substituent is, for example, a halogen atom, a C ₁ to C ₂₀ alkyl group substituted with a halogen atom (eg, CCF ₃ , CHCF ₂ , CH ₂ F, CCl ₃ etc.), C ₁ to C ₂₀ alkoxy, C ₂ to C ₂₀ alkoxyalkyl, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or its Salt, sulfonyl group, sulfamoyl group, sulfonic acid group or a salt thereof, phosphoric acid or a salt thereof, or C ₁ to C ₂₀ alkyl group, C ₂ to C ₂₀ alkenyl group, C ₂ to C ₂₀ alkynyl group, C ₁ to C ₂₀ heteroalkyl group, C ₆ to C ₂₀ aryl group, C ₆ to C ₂₀ arylalkyl group, C ₆ to C ₂₀ heteroaryl group, C ₇ to C ₂₀ heteroarylalkyl group, C ₆ to C ₂₀ heteroaryloxy group, and C It may be a ₆ to C ₂₀ heteroaryloxyalkyl group or a C ₆ to C ₂₀ heteroarylalkyl group.

For example, the substituent may be halogen, oxo, OH, CN, amino, nitro, C _1-6 alkyl, halogen or hydroxy substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _{1 -} and one or more substituents selected from the group consisting of ₆ alkoxy, C _2-6 alkoxyalkyl, C _1-6 alkylamino and di-(C _1-6 alkyl)-amino.

The term "isomer" of the term "stereoisomer" refers to a compound that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomer may be a diastereomer or an enantiomer. Enantiomers refer to isomers that do not overlap their mirror images, such as the relationship between the left and right hands, and are also called optical isomers. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when 4 or more substituents differ from each other at the chiral central carbon. Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers caused by different spatial arrangement of atoms. The diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.

The term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.

The term "salt" refers to inorganic and organic acid addition salts of compounds. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

The compound of Formula 1 may be a Leucine-rich repeat kinase 2 (LRRK2) inhibitor. The LRRK2 may be a protein belonging to a leucine-rich repeat kinase family. The LRRK2 may also be referred to as AURA17, DARDARIN, PARK8, RIPK7, or ROCO2. The LRRK2 is Uniprot No. It may be a protein comprising the amino acid sequence of Q5S007. The LRRK2 may include a Gly2019Ser mutation.

Another aspect of the present invention is to treat a disease or condition mediated by or related to LRRK2, including the compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to an aspect A pharmaceutical composition for preventing or treating is provided.

The compound of Formula 1, stereoisomer, solvate, pharmaceutically acceptable salt, and LRRK2 are the same as described above.

The disease or disorder mediated by or related to LRRK2 may be a neurodegenerative disease. The term "neurodegenerative disease" refers to any disease associated with degenerative changes in the nervous system, and specifically may refer to degenerative brain diseases associated with degenerative changes in the brain. The degenerative brain disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich's Syndrome, Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia It can be selected from the group consisting of.

In addition, diseases or disorders mediated by or associated with LRRK2 include dyskinesia; central nervous system disorders; cancer such as kidney cancer, breast cancer, prostate cancer, blood cancer, lung cancer, acute myeloid leukemia or multiple myelopathy; inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, amyotrophic lateral sclerosis, leprosy, Inflammatory Bowel Disease, tuberculosis, and the like.

The pharmaceutical composition may further include a known active ingredient having degenerative brain disease prevention, treatment, or amelioration activity. Known active ingredients having degenerative brain disease prevention, treatment, or amelioration activity are levodopa, catechol-O-methyltransferase (COMT) inhibitor, dopamine agonist, MAO-B (monoamine oxidase) B) an inhibitor, amantadine, an anticholinergic agent, an acetylcholinesterase inhibitor, or an NMDA receptor antagonist (N-Methyl-D-aspartate receptor antagonist). COMT inhibitors may be opicapone, entacapone and tolcapone. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, and apomorphine. and lisuride. MAO-B inhibitors are safinamide, selegiline, and rasagiline. The acetylcholinesterase inhibitor may be tacrine, rivastigmine, galantamine and donepezil. The NMDA receptor antagonist may be memantine. The compound represented by Formula 1, a derivative, stereoisomer, solvate, or pharmaceutically acceptable salt thereof and the known active ingredient may be a single or separate composition for simultaneous or sequential administration.

The term "prevention" refers to any action of inhibiting the onset of or delaying the onset of a disease or disorder mediated by or related to LRRK2 by administration of the pharmaceutical composition. The term “treatment” refers to any action in which the symptoms of a disease or disorder mediated by or related to LRRK2 are ameliorated or beneficially altered by administration of the pharmaceutical composition.

The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used in the sense of including excipients, diluents or adjuvants. The carrier may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pi It may be selected from the group consisting of rolidone, water, physiological saline, buffers such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, or a combination thereof.

The pharmaceutical composition may be prepared in any formulation according to a conventional method. The composition may be formulated, for example, as an oral dosage form (eg, a powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, an injection). In addition, the composition may be prepared as a systemic formulation, or as a topical formulation.

In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid formulation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid formulation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the oral liquid formulation may be a suspension, an internal solution, an emulsion, or a syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives. In the pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository. Non-aqueous solvents or suspending agents may include vegetable oils or esters. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin, or glycerogelatin.

The pharmaceutical composition includes the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. "Active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (eg, treatment of degenerative brain disease).

The pharmaceutical composition may include the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof in an effective amount. The term "effective amount" refers to an amount sufficient to effect the prevention or treatment of a disease or disorder when administered to a subject in need thereof. The effective amount can be appropriately selected by those skilled in the art depending on the cell or individual to be selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the individual, the degree of disease or disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof may be, for example, in an amount from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. may be administered in divided doses 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times in 1 month to 12 months. In the pharmaceutical composition, the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof is present in an amount of from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. may be included.

The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.

Another aspect of the present invention is to prevent a disease or disorder mediated by or related to LRRK2, comprising administering to an individual a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to an aspect or a method of treatment.

The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and diseases mediated by or related to LRRK2, prevention, and treatment are as described above.

The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject may be suffering from, or likely to suffer from, a condition associated with a disease mediated by or associated with LRRK2.

The method may further comprise administering to the subject a known active ingredient having an effect of preventing or treating a disease or disorder mediated by or related to LRRK2. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.

The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.

The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the severity of the disease or disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. The dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg, on an adult basis. can be The administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year.

Another aspect of the present invention is the use of a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect, for use in the prevention or treatment of a disease or condition mediated by or related to LRRK2. to provide.

Another aspect of the present invention is a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable compound according to one aspect, for preparing a medicament for preventing or treating a disease or condition mediated by or related to LRRK2. Uses of salts are provided.

The disease or disorder mediated by or related to LRRK2, prevention, treatment, compound of Formula 1, stereoisomer, solvate, and pharmaceutically acceptable salt are as described above.

The pyrimidine compound of Formula 1 according to the present invention has excellent LRRK2 inhibitory activity, and thus a pharmaceutical composition for preventing or treating a disease mediated by or related to LRRK2 (eg, Parkinson's disease), and treatment and prevention of a disease or disorder using the same method can be used effectively.

Hereinafter, it will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

제조예 1: 4-(아제판-1-일)아닐린Preparation Example 1: 4-(azepan-1-yl)aniline

단계 1: 1-(4-니트로페닐)아제판의 합성Step 1: Synthesis of 1-(4-nitrophenyl)azepane

4-fluoronitrobenzene (1.00 g, 7.08 mmol, 1.00 equiv) and hexamethyleneimine (1.00 g, 10.63 mmol, 1.50 equiv) in ACN (10 mL) were stirred mixed and DIEA (2.70 g, 21.26 mmol, 3.00 equiv) equivalent) was added. The resulting mixture was stirred at 80° C. for 2 h, and the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (10:1) to give 1-(4-nitrophenyl)azepane (1 g, 57.65%) as a yellow solid. . ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.11 (d, J = 12.0 Hz, 2H), 6.63 (d, J = 12.0 Hz, 2H), 3.62-3.53 (m, 4H), 1.91 -1.76 (m, 4H), 1.67-1.51 (m, 4H); MS m/z: 221 [M+H] ⁺ .

단계 2: 4-(아제판-1-일)아닐린의 합성Step 2: Synthesis of 4-(azepan-1-yl)aniline

Stir-mix 1-(4-nitrophenyl)azepane (1.00 g, 4.540 mmol, 1.00 equiv) and Pd/C (300 mg, 10%) in MeOH (15 mL) under hydrogen atmosphere at 25° C. for 1 h stirred for a while. The resulting mixture was filtered and the filter cake was washed with MeOH (3×30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 4-(azepan-1-yl)aniline (700 mg, 72.93%) as a black oil. . MS m/z: 191 [M+H] ⁺ .

제조예 2: 4-[1,4-디옥사-7-아자스피로[4.4]노난-7-일]아닐린Preparation 2: 4- [1,4-dioxa-7-azaspiro [4.4] nonan-7-yl] aniline

In the same manner as in Preparation Example 1, except that 1,4-dioxa-7-azaspiro[4.4]nonane was used instead of hexamethyleneimine in step 1 of Preparation Example 1, 4-[1,4-dioxa- 7-azaspiro[4.4]nonan-7-yl]aniline (77.52%) was obtained as a brown solid. MS m/z: 221 [M+H] ⁺ .

제조예 3: 2-클로로-4-사이클로펜틸-5-(트리플루오로메틸)피리미딘Preparation 3: 2-chloro-4-cyclopentyl-5- (trifluoromethyl) pyrimidine

2-chloro-5-(trifluoromethyl)pyrimidine (1.00 g, 5.47 mmol, 1.00 equiv) and cyclopentanecarboxylic acid (750 mg, 6.57 mmol) in ACN (7 mL) and H ₂ O (7 mL) , 1.20 equiv) were stirred and mixed, (NH ₄ ) ₂ S ₂ O ₈ (1.00 g, 4.38 mmol, 0.80 equiv) and AgNO ₃ (148 mg, 0.87 mmol, 0.16 equiv) were added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and partially concentrated under reduced pressure. The mixture was extracted with CH ₂ Cl ₂ (3×300 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography to give 2-chloro-4-cyclopentyl-5-(trifluoromethyl)pyrimidine (600 mg, 37.58%) off-white (off). -white) as an oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.75 (s, 1H), 3.53-3.36 (m, 1H), 2.14-2.01 (m, 2H), 2.00-1.85 (m, 4H), 1.84-1.67 (m, 2H); MS m/z: 251 [M+H] ⁺ .

제조예 4: 2-클로로-4-사이클로프로필-5-(트리플루오로메틸)피리미딘Preparation 4: 2-chloro-4-cyclopropyl-5- (trifluoromethyl) pyrimidine

2-chloro-4-cyclopropyl-5- (trifluoromethyl) pyrimidine (16.40 in the same manner as in Preparation Example 3, except that cyclopropanecarboxylic acid was used instead of cyclopentanecarboxylic acid in Preparation Example 3) %) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.95 (s, 1H), 2.33-2.18 (m, 1H), 1.35-1.30 (m, 2H), 1.30-1.20 (m, 2H); MS m/z: 223 [M+H] ⁺ .

제조예 5: 2-클로로-4-사이클로헥실-5-(트리플루오로메틸)피리미딘Preparation 5: 2-chloro-4-cyclohexyl-5- (trifluoromethyl) pyrimidine

2-chloro-4-cyclohexyl-5-(trifluoromethyl)pyrimidine (47.58) in the same manner as in Preparation Example 3, except that cyclohexanecarboxylic acid was used instead of cyclopentanecarboxylic acid in Preparation Example 3 %) as a colorless oil. MS m/z: 265/267 [M+H] ⁺ .

제조예 6: 2-클로로-4-(피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘Preparation 6: 2-chloro-4- (pyrrolidin-1-yl) -5- (trifluoromethyl) pyrimidine

2,4-dichloro-5-(trifluoromethyl)pyrimidine (300 mg, 1.38 mmol, 1.00 equiv) in DCM (5 mM) was stirred mixed and pyrrolidine (98 mg, 1.38 mmol, 1.00 equiv) and DIEA (536 mg, 4.14 mmol, 3.00 equiv) were added dropwise at -70°C under a nitrogen atmosphere. The resulting mixture was stirred at -70°C for 0.5 h under a nitrogen atmosphere. The resulting mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc/PE (1/2), to 2-chloro-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine (150 mg, 41%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.51 (s, 1H), 3.57 (s, 4H), 1.95-1.88 (m, 4H); MS m/z: 252/254 [M+H] ⁺ .

제조예 7: 4-[3-(트리플루오로메틸)피페리딘-1-일]아닐린Preparation 7: 4-[3-(trifluoromethyl)piperidin-1-yl]aniline

단계 1: 1-(4-니트로페닐)-3-(트리플루오로메틸)피페리딘Step 1: 1-(4-nitrophenyl)-3-(trifluoromethyl)piperidine

3-(trifluoromethyl)piperidine in ACN (10 mL); Methyl chloride (1.00 g, 4.91 mmol, 1.00 equiv) and 4-fluoronitrobenzene (1.10 g, 7.79 mmol, 1.59 equiv) were stirred to mix and DIEA (2.0 g, 15.47 mmol, 3.15 equiv) was added. The resulting mixture was stirred at 80° C. for 3 h under a nitrogen atmosphere and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 1-(4-nitrophenyl)-3-(trifluoromethyl)piperidine (1.2 g, 82.86%) light yellow. obtained as a solid. MS m/z: 275 [M+H] ⁺ .

단계 2: 4-[3-(트리플루오로메틸)피페리딘-1-일]아닐린Step 2: 4-[3-(trifluoromethyl)piperidin-1-yl]aniline

The compound obtained in step 1 (1.20 g, 4.376 mmol, 1.00 equiv) and Pd/C (300 mg, 10%) were mixed in MeOH (10 mL) under a hydrogen atmosphere (3 atm) at 25° C. by stirring for 1 hour. did. The solid was filtered off and the filtrate was concentrated under reduced pressure to obtain 4-[3-(trifluoromethyl)piperidin-1-yl]aniline (1 g, 84.21%) as a brown solid. MS m/z: 245 [M+H] ⁺ .

제조예 8: 4-브로모-2-클로로-6-요오도피리미딘Preparation 8: 4-bromo-2-chloro-6-iodopyrimidine

단계 1: 2-클로로-4-요오도피리미딘의 합성Step 1: Synthesis of 2-chloro-4-iodopyrimidine

2-Chloro-pyrimidine (2.00 g, 17.46 mmol, 1.00 equiv) was mixed by stirring in THF (15 mL) and TMPMgCl.LiCl (1.1M in THF) (17.50 mL, 19.21 mmol, 1.10 equiv) was placed in a nitrogen atmosphere. It was added dropwise at -60°C under The resulting mixture was stirred under a nitrogen atmosphere at -60°C for 2 h, and ZnCl ₂ (1.0 M in THF) (19.21 mL, 19.21 mmol, 1.10 equiv) was added dropwise at -60°C. The mixture was allowed to warm to room temperature, then to the resulting mixture was added dropwise I ₂ (6.65 g, 26.19 mmol, 1.50 equiv) dissolved in dry THF (15 mL), and the resulting mixture was stirred at 25° C. for 1 h. The reaction was quenched with saturated aqueous NH ₄ Cl (100 mL) and saturated aqueous Na ₂ S ₂ O ₃ (60 mL) at room temperature, the mixture was poured into water and extracted with ether (5×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography to give 2-chloro-4-iodopyrimidine (1.0 g, 19.1%) as a yellow oil; MS m/z: 241/243[M+H] ⁺ .

단계 2: 4-브로모-2-클로로-6-요오도피리미딘의 합성Step 2: Synthesis of 4-bromo-2-chloro-6-iodopyrimidine

The compound obtained in step 1 (900 mg, 3.74 mmol, 1.00 equiv) was mixed by stirring in THF (10 mL), and TMPMgCl.LiCl (1.1M in THF) (5.0 mL, 5.49 mmol, 1.47 equiv) was placed in a nitrogen atmosphere. It was added dropwise at -60 °C under The resulting mixture was stirred at -60°C under a nitrogen atmosphere for 1 hour, and then 1,2-dibromo-1,1,2,2-tetrachloroethane (1.82 g, 5.61 mmol, 1.50 eq.) in the resulting mixture. ) was added at -78°C and the resulting mixture was warmed to -65°C and stirred at -65°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give 4-bromo-2-chloro-6-iodopyrimidine (900 mg, 60.2%) as a yellow solid. MS m/z: 319/321/323[M+H] ⁺ .

제조예 9:(3S,4S)-N-벤질-4-메톡시-N-메틸피롤리딘-3-아민(화합물 5)Preparation 9: (3S, 4S) -N-benzyl-4-methoxy-N-methylpyrrolidin-3-amine (Compound 5)

단계 1: 화합물 2의 합성Step 1: Synthesis of compound 2

To a mixture of compound 1 (2 g, 11.82 mmol, 1 equiv) in DCM (50 mL) was added m-CPBA (3.60 g, 17.73 mmol, 85% purity, 1.5 equiv) at 20°C. The mixture was stirred at 20° C. for 24 h. To the mixture was added a saturated aqueous solution of Na ₂ S ₂ O ₃ (30 mL) and stirred at 20° C. for 10 minutes. The reaction was confirmed with potassium iodide-starch test paper to determine whether m-CPBA was decomposed. Otherwise, the process of adding Na ₂ S ₂ O ₃ aqueous solution was repeated and stirred until the test paper did not turn blue. The mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50mLx3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give compound 2 (1.85 g, 84.5%) as a yellow oil. . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.77 - 3.63 (m, 2 H), 3.59 (d, J = 3.6 Hz, 2 H), 3.24 (dd, J = 12.8, 4.8 Hz, 2 H), 1.37 (s, 9 H).

단계 2: 화합물 3의 합성Step 2: Synthesis of compound 3

To compound 2 (1.8 g, 9.72 mmol, 1 equiv) was added compound 6A (1.77 g, 14.58 mmol, 1.88 mL, 1.5 equiv) in EtOH (25 mL), the mixture was warmed to 95° C. and stirred for 16 h. . The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give compound 3 (1.3 g, 43.7% yield) as a mixture of optical isomers in the form of a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.28 - 7.37 (m, 5 H), 4.33 (d, J = 6.4 Hz, 1 H), 3.73 (s, 1 H), 3.66 - 3.52 (m, 3 H), 3.34 (br s, 1 H), 3.25 - 3.13 (m, 1 H), 3.09 (br s, 1 H), 2.25 (s, 3 H), 1.46 (s, 9 H); LCMS: Rt = 0.977 min, MS (ESI) m/z = 307.2 [M+H] ⁺ .

단계 3: 화합물 4의 합성Step 3: Synthesis of compound 4

The optical isomer mixture (1.1 g, 3.59 mmol, 1 equiv) obtained in step 2 above was mixed in THF (15 mL) and NaH (215.38 mg, 5.39 mmol, 60% purity, 1.5 equiv) was added at 0 °C and 20 min. stirred for a while. Then MeI (2.32 g, 16.35 mmol, 1.02 mL, 4.55 equiv) was added to the mixture at 0° C., then warmed to 20° C. and stirred for 2 h. The reaction was quenched with anhydrous NH ₄ Cl and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 4 (700 mg, 60.9%) as a mixture of optical isomers in the form of a yellow oil. ¹ H NMR(400 MHz, CDCl ₃ )δ ppm 7.16 (br d, J = 4.0 Hz, 3 H), 7.12 - 7.07 (m, 2 H), 3.96 - 3.57 (m, 2 H), 3.23 - 3.56 ( m, 4 H), 3.19 (s, 3 H), 3.15- 2.87 (m, 2 H), 2.05 (br s, 3 H), 1.30 (s, 9 H); LCMS: RT = 0.773 min, MS (ESI) m/z = 321.3 [M+H] ⁺ .

단계 4: 화합물 5((3R,4R)-N-벤질-4-메톡시-N-메틸피롤리딘-3-아민)의 합성Step 4: Synthesis of compound 5 ((3R,4R)-N-benzyl-4-methoxy-N-methylpyrrolidin-3-amine)

The optical isomer mixture obtained in step 3 above (500 mg, 1.56 mmol, 1 equiv) was mixed in DCM (6 mL) and TFA (2.31 g, 20.29 mmol, 1.50 mL, 13 equiv) was added in one portion at 0°C. The mixture was stirred at 0° C. for 3 min, then warmed to 20° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent and compound 5 (520 mg, 99.67%, TFA salt) was obtained as a mixture of optical isomers in the form of a yellow oil. LCMS: RT = 0.597 min, MS (ESI) m/z = 221.2 [M+H] ⁺ .

실시예 1: N2-[4-(아제판-1-일)페닐]-N4-[(1R,4R)-바이사이클로[2.2.1]헵탄-1-일]-5-(트리플루오로메틸)피리미딘-2,4-디아민Example 1: N2-[4-(azepan-1-yl)phenyl]-N4-[(1R,4R)-bicyclo[2.2.1]heptan-1-yl]-5-(trifluoromethyl ) pyrimidine-2,4-diamine

The compound of Example 1 was synthesized according to Scheme 1 below.

[Scheme 1]

단계 1: N-[4-(아제판-1-일)페닐]-4-클로로-5-(트리플루오로메틸)피리미딘-2-아민의 합성Step 1: Synthesis of N-[4-(azepan-1-yl)phenyl]-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine

DCE: Stir mixed 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.46 mmol, 1.00 equiv) in tBuOH (1:1) (3.00 mL), diethylether (1 mL) , 1.00 mmol, 2.17 eq _. ) was added dropwise at 0° C. under nitrogen atmosphere. After stirring for 1 h, the compound of Preparation 1 (96.47 mg, 0.507 mmol, 1.10 equiv) was added followed by DCE: TEA (51 mg, 0.50 mmol, 1.10 equiv) in tBuOH (1:1) (3.00 mL). The solution was added dropwise. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (10:1) to N-[4-(azepan-1-yl)phenyl]-4-chloro-5-(tri Fluoromethyl)pyrimidin-2-amine (100 mg, 52.66%) was obtained as a yellow solid. MS m/z: 371/373 [M+H] ⁺ .

단계 2: N2-[4-(아제판-1-일)페닐]-N4-[(1R,4R)-바이사이클로[2.2.1]헵탄-1-일]-5-(트리플루오로메틸)피리미딘-2,4-디아민의 합성Step 2: N2-[4-(azepan-1-yl)phenyl]-N4-[(1R,4R)-bicyclo[2.2.1]heptan-1-yl]-5-(trifluoromethyl) Synthesis of pyrimidine-2,4-diamine

N-[4-(azepan-1-yl)phenyl]-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.27 mmol, 1.00 equiv) in ACN (3.00 mL) and bicyclo[2.2.1]heptan-1-amine (32 mg, 0.29 mmol, 1.10 equiv) were stirred mixed and DIEA (139 mg, 1.07 mmol, 4.00 equiv) was added. The resulting mixture was stirred at 100° C. for 16 h, and the mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1). The crude product was purified by Prep-HPLC under the following conditions: column, Xselect CSH OBD column 30×150 mm, 5 um, n; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (80% Phase B, up to 90% in 8 min); Detector, UV 254 nm. The collected fractions were lyophilized to N2-[4-(azepan-1-yl)phenyl]-N4-[(1R,4R)-bicyclo[2.2.1]heptan-1-yl]-5-(tri Fluoromethyl)pyrimidine-2,4-diamine (compound of Example 1; 11 mg, 9.56%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.05 (s, 1H), 8.09 (s, 1H), 7.19 (br s, 2H), 6.60 (d, J = 9.2 Hz, 2H) ), 5.92 (m, 1H), 3.44-3.41 (m, 4H), 2.03-1.98 (m, 1H), 1.82-1.55 (m, 12H), 1.50-1.44 (m, 4H), 1.38-1.27 (m) , 2H); MS m/z: 446 [M+H] ⁺ .

실시예 2: N-(4-사이클로헥실페닐)-4-사이클로펜틸-5-(트리플루오로메틸)피리미딘-2-아민Example 2: N-(4-cyclohexylphenyl)-4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-amine

Compound of Preparation 3 (100 mg, 0.39 mmol, 1.00 equiv) and 4-cyclohexyl-benzeneamine (69 mg, 0.39 mmol, 1.00 equiv) in BuOH (2 mL) and concentrated hydrochloric acid (1 drop) at 80 °C Stir and mix for 1 hour. The mixture was cooled to room temperature. The crude product was purified by silica gel column chromatography, eluting with PE/EtOAc (10:1). The crude product was purified by Prep-HPLC under the following conditions: column, Xselect CSH OBD column 30×150 mm, 5 um; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (80% Phase B, up to 90% in 10 min); Detector, UV 254 nm. The collected fractions were lyophilized to obtain N-(4-cyclohexylphenyl)-4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-amine (compound of Example 2; 9.7 mg, 6.22%). It was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.03 (s, 1H), 8.61 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 3.30-3.26 (m, 1H), 2.49-2.42 (m, 1H), 2.07-1.67 (m, 13H), 1.55-1.15 (m, 5H); MS m/z: 390 [M+H] ⁺ .

실시예 3: 4-사이클로프로필-N-(4-사이클로프로필페닐)-5-(트리플루오로메틸)피리미딘-2-아민Example 3: 4-cyclopropyl-N-(4-cyclopropylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine

The compound of preparation 4 (330 mg, 1.48 mmol, 1.00 equiv) and 4-cyclopropylaniline (237 mg, 1.78 mmol, 1.20 equiv) in ACN (5 mL) were stirred and mixed, followed by DIEA (574 mg, 4.44 mmol, 3.00 equiv) was added dropwise. The resulting mixture was stirred at 80° C. for 12 h under a nitrogen atmosphere, and the mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with DCM/MeOH (10:1) to give the crude product. The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C18 ExRS, 30×150 mm, 5 um; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (70% Phase B, up to 90% in 10 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 4-cyclopropyl-N-(4-cyclopropylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine (compound of Example 3; 8.4 mg, 1.77%). It was obtained as a white solid. ¹ H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.91 (s, 1H), 8.55 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.1) Hz, 2H), 2.20-2.10 (m, 1H), 1.90-1.78 (m, 1H), 1.25-0.98 (m, 4H), 0.98-0.75 (m, 2H), 0.70-0.50 (m, 2H); MS m/z: 320 [M+H] ⁺ .

실시예 4: 1-(4-{[4-사이클로헥실-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-온Example 4: 1-(4-{[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-one

The compound of Example 4 was synthesized according to Scheme 2 below.

[Scheme 2]

단계 1: 4-사이클로헥실-N-(4-[1,4-디옥사-7-아자스피로[4.4]노난-7-일]페닐)-5-(트리플루오로메틸)피리미딘-2-아민의 합성Step 1: 4-Cyclohexyl-N-(4-[1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]phenyl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of amines

The compound of preparation 5 (200 mg, 0.75 mmol, 1.00 equiv) was stirred mixed in DCE (8 mL) and t-BuOH (8 mL) and ZnCl ₂ in Et ₂ O (2.26 mL, 2.26 mmol, 3.00 equiv) (1M) was added at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere. To the reaction was added the compound of Preparation 2 (183 mg, 0.83 mmol, 1.10 equiv) and TEA (84 mg, 0.83 mmol, 1.10 equiv) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to 4-cyclohexyl-N-(4-[1,4-dioxa-7-aza) Spiro[4.4]nonan-7-yl]phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (120 mg, 32.93%) was obtained as a pale yellow solid. MS m/z: 449 [M+H] ⁺ .

단계 2: 1-(4-{[4-사이클로헥실-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-온의 합성Step 2: Synthesis of 1-(4-{[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-one

4-cyclohexyl-N-(4-[1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]phenyl) in HCl (1 mL) and 1,4-dioxane (3 mL) A solution of-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.22 mmol, 1.00 equiv) was stirred under nitrogen atmosphere at 60° C. for 1 h. The resulting mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC under the following conditions: column, Xselect CSH OBD column 30×150 mm, 5 um, n; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (Phase B 65%, up to 85% in 7 min); Detector, UV 254/220 nm. The product fractions were lyophilized to obtain 1-(4-{[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-one (compound of Example 4) 8.5 mg, 9.41%) was obtained as a white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.86 (s, 1H), 8.56 (s, 1H), 7.59 (d, J = 7.5 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 3.65-3.56 (m, 3H), 2.77-2.64 (m, 3H), 1.84-1.64 (m, 7H), 1.36-1.1.25 (m, 3H); MS m/z: 405 [M+H] ⁺ .

실시예 5: 1-(4-{[4-사이클로헥실-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 5: 1-(4-{[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol

1-(4-{[4-cyclohexyl-5-(trifluoro Rhomethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 5; 5.2 mg, 8.12%) was obtained as an off-white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.90 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.80 (d, J = 4.8 Hz, 1H), 3.64-3.52 (m, 2H), 3.43-3.39 (m, 1H), 2.81-2.73 (m, 1H), 2.62-2.54 (m) , 1H), 2.47-2.41 (m, 1H), 1.89-1.50 (m, 10 H), 1.47-1.18 (m, 4H); MS m/z: 421 [M+H] ⁺ .

실시예 6: N-(4-사이클로헥실페닐)-4-(피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-아민Example 6: N-(4-cyclohexylphenyl)-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine

N-(4-cyclohexylphenyl)-4-(pyrrolidin-1-yl) in the same manner as in Example 2, except that the compound of Preparation Example 6 was used instead of the compound of Preparation Example 3 in Example 2 5-(trifluoromethyl)pyrimidin-2-amine (compound of Example 6; 7%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 9.52 (s, 1H), 8.30 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 3.59 (s, 4H), 2.44-2.39 (m, 1H), 1.94-1.92 (m, 4H), 1.90-1.67 (m, 5H), 1.41-1.33 (m, 4H), 1.29 -1.25 (m, 1H); MS m/z: 391 [M+H] ⁺ .

실시예 7: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5H,6H,7H-사이클로펜타[d]피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 7: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5H,6H,7H-cyclopenta[d]pyrimidine- 2-yl}amino)phenyl]piperidin-3-ol

The compound of Example 7 was prepared according to Scheme 3 below.

[Scheme 3]

단계 1: (3S,4S)-1-[2-클로로-5H,6H,7H-사이클로펜타[d]피리미딘-4-일]-3,4-디플루오로피롤리딘의 합성Step 1: Synthesis of (3S,4S)-1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-3,4-difluoropyrrolidine

(3S, 4S)-3,4-difluoropyrrolidine hydrochloride (60 mg, 0.42 mmol, 1.00 equiv) in DCM (5 mL) was mixed with stirring and 2,4- in DCM (2 mL) Dichloro-5H, 6H, 7H-cyclopenta[d]pyrimidine (94 mg, 0.502 mmol, 1.20 equiv) and DIEA (162 mg, 1.25 mmol, 3.00 equiv) in DCM (1 mL) under nitrogen atmosphere at -78 °C was added dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 15 min. The mixture was warmed to room temperature, and the resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (1:10) to (3S,4S)-1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- yl]-3,4-difluoropyrrolidine (70 mg, 64.50%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 6.53 (s, 1H), 6.36 (s, 1H), 4.25-3.75 (m, 4H), 3.25-3.10 (m, 2H), 2.80- 2.60 (m, 2H), 2.10-1.80 (m, 2H); MS m/z: 260/262 [M+H] ⁺ .

단계 2: 1-[4-([4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5H,6H,7H-사이클로펜타[d]피리미딘-2-일]아미노)페닐]피페리딘-3-올의 합성Step 2: 1-[4-([4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5H,6H,7H-cyclopenta[d]pyrimidine-2 Synthesis of -yl]amino)phenyl]piperidin-3-ol

1-(4-aminophenyl)piperidine prepared in the same manner as in Preparation Example 7 using 3-hydroxypiperidine instead of 3-(trifluoromethyl)piperidine in Step 1 of Preparation Example 7 -3-ol (62 mg, 0.32 mmol, 1.20 equiv) and the compound obtained in step 1 (70 mg, 0.27 mmol, 1.00 equiv) were stirred and mixed in n-BuOH (2mL) and HCl (1 drop) was added. . The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 6 hours. The mixture was cooled to room temperature and purified by silica gel column chromatography eluting with DCM/MeOH (10:1) to give the crude product. The crude product was purified by Prep-HPLC under the following conditions: column, X Bridge Prep phenyl OBD column, 19 x 250 mm, 5um; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (up to 70% in 40% Phase B in 7 min); Detector, UV 254 & 220 nm. The collected fractions were freeze-dried to 1-[4-([4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5H,6H,7H-cyclopenta[d] Pyrimidin-2-yl]amino)phenyl]piperidin-3-ol (compound of Example 7; 9.8 mg, 8.57%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.72 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 5.58-5.30 (m, 2H), 4.76 (d, J = 4.8 Hz, 1H), 4.12-3.75 (m, 4H), 4.65-3.50 (m, 1H), 3.50-3.39 (m, 1H), 3.38-3.33 (m) , 1H), 3.15-2.90 (m, 2H), 2.70-2.55 (m, 2H), 2.50-2.45 (m, 1H), 2.40-2.30 (m, 1H), 2.00-1.78 (m, 3H), 1.80 -1.69 (m, 1H), 1.65-1.45 (m, 1H), 1.28-1.10 (m, 1H); MS m/z: 416 [M+H] ⁺ .

실시예 8: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-7H-피롤로[2,3-d]피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 8: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine- 2-yl}amino)phenyl]piperidin-3-ol

In step 1 of Example 7, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was used instead of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine. Except in the same manner as in Example 7, 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-7H-pyrrolo[2,3 -d]pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 8; 6.0%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 11.12 (s, 1H), 8.43 (s, 1H), 7.63 (d, J = 9.0 Hz, 2H), 6.85-6.75 (m, 3H) , 6.50-6.40 (m, 1H), 5.58-5.30 (m, 2H), 4.76 (d, J = 4.8 Hz, 1H), 4.20-3.99 (m, 3H), 3.99-3.85 (m, 1H), 3.65 -3.57 (m, 1H), 3.48-3.44 (m, 1H), 3.32-3.29 (m, 1H), 2.45-2.30 (m, 2H), 1.90-1.80 (m, 1H), 1.80-1.65 (m, 1H), 1.65-1.45 (m, 1H), 1.28-1.10 (m, 1H); LCMS (ES, m/z): 415 [M+H] ⁺ .

실시예 9: 1-[4-({6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-9H-퓨린-2-일}아미노)페닐]피페리딘-3-올Example 9: 1-[4-({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl}amino)phenyl]piperi din-3-ol

In the same manner as in Example 7, except that 2,6-dichloro-9H-purine was used instead of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine in step 1 of Example 7 1-[4-({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl}amino)phenyl]piperidin-3- All (compound of Example 9; 3.8%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 12.46 (s, 1H), 8.64 (s, 1H), 7.81 (s, 1H), 7.61 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 5.60-5.43 (m, 2H), 4.76 (d, J = 4.8 Hz, 1H), 4.70-3.75 (m, 4H), 3.70-3.52 (m, 1H), 3.52-3.40 (m, 1H), 3.40-3.35 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.35 (m, 1H), 1.95-1.80 (m, 1H), 1.80-1.65 (m) , 1H), 1.64-1.45 (m, 1H), 1.30-1.10 (m, 1H); MS m/z: 416 [M+H] ⁺ .

실시예 9(S): (3S)-1-[4-({6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-9H-퓨린-2-일}아미노)페닐]피페리딘-3-올Example 9(S): (3S)-1-[4-({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl }amino)phenyl]piperidin-3-ol

In step 1 of Example 7, 2,6-dichloro-9H-purine was used instead of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine, and in step 2 of Example 7, 1- Instead of (4-aminophenyl) piperidin-3-ol, (S)-3-hydroxypiperidine was used instead of 3- (trifluoromethyl) piperidine in Step 1 of Preparation Example 7 and (3S)-1-[4] in the same manner as in Example 7, except that (S)-1-(4-aminophenyl)piperidin-3-ol prepared in the same manner as in Preparation Example 7 was used. -({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl}amino)phenyl]piperidin-3-ol (Example 9(S)) was obtained as a brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 12.47 (brs, 1H), 8.62 (s, 1H), 7.82 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.58 (brs, 1H), 5.45 (brs, 1H), 4.75 (d, J = 4.4 Hz, 1H), 4.12-4.04 (m, 4H), 3.61-3.59 (m, 1H), 3.49-3.46 (m, 1H), 3.31 (m, 1H), 2.57 (m, 1H), 2.40 (t, J = 10.0 Hz, 1H), 1.90-1.87 (m, 1H), 1.77-1.73 (m, 1H), 1.57-1.54 (m, 1H) ), 1.27-1.24 (m, 1H; MS m/z: 416 [M+H] ⁺ .

실시예 9(R): (3R)-1-[4-({6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-9H-퓨린-2-일}아미노)페닐]피페리딘-3-올Example 9(R): (3R)-1-[4-({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl }amino)phenyl]piperidin-3-ol

In step 1 of Example 7, 2,6-dichloro-9H-purine was used instead of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine, and in step 2 of Example 7, 1- In place of (4-aminophenyl) piperidin-3-ol, (R) -3-hydroxypiperidine was used instead of 3- (trifluoromethyl) piperidine in Step 1 of Preparation Example 7 (3R)-1-[4 in the same manner as in Example 7, except that (R)-1-(4-aminophenyl)piperidin-3-ol prepared in the same manner as in Preparation Example 7 was used. -({6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-9H-purin-2-yl}amino)phenyl]piperidin-3-ol (Example 9(R)) was obtained as a brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 12.47 (brs, 1H), 8.62 (s, 1H), 7.82 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.58 (brs, 1H), 5.45 (brs, 1H), 4.75 (d, J = 4.4 Hz, 1H), 4.10-3.97 (m, 4H), 3.61-3.60 (m, 1H), 3.49-3.46 (m, 1H), 3.31 (m, 1H), 2.57-2.50 (m, 1H), 2.40 (t, J = 9.6 Hz, 1H), 1.90-1.87 (m, 1H), 1.77-1.73 (m, 1H), 1.59-1.51 (m) , 1H), 1.22-1.18 (m, 1H); MS m/z: 416 [M+H] ⁺ .

실시예 10: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-1H-피라졸로[3,4-d]피리미딘-6-일}아미노)페닐]피페리딘-3-올Example 10: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine- 6-yl}amino)phenyl]piperidin-3-ol

Using 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine instead of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine in step 1 of Example 7 Except in the same manner as in Example 7, 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-1H-pyrazolo[3,4 -d]pyrimidin-6-yl}amino)phenyl]piperidin-3-ol (compound of Example 10; 4.31%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 12.86 (s, 1H), 8.81 (s, 1H), 7.97 (s, 1H), 7.62 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.63-5.48 (m, 2H), 4.77 (d, J = 4.8 Hz, 2H), 4.30-3.80 (m, 4H), 3.65-3.52 (m, 1H), 3.52-3.42 (m, 1H), 3.42-3.39 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.35 (m, 1H), 1.95-1.80 (m, 1H), 1.80-1.65 (m) , 1H), 1.64-1.45 (m, 1H), 1.32-1.15 (m, 1H); MS m/z: 416 [M+H] ⁺ .

실시예 11: 5-요오도-N4-[(1R,4R)-2-옥사바이사이클로[2.2.1]헵탄-4-일]-N2-{4-[3-(트리플루오로메틸)피페리딘-1-일]페닐}피리미딘-2,4-디아민Example 11: 5-iodo-N4-[(1R,4R)-2-oxabicyclo[2.2.1]heptan-4-yl]-N2-{4-[3-(trifluoromethyl)p Peridin-1-yl]phenyl}pyrimidine-2,4-diamine

The compound of Example 11 was prepared according to Scheme 4 below.

[Scheme 4]

단계 1: 2-클로로-5-요오도-N-[2-옥사바이사이클로[2.2.1]헵탄-4-일]피리미딘-4-아민의 합성Step 1: Synthesis of 2-chloro-5-iodo-N-[2-oxabicyclo[2.2.1]heptan-4-yl]pyrimidin-4-amine

2,4-dichloro-5-iodopyrimidine (360 mg, 1.31 mmol, 1.00 equiv) and 2-oxabicyclo[2.2.1]heptan-4-amine (150 mg, 1.32 mmol, 1.01 equiv) were combined with ACN (5 mL) was stirred and DIEA (513 mg, 3.96 mmol, 3.03 equiv) was added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (2:1), and 2-chloro-5-iodo-N-[2-oxabicyclo[2.2.1]heptan-4-yl]pyrimidine -4-amine (220 mg, 43.96%) was obtained as a yellow solid. MS m/z: 352/354 [M+H] ⁺ .

단계 2: 5-요오도-N4-[(1R,4R)-2-옥사바이사이클로[2.2.1]헵탄-4-일]-N2-{4-[3-(트리플루오로메틸)피페리딘-1-일]페닐}피리미딘-2,4-디아민의 합성Step 2: 5-Iodo-N4-[(1R,4R)-2-oxabicyclo[2.2.1]heptan-4-yl]-N2-{4-[3-(trifluoromethyl)piperi Synthesis of diin-1-yl]phenyl}pyrimidine-2,4-diamine

The compound obtained in step 1 (100 mg, 0.28 mmol, 1.00 equiv) and concentrated hydrochloric acid (1 drop) were mixed with stirring in n-BuOH (3 mL), and the compound of Preparation 7 (90 mg, 0.36 mmol, 1.30 equiv.) ) was added. The resulting mixture was stirred at 80° C. for 4 h under a nitrogen atmosphere and cooled to room temperature. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with DCM/MeOH (5:1). The crude product was purified by Prep-HPLC under the following conditions: column, Xselect CSH OBD column 30 x 150mm 5um; mobile phase, water (10 mmol/L NH4HCO3+0.1% NH3.H2O) and ACN (36% PhaseB, up to 48% in 11 min); Detector, UV 254/220 nm. The product fractions were lyophilized to 5-iodo-N4-[(1R,4R)-2-oxabicyclo[2.2.1]heptan-4-yl]-N2-{4-[3-(trifluoromethyl )piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (compound of Example 11; 9.4 mg, 5.90%) was obtained as a light yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.48 (s, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.64 (s, 1H), 4.27-4.25 (m, 1H), 4.10-4.00 (m, 2H), 3.72-3.69 (m, 1H), 3.61-3.58 (m, 1H), 2.67 -2.57 (m, 2H), 2.02-1.94 (m, 3H), 1.85-1.51 (m, 6H), 1.48-1.36 (m, 1H); MS m/z: 560 [M+H] ⁺ .

실시예 12: 1-[4-([4-클로로-6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노)페닐]피페리딘-3-올Example 12: 1-[4-([4-chloro-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino)phenyl] piperidin-3-ol

The compound of Example 12 was prepared according to Scheme 5 below.

[Scheme 5]

단계 1: 1-[4-[(4,6-디클로로피리미딘-2-일)아미노]페닐]피페리딘-3-올의 합성Step 1: Synthesis of 1-[4-[(4,6-dichloropyrimidin-2-yl)amino]phenyl]piperidin-3-ol

2,4,6-trichloro-pyrimidine (1.00 g, 5.452 mmol, 1.00 equiv) was stirred mixed in DCE (10 mL) and t-BuOH (10 mL) and ZnCl ₂ (1M) in ether (10.85 mL) , 10.85 mmol, 1.99 equiv) were added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, and 1-(4-aminophenyl)piperidin-3-ol (1.04 g, 5.40 mmol, 0.99 equiv) was added dropwise at 0 °C. The resulting mixture was stirred under a hydrogen atmosphere at 0° C. for 0.5 h. To the mixture was added dropwise TEA (606 mg, 5.98 mmol, 1.10 equiv), the resulting mixture was stirred under nitrogen atmosphere at room temperature for 12 h, and the resulting mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (1:5) to 1-[4-[(4,6-dichloropyrimidin-2-yl)amino]phenyl]piperidine-3- The ol (80 mg, 3.5%) was obtained as a yellow oil. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 10.12(s, 1H), 7.55-7.30 (m, 2H), 7.15-6.75 (m, 3H), 3.75-3.50 (m, 2H), 3.50-3.00 (m, 1H), 2.75-2.55 (m, 1H), 2.50-2.35 (m, 1H), 2.00-1.82 (m, 1H), 1.82-1.65 (m, 1H), 1.65-1.35 (m) , 1H), 1.35-1.15 (m, 1H); MS m/z: 339 [M+H] ⁺ .

단계 2: 1-[4-([4-클로로-6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노)페닐]피페리딘-3-올의 합성Step 2: 1-[4-([4-chloro-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino)phenyl]pi Synthesis of peridin-3-ol

Compound obtained in step 1 (80 mg, 0.23 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (40 mg, 0.28 mmol, 1.20 equiv) were mixed with ACN (2mL) Stir to mix and DIEA (89 mg, 0.70 mmol, 3.00 equiv) was added dropwise. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 6 hours. The mixture was cooled to room temperature. The crude product was purified by Prep-HPLC under the following conditions: column, Xselect CSH OBD column 30 x 150mm 5um, n; mobile phase, water (10 mmol/L NH4HCO3 + 0.1% NH ₃ ^. H ₂ O) and ACN (30% PhaseB, up to 60% in 8 min); Detector, UV 254&220nm. The collected fractions were freeze-dried to 1-[4-([4-chloro-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino )phenyl]piperidin-3-ol (compound of Example 12; 8.3 mg, 8.5%) was obtained as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.30 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 6.07 (s) , 1H), 5.75-5.35 (m, 2H), 4.78 (s, 1H), 4.10-3.35 (m, 7H), 2.65-2.52 (m, 1H), 2.45-2.30 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.65 (m, 1H), 1.65-1.45 (m, 1H), 1.28-1.10 (m, 1H); MS m/z: 410 [M+H] ⁺ .

실시예 13 및 14: 1-[4-({4-브로모-6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일}아미노)페닐]피페리딘-3-올 및 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-요오도피리미딘-2-일}아미노)페닐]피페리딘-3-올Examples 13 and 14: 1-[4-({4-bromo-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl}amino )phenyl]piperidin-3-ol and 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-iodopyrimidine- 2-yl}amino)phenyl]piperidin-3-ol

1-[4-({4-bromo-6 -[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 13; 6.43% ) and 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-iodopyrimidin-2-yl}amino)phenyl]p Peridin-3-ol (compound of Example 14; 14.0%) was obtained as a white solid, respectively.

1-[4-({4-브로모-6-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일}아미노)페닐]피페리딘-3-올(실시예 13의 화합물)1-[4-({4-bromo-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl}amino)phenyl]piperidine -3-ol (compound of Example 13)

1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.32 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.21 (s) , 1H), 5.65-5.30 (m, 2H), 4.77 (d, J = 4.5 Hz, 1H), 4.10-3.35 (m, 7H), 2.48-2.30 (m, 2H), 1.90-1.80 (m, 1H) ), 1.80-1.65 (m, 1H), 1.65-1.35 (m, 1H), 1.35-1.10 (m, 1H); MS m/z: 454 [M+H] ⁺ .

1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-요오도피리미딘-2-일}아미노)페닐]피페리딘-3-올(실시예 14의 화합물)1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-iodopyrimidin-2-yl}amino)phenyl]piperidine -3-ol (compound of Example 14)

1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.25 (s, 1H), 7.53 (d, J =9.0 Hz, 2H), 6.83 (d, J =9.0 Hz, 2H), 6.44 (s) , 1H), 5.57-5.55 (m, 1H), 5.40-5.38 (m, 1H), 4.77 (d, J =4.8 Hz, 1H), 4.05-3.38 (m, 7H), 2.45-2.32 (m, 2H) ), 1.95-1.80 (m, 1H), 1.80-1.62 (m, 1H), 1.62-1.40 (m, 1H), 1.30-1.10 (m, 1H); 502[M+H] ⁺ .

실시예 15: 1-[4-([4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노)페닐]피페리딘-3-올Example 15: 1-[4-([4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino)phenyl]piperidine- 3-ol

The compound of Example 15 was prepared according to Scheme 6 below.

[Scheme 6]

단계 1: 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘의 합성Step 1: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine

Mix 2,4-dichloropyrimidine (51 mg, 0.34 mmol, 1.00 equiv) and DIEA (230 mg, 1.03 mmol, 3.00 equiv) in DMF (2 mL) by stirring, (3S,4S)-3,4 -difluoropyrrolidine hydrochloride (49 mg, 0.34 mmol, 1.00 equiv) was added. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 0.5 h. The reaction was quenched by addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were collected, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (3:1) and purified by silica gel column chromatography to 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine (60 mg, 81.1%) was obtained as a white solid. MS m/z: 220/222[M+H]+.

단계 2: 1-[4-([4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노)페닐]피페리딘-3-올의 합성Step 2: 1-[4-([4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino)phenyl]piperidin-3 -Synthesis of ol

Compound obtained in step 1 (50 mg, 0.20 mmol, 1.00 equiv) and 1-(4-aminophenyl)piperidin-3-ol (43 mg, 0.20 mmol, 1.00 equiv) were mixed with n-BuOH (2.00mL) Stir to mix and add HCl (1 drop). The resulting mixture was stirred at 120° C. under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature and the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Prep phenyl OBD column, 19 x 250 mm, 5um; Mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ ^. H ₂ O) and ACN (32% Phase B, up to 62% in 7 min). The collected fractions were freeze-dried to 1-[4-([4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl]amino)phenyl]pyr Peridin-3-ol (compound of Example 15; 5.1 mg, 6.3%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): δ 8.85 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H), 6.83 (m, J = 9.0 Hz, 2H), 5.98 (d, J = 5.8 Hz, 1H), 5.58-5.40 (m, 2H), 4.77 (d, J = 4.8 Hz, 1H), 4.08-3.41 (m) , 6H), 3.36-3.34 (m, 1H), 2.602.56 (m, 1H), 2.42-2.35 (m, 1H), 1.97-1.80 (m, 1H), 1.77-1.74 (m, 1H), 1.60 -1.50 (m, 1H), 1.28-1.18 (m, 1H); MS m/z: 376 [M+H] ⁺ .

실시예 16: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-메틸피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 16: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-methylpyrimidin-2-yl}amino)phenyl] piperidin-3-ol

In the same manner as in Example 15, 1-[4-({4-[ (3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-methylpyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 16; 11.78%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.66 (s, 1H), 7.74 (s, 1H), 7.54 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 5.52-5.33 (m, 2H), 4.73 (d, J = 4.8 Hz, 1H), 4.18-3.88 (m, 4H), 3.64-3.56 (m, 1H), 3.49-3.45 (m) , H), 3.35-3.33 (m, 1H), 2.57-2.55 (m, 1H), 2.43-2.36 (m, 1H), 2.23 (s, 3H), 1.93-1.85 (m, 1H), 1.76-1.73 (m, 1H), 1.65-1.55 (m, 1H), 1.30-1.12 (m, 1H); MS m/z: 390 [M+H] ⁺ .

실시예 17: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-에틸피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 17: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-ethylpyrimidin-2-yl}amino)phenyl] piperidin-3-ol

In the same manner as in Example 15, 1-[4-({4-[ (3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-ethylpyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 17; 4.48%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.76 (s, 1H), 7.83 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 5.51-5.38 (m, 2H), 4.78 (d, J = 4.8 Hz, 1H), 4.12-3.85 (m, 4H), 3.79-3.67 (m, 2H), 2.69-2.57 (m) , 2H), 2.40-2.35 (m, 1H), 1.95-1.86 (m, 1H), 1.81-1.72 (m, 1H), 1.64-1.60 (m, 1H) 1.25-1.15 (m, 1H), 1.10- 1.00 (m, 3H); MS m/z: 404 [M+H] ⁺ .

실시예 18: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-메틸피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 18: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-methylpyrimidin-2-yl}amino)phenyl] piperidin-3-ol

In the same manner as in Example 15, 1-[4-({4-[ (3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-methylpyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 18; 8.48%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.83 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.86 (s, 1H), 5.57-5.54 (m, 1H), 5.48-5.41 (m, 1H), 4.76 (d, J = 4.8 Hz, 1H), 3.80-3.66 (m, 4H), 3.61-3.54 (m , 1H), 3.48-3.44 (m, 1H), 3.35-3.32 (m, 1H), 2.55-2.54 (m, 1H), 2.41-2.35 (m, 1H), 2.16 (s, 3H), 1.89-1.87 (m, 1H), 1.86-1.70 (m, 1H), 1.57-1.48 (m, 1H), 1.25-1.16 (m, 1H); MS m/z: 390 [M+H] ⁺ .

실시예 19: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-에틸피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 19: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-ethylpyrimidin-2-yl}amino)phenyl] piperidin-3-ol

In the same manner as in Example 15, 1-[4-({4-[ (3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-ethylpyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 19; 12.24%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.81 (s, 1H), 7.63-7.59 (m, 2H), 6.84-6.80 (m, 2H), 5.86 (s, 1H), 5.57-5.56 (m, 1H), 5.48-5.44 (m, 1H), 4.76 (d, J = 4.8 Hz, 1H), 3.85-3.76 (m, 3H), 3.75-3.67 (m, 1H), 3.60- 3.56 (m, 1H), 3.48-3.44 (m, 1H), 3.35-3.32 (m, 1H), 2.55-2.51 (m, 1H), 2.49-2.35 (m, 3H), 1.89-1.85 (m, 1H) ), 1.74-1.70 (m, 1H), 1.54-1.51 (m, 1H), 1.23-1.17 (m, 4H); 404 [M+H] ⁺ .

실시예 20: 5-((4-((3R,4R)-3-메톡시-4-(메틸아미노)피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온Example 20: 5-((4-((3R,4R)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)-2-methylisoindolin-1-one

The compound of Example 20 was prepared according to Scheme 7 below.

[Scheme 7]

단계 1: (3R,4R)-N-벤질-1-(2-클로로-5-(트리플루오로메틸)피리미딘-4-일)-4-메톡시-N-메틸피롤리딘-3-아민(화합물 7-1)의 합성Step 1: (3R,4R)-N-benzyl-1-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-4-methoxy-N-methylpyrrolidine-3- Synthesis of amines (Compound 7-1)

Mixture of optical isomers of compound 5 obtained in Preparation 9 (compound 5-1; 520 mg, 1.56 mmol, 1 equiv, TFA) and compound 6 (337.47 mg, 1.56 mmol, 1 equiv) in DMF (5 mL) and DIPEA (402.02 mg, 3.11 mmol, 541.81 uL, 2 eq) was added. The mixture was stirred at 20° C. for 12 h. To the mixture was added ethyl acetate (50 mL). The combined organic phases were washed with brine (60 mLx3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-HPLC (method: water (0.1% TFA-ACN; column: phenomenex Luna C18 100^30 mm*5 µm)) (3R,4R)-N-benzyl-1-(2-chloro-5) -(trifluoromethyl)pyrimidin-4-yl)-4-methoxy-N-methylpyrrolidin-3-amine (compound 7-1) (150 mg, 24.1%) yellow as a mixture of optical isomers Obtained in the form of an oil: ¹ H NMR (400 MHz, CDCl ₃ )δ ppm 8.53 (s, 1 H), 7.49 (br s, 3 H), 7.47 - 7.48 (m, 2 H), 4.71 (d, J = 6.4 Hz, 1 H) 4.38 - 4.51 (m, 2 H), 4.21 - 4.34 (m, 2 H), 4.06 - 4.20 (m, 1 H), 3.66 - 3.81 (m, 2 H), 3.45 - 3.49 (m, 3 H), 2.76 - 2.81 (m, 3 H) LCMS: RT = 0.823 min, MS (ESI) m/z = 401.1 [M+H] ⁺ .

단계 2: 5-((4-((3R,4R)-3-(벤질(메틸)아미노)-4-메톡시피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온(화합물 8-1)의 합성Step 2: 5-((4-((3R,4R)-3-(benzyl(methyl)amino)-4-methoxypyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2 Synthesis of -yl)amino)-2-methylisoindolin-1-one (Compound 8-1)

The optical isomer mixture obtained in step 1 above (160.00 mg, 399.18 umol, 1 equiv) and compound 2A (97.11 mg, 598.77 µmol, 1.5 equiv) were mixed in dioxane (8 mL), XPhos (38.06 mg, 79.84 µmol) , 0.2 eq), Cs ₂ CO ₃ (260.12 mg, 798.35 μmol, 2 eq), and Pd ₂ (dba) ₃ (36.55 mg, 39.92 μmol, 0.1 eq) were added in one portion at 20° C. under N ₂ . The mixture was warmed to 110° C. and stirred under N ₂ for 12 h. The mixture was cooled to 20° C. and then diluted with ethyl acetate. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate = 1:1) to obtain 5-((4-((3R,4R)-3-(benzyl(methyl)amino)-4-methoxypyrroly) Din-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylisoindolin-1-one (compound 8-1) (40 mg, 19.0%) optically Obtained in the form of a yellow solid as a mixture of isomers. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.22 (s, 1 H), 7.87 - 7.69 (m, 2 H), 7.66 - 7.49 (m, 1 H), 7.26 - 7.15 (m, 4 H), 6.89 (br s, 1 H), 4.35 - 4.10 (m, 2 H), 4.07 - 3.86 (m, 2 H), 3.85 - 3.66 (m, 2 H), 3.64 - 3.45 (m, 3 H), 3.34 (s, 3 H), 3.30 - 3.21 (m, 1 H), 3.17 - 3.02 (m, 3 H), 2.19 (d, J = 4.0 8 Hz, 3 H); LCMS: RT = 1.280 min, MS (ESI) m/z = 527.2 [M+H] ⁺ .

단계 3: 5-((4-((3R,4R)-3-메톡시-4-(메틸아미노)피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온의 합성Step 3: 5-((4-((3R,4R)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl Synthesis of )amino)-2-methylisoindolin-1-one

The mixture of optical isomers obtained in step 2 above (20 mg, 37.98 μmol, 1 eq) was mixed in THF (2 mL) and Pd(OH) ₂ /C (10.67 mg, 7.60 μmol, 10% purity, 0.2 eq) was added. The suspension was degassed under vacuum and purged 3 times with H ₂ . The mixture was stirred under H ₂ (15 psi) at 20° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (SiO ₂ , dichloromethane:methanol = 20:1) to 5-((4-((3R,4R)-3-methoxy-4-(methylamino)pyrrolidine-1) Obtained -yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylisoindolin-1-one (compound of Example 20; 5.4 mg, 31.0%) as a white solid did. ¹ H NMR (400 MHz, CDCl ₃ )δ ppm 8.19 - 8.32 (m, 1 H), 7.72 - 7.86 (m, 2 H), 7.62 - 7.69 (m, 1 H), 6.91 (br s, 1 H) , 4.28 - 4.42 (m, 2 H), 3.77 - 3.94 (m, 3 H), 3.56 - 3.72 (m, 2 H), 3.44 - 3.56 (m, 1 H), 3.40 (s, 3 H), 3.28 - 3.35 (m, 1 H), 3.14 - 3.23 (m, 3 H), 2.53 (d, J = 16.8 Hz, 3 H); LCMS: product RT = 0.716 min, MS (ESI) m/z = 437.2 [M+H] ⁺ ; HPLC: purity = 95.2% (area %); Chiral SFC: ee% = 97.1% (area %).

실시예 21: 5-((4-((3S,4S)-3,4-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온Example 21: 5-((4-((3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) -2-methylisoindolin-1-one

The compound of Example 21 was prepared according to Scheme 8 below.

[Scheme 8]

단계 1: 5-((4-클로로-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온의 합성Step 1: Synthesis of 5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylisoindolin-1-one

5-((4-chloro- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylisoindolin-1-one was obtained as a white solid (78.9 mg, 0.20 mmol, 43 % yield). 1H NMR (400 MHz, DMSO-d ₆ ); δ 8.87 (s, 1H), 8.00 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 3.05 (s, 3H).

단계 2: 5-((4-((3S,4S)-3,4-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸이소인돌린-1-온의 합성Step 2: 5-((4-((3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- Synthesis of 2-methylisoindolin-1-one

The compound obtained in step 1 and (3S,4S)-3,4-difluoropyrrolidine were reacted in the same manner as in step 1 of Example 20 to 5-((4-((3S,4S)-3 ,4-Difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylisoindolin-1-one (compound of Example 21; 25.6 mg, 0.06 mmol, 29%) were obtained as a white powder. 1H NMR (400 MHz, DMSO-d ₆ ); δ 10.10 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 5.58 (brs, 1H), 5.44 (brs, 1H), 4.44 (s, 2H), 4.05-3.93 (m, 4H), 3.05 (s, 3H); MS m/z 414 [M+H] ⁺ _.

실험예 1. LRRK2 효소 억제 효과의 확인Experimental Example 1. Confirmation of LRRK2 enzyme inhibitory effect

It was confirmed whether the compound prepared in Examples had LRRK2 enzyme inhibitory activity. LRRK2 enzyme inhibitory activity was determined by Nat Biotechnol. 2011 Oct 30;29(11):1039-45.

A stock solution was prepared by dissolving the compound in 100% DMSO. In order to determine the 50% inhibitory concentration (half maximal inhibitory concentration: IC ₅₀ ), the compound was prepared at a maximum concentration of 10 μM and diluted 3 times to 10 concentrations.

LRRK2 G2019S enzyme (Invitrogen, PR8764C) and LRRKtide (SignalChem, L10-58) as a substrate were prepared. 30 nM LRRK2 (G2019S), 20 μM LRRKtide, 10 μM ATP, and reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.01% (v/v) Brij35, 0.02 mg/mL BSA) , 0.1 mM Na ₃ VO ₄ , 2 mM DTT, and 1% (w/v) DMSO) were prepared.

20 μM LRRKtide was added to fresh reaction buffer, 30 nM LRRK2 (G2019S) enzyme was added, and then gently mixed. The prepared compound (in 100% DMSO) was added to the LRRK2 (G2019S) mixture using Acoustic technology (Echo550; nano level). ³³ P-ATP was added to the reaction mixture to initiate the reaction, followed by incubation at room temperature for 2 hours. The IC ₅₀ for LRRK2 (G2019S) was calculated by the P81 filter-binding method, and the results were evaluated based on the criteria in Table 1 below, and are shown in Table 2.

IC₅₀(LRRK2 G2019S)IC ₅₀ (LRRK2 G2019S)
기준(IC₅₀)Criterion (IC ₅₀ )	<50nM<50nM	50-500nM50-500nM	>500nM>500nM
표시값display value	++++++	++++	++

	LRRK2 길항 활성(IC₅₀, nM)LRRK2 antagonist activity (IC ₅₀ , nM)
실시예 1의 화합물compound of example 1	++++
실시예 2의 화합물compound of example 2	--
실시예 3의 화합물compound of example 3	++++
실시예 4의 화합물compound of example 4	++++
실시예 6의 화합물compound of example 6	++
실시예 7의 화합물compound of example 7	++
실시예 8의 화합물compound of example 8	++++++
실시예 9의 화합물compound of example 9	++++++
실시예 9(S)의 화합물Compound of Example 9(S)	++++++
실시예 9(R)의 화합물compound of example 9(R)	++++++
실시예 10의 화합물compound of example 10	++++++
실시예 11의 화합물compound of example 11	--
실시예 12의 화합물compound of example 12	--
실시예 13의 화합물compound of example 13	++
실시예 14의 화합물compound of example 14	++
실시예 15의 화합물compound of example 15	++
실시예 16의 화합물compound of example 16	++++
실시예 17의 화합물compound of example 17	++++
실시예 18의 화합물compound of example 18	--
실시예 19의 화합물compound of example 19	++
실시예 20의 화합물compound of example 20	++++
실시예 21의 화합물compound of example 21	++++++

From the experimental results in Table 2, it was confirmed that the present compound exhibited excellent LRRK2 antagonistic activity.

Claims

A compound represented by the following formula (1), a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R 1 and R 2 are each independently H, halogen, OH, CN, amino, nitro, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, or halogen substituted C 1 -6 alkoxy, or R 1 and R 2 together are substituted or unsubstituted 4-7 membered saturated or partially unsaturated carbocyclyl ring, or substituted or unsubstituted 4 membered containing 1 to 3 nitrogen atoms to 7 membered heteroaryl or heterocyclyl ring;

R 3 is —NR 31 R 32 or substituted or unsubstituted C 3-8 cycloalkyl,

any one of R 31 and R 32 is H and the other is a substituted or unsubstituted 3- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring optionally containing 1 nitrogen or oxygen atom, wherein The carbocyclyl or heterocyclyl ring may optionally be bridged or form a spiro ring, or

R 31 and R 32 together with the nitrogen atom to which they are attached may form a substituted or unsubstituted 3- to 10-membered monocyclic or bicyclic heterocyclyl ring containing 1 or 2 nitrogen atoms;

R 4 is ring X and R 5 is H, or

R 4 and R 5 may be connected to a *-CO-NR 6 -CH 2 - group together with a carbon atom of the benzene ring to which they are attached to form a 5-membered lactam ring, wherein * represents the position at which R 4 is bonded to the benzene ring. indicate,

Ring X is -NR X1 R X2 or substituted or unsubstituted C 3-8 cycloalkyl, wherein R X1 and R X2 together with the nitrogen atom to which they are attached are substituted or unsubstituted containing 1 or 2 nitrogen atoms to form a 3- to 10-membered monocyclic or bicyclic heterocyclyl ring,

R 6 is H, C 1-6 alkyl, or C 1-6 alkyl substituted with a halogen atom;

The "substitution" is each independently halogen, oxo, OH, CN, amino, nitro, C 1-6 alkyl, halogen or hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C means substituted with one or more substituents selected from the group consisting of 1-6 alkoxy, C 2-6 alkoxyalkyl, C 1-6 alkylamino and di-(C 1-6 alkyl)-amino;

provided that R 3 is —NR 31 R 32 , R 31 and R 32 form a substituted or unsubstituted 3- to 10-membered heterocyclyl ring, R 4 is Ring X, and Ring X is —NR X1 R In case of X2 , if any one of R 1 and R 2 is H, the other of R 1 and R 2 is not C 1-6 alkyl substituted with halogen.
According to claim 1,

R 3 is —NR 31 R 32 or substituted or unsubstituted C 3-6 cycloalkyl,

any one of R 31 and R 32 is H and the other is a substituted or unsubstituted 5-8 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring optionally containing 1 oxygen atom, wherein the carbocycle the ryl or heterocyclyl ring may optionally be bridged or form a spiro ring, or

R 31 and R 32 together with the nitrogen atom to which they are attached may form a substituted or unsubstituted 4-7 membered heterocyclyl ring containing 1 nitrogen atom;

In the above definitions of R 3 , R 31 and R 32 “substitution” is each independently halogen, OH, CN, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino and di-(C A compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof, which means substituted with one or more substituents selected from the group consisting of 1-4 alkyl)amino.
3. The method of claim 2,

any one of R 31 and R 32 is H, and the other is cyclohexyl, cycloheptyl, cyclooctyl, oxacyclohexyl, oxacycloheptyl, oxacyclooctyl, bicyclohexanyl, bicycloheptanyl, bicyclooctanyl , oxabicyclohexanyl, oxabicycloheptanyl, oxabicyclooctanyl, spirohexanyl, spiroheptanyl, spirooctanyl, oxaspirohexanyl, oxaspiroheptanyl and oxaspirooctanyl , or

R 31 and R 32 together with the nitrogen atom to which they are attached may form azetidinyl, pyrrolidinyl or piperidinyl;

wherein R 31 and R 32 are each independently optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, OH, amino, C 1-4 alkoxy and C 1-4 alkylamino, a compound, a stereoisomer thereof , a solvate or a pharmaceutically acceptable salt.
4. The method according to any one of claims 1 to 3,

R 1 and R 2 are each independently H, halogen, C 1-4 alkyl, or halogen-substituted C 1-4 alkyl, a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4,

wherein any one of R 1 and R 2 is H and the other is halogen, C 1-4 alkyl, or halogen-substituted C 1-4 alkyl, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. .
4. The method according to any one of claims 1 to 3,

R 1 and R 2 taken together form a 5 or 6 membered saturated or partially unsaturated carbocyclyl ring, or a 5 or 6 membered heteroaryl or heterocyclyl ring comprising 1 or 2 nitrogen atoms, A stereoisomer, solvate or pharmaceutically acceptable salt thereof.
7. The method according to any one of claims 1 to 6,

Ring X is -NR X1 R X2 or substituted or unsubstituted C 3-6 cycloalkyl, wherein R X1 and R X2 together with the nitrogen atom to which they are attached are substituted or unsubstituted 4 membered containing one nitrogen atom to 7 membered heterocyclyl ring;

“Substitution” in the above definition of Ring X means halogen, oxo, OH, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy and halogen A compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, which means substituted with one or more substituents selected from the group consisting of C 1-4 alkoxy substituted with .
8. The method of claim 7,

ring X is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl and azepanyl;

wherein ring X is optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, oxo, OH, C 1-4 alkyl and halogen-substituted C 1-4 alkyl, compound, stereoisomer, solvate thereof or a pharmaceutically acceptable salt.
6. The method according to any one of claims 1 to 5,

R 4 and R 5 are connected with a carbon atom of the benzene ring to which they are attached to a *-CO-NR 6 -CH 2 - group to form a 5-membered lactam ring, wherein * represents the position at which R 4 is bonded to the benzene ring, R 6 is H or C 1-4 alkyl, a stereoisomer, solvate or pharmaceutically acceptable salt thereof.
10. The method according to any one of claims 1 to 9,

A compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

;
;

;
;

;
;

;
;

;
;

;
;

;
;

;
;

;
;

;
;

;
; and
.
A disease or disorder mediated by or related to Leucine-rich repeat kinase 2 (LRRK2) comprising the compound according to any one of claims 1 to 10, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof A pharmaceutical composition for preventing or treating.
12. The method of claim 11,

The disease or disorder mediated by or related to the LRRK2 is a degenerative brain disease pharmaceutical composition.
13. The method of claim 12,

The degenerative brain disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich's Syndrome, Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia A pharmaceutical composition selected from the group consisting of.
Prevention of a disease or disorder mediated by or related to LRRK2, comprising administering to a subject a compound according to any one of claims 1 to 10, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof or how to treat it.
Use of a compound according to any one of claims 1 to 10, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of a disease or condition mediated by or associated with LRRK2.
Use of a compound according to any one of claims 1 to 10, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disease or condition mediated by or related to LRRK2 .