KR102666918B1 - Novel LRRK2 inhibitors - Google Patents

Abstract

The present invention provides a novel leucine-rich repeat kinase 2 (LRRK2) inhibitor of Formula 1, a pharmaceutical composition containing the same for preventing or treating diseases or disorders mediated by or related to LRRK2, and the same. It relates to treatment and prevention methods for diseases. The compound according to the present invention has excellent LRRK2 inhibitory activity and can be effectively used for the prevention or treatment of diseases or conditions mediated by or related to LRRK2 (eg, Parkinson's disease).

Description

Novel LRRK2 inhibitors

The present invention relates to a leucine-rich repeat kinase 2 (LRRK2) inhibitor of Formula 1, a pharmaceutical composition containing the same for preventing or treating diseases or disorders mediated by or related to LRRK2, and diseases using the same. It relates to treatment and prevention methods.

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 movements.

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in hereditary Parkinson's disease. For example, the LRRK2 Gly2019Ser mutation causes increased kinase activity, causing 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 is known that LRRK2 is related to Crohn's disease through genomic linkage analysis (Teri A. Manolio, N Engl J Med 2010;363:166-176). As the relationship between LRRK2 and diseases becomes known, regulators or inhibitors of LRRK2 are being developed (e.g., Patent Publication No. 2020-0085779 (2020.07.15)).

Therefore, the object of the present invention is to provide a compound of formula 1 that exhibits excellent inhibitory activity against LRRK2, and using the same, has high efficacy in the treatment and prevention of diseases or disorders mediated by or related to LRRK2, such as neurodegenerative diseases. is to achieve.

The object of the present invention is to provide compounds of formula (1).

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases or disorders mediated by or related to LRRK2.

Another object of the present invention is to provide a method for preventing or treating diseases or conditions mediated by or related to LRRK2 using an LRRK2 inhibitor.

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. Additionally, the scope of the present application cannot be considered limited by the specific description described below.

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

[Formula 1]

In Formula 1, R ¹ may be C _1-6 alkyl substituted with halogen. In addition, R ¹ may be C _1-3 alkyl substituted with 1 to 3 halogen atoms each independently selected from the group consisting of F, Cl, Br and I. For example, R ¹ is CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ CHF ₂ , CH ₂ CH ₂ F, CH ₂ CH ₂ CF ₃ , CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ CH ₂ F, CCl ₃ , CHCl ₂ , CH ₂ Cl, CH ₂ CCl ₃ , CH ₂ CHCl ₂ , CH ₂ CH ₂ Cl, CH ₂ CH ₂ CCl ₃ , CH ₂ CH ₂ CHCl ₂ , CH ₂ CH ₂ CH ₂ Cl , CBr ₃ , CHBr ₂ , CH ₂ Br, CH ₂ CBr ₃ , CH ₂ CHBr ₂ , CH ₂ CH ₂ Br, CH ₂ CH ₂ CBr ₃ , CH ₂ CH ₂ CHBr ₂ , CH ₂ CH ₂ CH ₂ Br, CI ₃ , CHI ₂ , CH ₂ I, CH ₂ CI ₃ , CH ₂ CHI ₂ , CH ₂ CH ₂ I, CH ₂ CH ₂ CI ₃ , CH ₂ CH ₂ CHI ₂ , CH ₂ CH ₂ CH ₂ I, etc.

In Formula 1, R ² is halogen; OH; CN; Amino; nitro; C _1-6 alkyl; C _1-6 alkoxy; formyl; C _1-6 alkylcarbonyl; mono- or di-C _1-6 alkylamino; formylamino; C _1-6 alkylcarbonylamino; mono- or di-C _1-6 alkylaminocarbonyl; formyloxy; and C _1-6 alkylcarbonyloxy. In R ² the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl, mono- or di-C _1-6 alkylamino, C _1-6 alkylcarbonylamino, mono- or di- C _1-6 alkylaminocarbonyl, and C _1-6 alkylcarbonyloxy may be optionally substituted with halogen, OH, CN, amino or nitro. At this time, n may be an integer from 0 to 3.

Additionally, R ² is halogen; OH; CN; Amino; nitro; C _1-6 alkyl; C _1-6 alkoxy; C _1-6 alkylcarbonyl; and mono- or di-C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl, and mono- or di-C _1-6 Alkylamino may be optionally substituted with halogen, OH, CN, amino or nitro. In this case, n may be an integer from 0 to 2. In one embodiment, R ² is halogen, CN, C _1-6 alkyl optionally substituted with halogen, C _1-6 alkoxy optionally substituted with halogen, C 1-6 alkylcarbonyl optionally substituted with halogen, or C _1-6 alkyl optionally substituted with halogen. may be an optionally substituted mono- or di-C _1-6 alkylamino. At this time, n may be an integer from 0 to 2.

In formula 1 above, rings A and B are each independently a 3- to 10-membered heteromono, optionally comprising one additional heteroatom selected from N, O and S, with N bonded to the phenyl ring or pyrimidine ring. It may be a cyclyl.

In addition, the rings A and B are each independently a 4- to 9-membered heteromonocyclyl group optionally comprising one additional heteroatom selected from N, O and S, with N attached to the phenyl ring or pyrimidine ring. You can. In one embodiment, Ring A and Ring B are each independently a 4- to 7-membered heteromono, optionally including one additional heteroatom selected from N, O, and S, with N bonded to a phenyl ring or a pyrimidine ring. It may be a cyclyl.

In addition, the rings A and B are each independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl and oxazepanyl, thiazepanyl. It may be selected from a group consisting of: In one embodiment, rings A and B can each independently be azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, or oxazepanyl. In one embodiment, at least one of Ring A and Ring B is a 5-membered or 6-membered ring, each independently comprising one additional heteroatom selected from N, O and S, with N bonded to the phenyl ring or pyrimidine ring. It may be a circular heteromonocyclyl.

In one embodiment, the size of ring A can be the same or larger than the size of ring B. For example, when Ring B is a 4-membered heteromonocyclyl, Ring A may be a 4-membered or more heteromonocyclyl. Alternatively, when Ring B is a 5-membered heteromonocyclyl, Ring A may be a 5-membered heteromonocyclyl or more. In one embodiment, Ring B can be a 4-membered heteromonocyclyl and Ring A can be a 4-, 5-, 6-, or 7-membered heteromonocyclyl. In one embodiment, Ring B is a 5-membered heteromonocyclyl and Ring A can be a 5-, 6-, or 7-membered heteromonocyclyl. In one embodiment, Ring B is a 6-membered heteromonocyclyl and Ring A can be a 6- or 7-membered heteromonocyclyl. In one embodiment, Ring B can be azetidinyl and Ring A can be azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, or oxazepanyl. In one embodiment, Ring B can be pyrrolidinyl and Ring A can be pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, or oxazepanyl. In one embodiment, Ring B can be piperidinyl or morpholinyl and Ring A can be piperidinyl, morpholinyl, azepanyl, or oxazepanyl.

In one embodiment, ring B can be pyrrolidinyl. In this case, the pyrrolidinyl may be substituted with two or more halogens. For example, the pyrrolidinyl may be substituted with a first halogen and a second halogen. In one embodiment, the first halogen and the second halogen may be geminal substituted at position 3 of the pyrrolidinyl ring, or may be geminal substituted at position 4 of the pyrrolidinyl ring. Alternatively, the first halogen and the second halogen may be substituted vicinal at positions 3 and 4 of the pyrrolidinyl ring. In this case, the first halogen and the second halogen may have a cis or trans positional relationship. Preferably, the first halogen and the second halogen may have a trans position relationship.

In Formula 1, rings A and B are halogen; OH; CN; oxo; Amino; nitro; C _1-6 alkyl; C _1-6 alkoxy; mono- or di-C _1-6 alkylamino; and 3- to 8-membered heteromonocyclyl containing 1 to 3 heteroatoms selected from N, O and S. At this time, the C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkylamino may be optionally substituted with halogen, OH, CN, oxo, amino or nitro, and the 3-membered to The 8-membered heteromonocyclyl may be optionally substituted with halogen, OH, CN, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-C _1-6 alkylamino.

Additionally, rings A and B are each independently halogen; OH; CN; oxo; Amino; C _1-6 alkyl; C _1-6 alkoxy; pyrrolidinyl; piperidinyl; piperazine; morpholine; and thiomorpholinyl. In one embodiment, rings A and B are each independently selected from halogen; OH; CN; oxo; Amino; C _1-6 alkyl; and morpholinyl.

In one embodiment, at least one of Ring A and Ring B is halogen; OH; or substituted with oxo, or at least one of Ring A and Ring B may be a heteromonocyclyl further comprising O, with N bonded to a phenyl ring or a pyrimidine ring, respectively. In one embodiment, at least one of Ring A and Ring B is substituted with OH or oxo, or at least one of Ring A and Ring B is a hetero ring further comprising O, with N bonded to a phenyl ring or pyrimidine ring, respectively. It may be monocyclyl.

In one embodiment, Ring A or Ring B is pyrrolidinyl; piperidinyl; piperazine; morpholine; When substituted with a substituent selected from the group consisting of thiomorpholinyl, the nitrogen atom of the substituent may be bonded to ring A or ring B. For example, the substituent is 1-pyrrolidinyl; 1-piperidinyl; 1-piperazine; 4-morpholinyl; Or it may be 4-thiomorpholine.

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 an alkyl group of C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ . 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. there is.

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 “hydroxy” refers to the -OH functional group (hydroxyl group).

The term “alkoxy” refers to an alkyl bonded to an oxygen atom. For example, the C ₁ to C ₆ alkoxy group may be a C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ alkoxy group. The alkoxy group may be methoxy, ethoxy, or propoxy.

The term “amino” group refers to -NH ₂ .

The term “nitro” refers to -NO ₂ .

The term “cyano” is -CN, which refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

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

The term "alkylamino" refers to a functional group in which one or two hydrogen atoms of an amino (-NH ₂ ) group are replaced by one or two of the above-mentioned alkyl groups, and includes both mono-alkylamino groups and di-alkylamino groups. , the two alkyl groups in the di-alkylamino group may be the same or different. Specifically, mono-C _1-6 alkylamino has one hydrogen atom of the amino (-NH ₂ ) group substituted with C _1-6 alkyl, and di-C _1-6 alkylamino has the amino (-NH ₂ ) group replaced with C 1-6 alkyl. Two hydrogen atoms may be substituted with the same or different C _1-6 alkyl. For example, mono-C _1-6 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tertiary-butylamino, pentylamino, hexylamino, etc. It can be included. Di-C _1-6 alkylamino groups are, for example, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, ethylpropylamino, ethyliso It may include propylamino, ethyl isobutylamino, isopropyl isobutylamino, methylhexylamino, ethylhexylamino, etc.

The term “alkylcarbonyl” refers to an alkyl group connected to the remainder of the molecule through a carbonyl (CO) group, where “alkyl” has the meaning defined above. For example, C _1-6 alkylcarbonyl includes acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, etc.

The term "alkylcarbonylamino" refers to the group alkyl-C(O)-NH-, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valeryl amino, isovalerylamino, pivaloylamino. , hexanoylamino, heptanoylamino, etc.

The term “alkylaminocarbonyl” refers to an alkyl-NHC(O)-group, such as C _1-6 alkylaminocarbonyl is acetamido, propylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, Includes pentylaminocarbonyl, hexylaminocarbonyl, etc.

The term "alkylcarbonyloxy" refers to an alkyl-C(O)-O-group, such as C _1-6 alkylcarbonyloxy is acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryl. Includes oxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, etc.

The term "formyl" refers to the HC(O)-group, the term "formyloxy" refers to the HC(O)-O-group and the term "formylamino" refers to the HC(O)-NH-group. .

The term “heteromonocyclyl” refers to a saturated or partially unsaturated monocyclic hydrocarbon group containing at least one heteroatom. Heteromonocyclyl groups are 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, and 4 to 7. , may contain 4 to 6 ring atoms. The heteroatom may be any one or more selected from the group consisting of N, O, and S. The heteroatoms may be 1 to 3 heteroatoms selected from the group consisting of N, O, and S. Additionally, the heteroatom may be one or two heteroatoms selected from N and O.

Non-limiting examples of heteromonocyclyl include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl. Examples include the date of plate making, etc.

The term "substitution" in the above "substituted or unsubstituted" refers to introduction in place 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 the introduced atomic group. . Substituents are for example halogen, OH, CN, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, mono- or di-(C _1-6 alkyl)amino, or N, O and S. It may be a 3- to 8-membered heteromonocyclyl containing 1 to 3 heteroatoms selected from, and the substituents include halogen, OH, CN, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, may be further substituted with mono- or di-(C _1-6 alkyl)amino.

The compound of Formula 1 can be prepared according to Scheme A below.

[Scheme A]

In step 1, the amine compound containing ring A and the 4-fluoro-nitrobenzene compound substituted with R ² are dissolved in a suitable organic solvent, such as N,N-diisopropylethylamine (abbreviated as DIPEA or DIEA), The reaction can be performed in acetonitrile (ACN) or dichloromethane (DCM). In one embodiment, the reaction is performed at about 10°C to about 120°C, about 20°C to about 100°C, or about 50°C to about 80°C for about several hours to overnight, about 12 hours to about 18 hours, about It can be performed for 16 hours.

In step 2, the -NO ₂ group of the product obtained in step 1 can be reduced to an NH ₂ group under appropriate reduction reaction conditions, for example, in a hydrogen atmosphere in the presence of a Pd/C catalyst. In one embodiment, the reduction reaction is carried out in an alcohol solvent such as EtOH at about 10°C to about 50°C, about 20°C to about 40°C, or at room temperature, for about tens of minutes to several hours, about 30 minutes to about 5 hours, or about 1 hour. It can be performed for about 4 hours.

In step 3, the aniline compound and dichloropyrimidine compound obtained in step 2 are optionally reacted with a suitable catalyst such as ZnCl ₂ , triethylammonium (TEA) in a suitable organic solvent such as dichloroethane (DCE), t-butanol (tBuOH), etc. The reaction can be carried out by mixing in the presence of etc. 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 4, the compound obtained in step 3 is mixed with an amine compound containing ring B in a suitable organic solvent such as DIPEA, ACN at about 10°C to about 80°C, about 20°C to about 60°C, or at room temperature for 1 hour. The reaction may be performed overnight or for 2 to 18 hours.

According to rings A and B, R ¹ and R ² , the compound of Formula 1 is obtained by separately reacting a dichloropyrimidine compound with an amine compound containing ring B, as shown in Scheme A-1, and the product obtained in the above steps is It can be manufactured by reacting with the product of 2.

[Scheme A-1]

In Scheme A-1, steps 3-1 and 4-1 can be performed by appropriately modifying steps 3 and 4 of Scheme A. For example, step 3-1 is carried out in a suitable solvent such as DIPEA, DMF, DCM, NMP (N-methylpyrrolidone), by adding an appropriate reagent such as K ₂ CO ₃ as needed, at about -80°C to about 50°C; The reaction can be performed at about -70°C to about 30°C or about room temperature for several tens of minutes to overnight, about 20 minutes to about 18 hours, or about 30 minutes to about 12 hours.

In addition, step 4-1 is carried out in a suitable solvent such as DIPEA, n-BuOH, etc., by adding an appropriate reagent such as concentrated hydrochloric acid as needed, at about room temperature to about 150°C, about 50°C to about 100°C, or about 80°C to about The reaction can be performed at 100°C for tens of minutes to tens of hours, about 30 minutes to about 18 hours, or about 1 hour to about 12 hours.

The method for preparing the compound of Formula 1 described above is an example and can be modified by selecting an appropriate solvent, catalyst, reaction conditions, etc. depending on the type of starting material to obtain the final compound. etc. are widely known to those skilled in the art.

The compound of Formula 1 may be selected from the group consisting of the following compounds:

.

.

The term “isomer” in the term “stereoisomer” refers to a compound that has the same molecular formula, but the connection method or spatial arrangement of the constituent atoms in the molecule is not the same. 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 with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified into R (Rectus: clockwise) and S (Sinister: counterclockwise) when the chiral center carbon has 4 or more different substituents. Diastereomers are stereoisomers that are not mirror images, and are isomers that occur in different spatial arrangements of atoms. The diastereomers can be divided into cis-trans isomers and conformational isomers (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 a compound. 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 physical properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salts include formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, and trifluoroacetate. , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspart. It may be an acid salt. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

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

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

The compound of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and LRRK2 are as described above.

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

The disease or disorder mediated by or related to LRRK2 may be a disease selected from the group consisting of dyskinesia, central nervous system disorder, cancer, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease (Inflammatory Bowel Disease), and tuberculosis.

The pharmaceutical composition may further include known active ingredients that have activity in preventing, treating, or improving degenerative brain diseases. Known active ingredients with activity in preventing, treating, or improving degenerative brain diseases include, for example, decarboxylase inhibitors such as carbidopa, levodopa, and catechol-O-methyltransferase. O-methyltransferase (COMT) inhibitors, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, amantadine, anticholinergics, acetylcholinesterase inhibitors, or NMDA receptor antagonists (N-Methyl-D-aspartate receptor antagonist) It can be. 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. Acetylcholinesterase inhibitors may be tacrine, rivastigmine, galantamine, and donepezil. The NMDA receptor antagonist may be memantine. The compound represented by Formula 1, its derivative, stereoisomer, solvate, or pharmaceutically acceptable salt and the known active ingredient may be a single or separate composition for simultaneous or sequential administration.

The term “prevention” refers to any action that inhibits or delays the onset of a disease or condition mediated by or related to LRRK2 by administering the pharmaceutical composition. The term “treatment” refers to any action that improves or beneficially changes the symptoms of a disease or disorder mediated by or related to LRRK2 by administration of the pharmaceutical composition.

The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to include an excipient, diluent, or auxiliary agent. The carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl chloride. It may be selected from the group consisting of rolidone, water, physiological saline, buffer solutions such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.

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

In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further include excipients. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. Additionally, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid preparation for oral administration may be a suspension, oral solution, emulsion, or syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain excipients such as wetting agents, sweeteners, flavoring agents, or preservatives. In the pharmaceutical composition, preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried products, and suppositories. Non-aqueous solvents or suspensions may contain vegetable oil or ester. 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, laurel, or glycerogelatin.

The pharmaceutical composition includes the compound according to one aspect, its stereoisomer, solvate, or pharmaceutically acceptable salt as an active ingredient of the pharmaceutical composition. “Active ingredient” refers to a bioactive substance used to achieve pharmacological activity (e.g., treatment of degenerative brain diseases).

The pharmaceutical composition may include an effective amount of the compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof. The term “effective amount” refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to an individual in need of such prevention or treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or organism selected. The preferred dosage of the pharmaceutical composition varies depending on the individual's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art. However, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt may be administered in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg. Can be administered 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt is present in an amount of about 0.0001% to about 10% by weight, or 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. Methods of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.

Another aspect of the present invention is the prevention of diseases or disorders mediated by or associated with LRRK2, comprising administering to a subject a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect. Or provide a treatment method.

The compound of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, diseases or conditions 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 individual may be suffering from, or is likely to suffer from, a disease mediated by or related to LRRK2 or symptoms associated with the condition.

The method may further include administering to the subject a known active ingredient that has the effect of preventing or treating a disease or condition 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 one aspect, its stereoisomer, solvate, or pharmaceutically acceptable salt.

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

The preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person 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 based on adults. It can be. The administration may be 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, solvate, or pharmaceutically acceptable salt thereof according to one aspect, for use in the prevention or treatment of a disease or condition mediated by or associated with LRRK2. to provide.

Another aspect of the present invention is to provide a compound of Formula 1, a stereoisomer thereof, a solvate, or a pharmaceutically acceptable pharmaceutical composition according to one aspect, for preparing a medicament for preventing or treating a disease or condition mediated by or related to LRRK2. Provides uses for salts.

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

The compound of formula 1 according to the present invention has excellent LRRK2 inhibitory activity and can be used in pharmaceutical compositions for preventing or treating diseases or disorders mediated by or related to LRRK2 (e.g., Parkinson's disease), and methods for treating and preventing diseases using the same. It can be used effectively.

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

Preparation Example 1: 2-Chloro-4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine

3,3-difluoropyrrolidine hydrochloride (330.83 mg, 2.30 mmol, 1 equiv) and DIEA (595.64 mg, 4.61 mmol, 802.75 uL, 2 equiv) were added and the mixture was stirred at 20°C for 12 hours. TLC (petroleum ether: ethyl acetate = 10:1, desired product Rf = 0.4) showed the reaction was complete. LCMS (t=1.323) showed the desired product. The mixture was then concentrated under reduced pressure, and the residue was poured into ice water (15 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, 10/1) to obtain 2-chloro-4-(3,3-difluoropyrrolidin-1-yl)-5-( Trifluoromethyl)pyrimidine (210 mg, 31.7% yield) was obtained as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.47 (s, 1 H), 4.08-3.91 (m, 4 H), 2.57-2.39 (m, 2 H); LCMS: RT = 1.323 min, MS m/z: 288.4 [M+H] ⁺ .

Preparation Example 2: (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol

Step 1: Synthesis of (3S,4R)-3-hydroxy-4-methylpyrrolidine trifluoroacetate

Mix a solution of tert-butyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1 equiv) in DCM (5 mL) and Acetic acid (TFA) (5.39 g, 47.27 mmol, 3.5 mL, 19.03 equiv) was added at 0°C. The mixture was stirred at 20°C for 5 hours. TLC (methylene chloride:methanol = 10:1, desired product Rf = 0.13) showed the reaction was complete. The mixture was concentrated under reduced pressure to afford (3S,4R)-3-hydroxy-4-methylpyrrolidine trifluoroacetate (230 mg, crude, TFA) as a brown oil. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 9.48 (br s, 1 H), 4.04-4.16 (m, 1 H), 3.92 (br s, 1 H), 3.20-3.34 (m, 2 H), 2.92 (br s, 1 H), 2.69-2.83 (m, 1 H), 2.21-2.39 (m, 1 H), 0.84-1.02 (m, 3 H).

Step 2: Synthesis of (3S,4R)-4-methyl-1-(4-nitrophenyl)pyrrolidin-3-ol

N-methyl-2-p of the compound obtained in step 1 (230 mg, 1.07 mmol, 1 equivalent, TFA) and 1 - fluoro-4-nitrobenzene (150.82 mg, 1.07 mmol, 113.40 uL, 1 equivalent) K ₂ CO ₃ (147.74 mg, 1.07 mmol, 1 equivalent) was added to a solution of rolidone (NMP) (2 mL) and stirred at 20°C for 12 hours. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.4) showed that the reaction was complete. LCMS (t=1.420) showed the desired product. The residue was poured into ice water (w/w = 1/1) (30 mL). The resulting precipitate was filtered and the filtered cake was collected and dried to produce (3S,4R)-4-methyl-1-(4-nitrophenyl)pyrrolidin-3-ol (185 mg, 77.9% yield) as a yellow solid. was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.37-7.59 (m, 2 H), 6.60-6.73 (m, 2 H), 4.39 (d, J = 4.4 Hz, 1 H) 3.12 (q, J = 4.8 Hz, 2 H), 2.18-2.38 (m, 3 H), 1.78-1.90 (m, 1 H), 0.18 (s, 3 H); LCMS: RT = 1.420 min, MS m/z: 223.5 [M+H] ⁺ .

Step 3: Synthesis of (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol

Pd/C (26.5 mg, 25.00 umol, 10% purity) was added to the EtOH (2 mL) solution of the compound (265 mg, 1.19 mmol, 1 equivalent) obtained in step 2 above. The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred at 25° C. under H ₂ (15 psi) for 2 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.2) showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to give (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol (210 mg, 91.60% yield) as a brown solid. It was used in the next step without further purification. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 6.82-6.92 (m, 1 H), 6.57-6.72 (m, 2 H), 6.38-6.56 (m, 1 H), 4.41 (br s , 2 H), 3.46-3.71 (m, 2 H), 2.40 (t, J = 8.0 Hz, 3 H), 2.17-2.34 (m, 1 H), 1.86-2.10 (m, 3 H), 1.11 ( d, J = 7.2 Hz, 3 H); LCMS: RT = 0.360 min, MS m/z: 193.1 [M+H] ⁺ .

Preparation Example 3: 2-Chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidine

Stir-mix 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 g, 4.60 mmol, 1.00 equiv) and DIEA (1.7 g, 13.82 mmol, 3.00 equiv) in DCM (15 mL) and add to DCM. (3S,4S)-3,4-difluoropyrrolidine hydrochloride (661 mg, 4.60 mmol, 1.00 equiv) in (5 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 30 minutes and concentrated under reduced pressure. The residue was eluted with PE/EtOAc (2:1) and purified by silica gel column chromatography to obtain 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5. -(Trifluoromethyl)pyrimidine (800 mg, 54%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.50 (s, 1H), 5.38-5.35 (m, 1H), 5.26-5.23 (m, 1H), 4.19-4.07 (m, 2H), 4.00-3.94 (m, 1H), 3.90-3.84 (m, 1H); MS m/z: 288/290 [M+H] ⁺ .

Preparation Example 4: 4-[3-(benzyloxy)piperidin-1-yl]aniline

Step 1: Synthesis of 1-(4-nitrophenyl)piperidin-3-ol

Piperidin-3-ol (1.00 g, 9.88 mmol, 1.00 equiv) and 4-fluoronitrobenzene (2.79 g, 19.77 mmol, 2.00 equiv) were stirred mixed in ACN (10 mL) and DIEA (3.83 g, 29.63 mmol, 3.00 equivalent) was added. The resulting mixture was stirred at 85° C. for 16 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to yield 1-(4-nitrophenyl)piperidin-3-ol (1 g, 43.24%). was obtained as a yellow solid. MS m/z: 223 [M+H] ⁺ .

Step 2: Synthesis of 3-(benzyloxy)-1-(4-nitrophenyl)piperidine

1-(4-nitrophenyl)piperidin-3-ol (1.00 g, 4.50 mmol, 1.00 equiv) was stirred mixed in DMF (10 mL) and NaH (216 mg, 9.00 mmol, 2.00 equivalent) was added in portions. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere, and benzyl chloride (1.14 g, 9.00 mmol, 2.00 equivalents) was added to the mixture. The resulting mixture was further stirred at 25° C. for 2 hours and the reaction was quenched with water/ice (50 mL). The resulting mixture was extracted with EtOEt (2*50 mL) and the organic layers were combined, washed with brine (2*50 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 3-(benzyloxy)-1-(4-nitrophenyl)piperidine (1g, 67.59). %) was obtained as a yellow solid. MS m/z: 313 [M+H] ⁺ .

Step 3: Synthesis of 4-[3-(benzyloxy)piperidin-1-yl]aniline

3-(Benzyloxy)-1-(4-nitrophenyl)piperidine (1.00 g, 3.20 mmol, 1.00 equiv) was stirred mixed in MeOH (10 mL) and Pd/C (10%, 300 mg) was stirred. Added. The mixture was hydrogenated using a hydrogen balloon for 1 hour at room temperature under a hydrogen atmosphere, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 4-[3-(benzyloxy)piperidin-1-yl]aniline (700 mg, 73.56%) as a light yellow solid. Obtained. MS m/z: 283 [M+H] ⁺ .

Preparation Example 5: 2,4-dichloro-5-(3,3,3-trifluoropropyl)pyrimidine

Step 1: Synthesis of 2,4-dimethoxy-5-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]pyrimidine

2,4-dimethoxypyrimidin-5-ylboronic acid (1.00 g, 5.43 mmol, 1.00 equiv) and (1E)-1-chloro-3,3 in THF (10 mL) and H ₂ O (2 mL). ,3-trifluoroprop-1-ene (1.42 g, 10.88 mmol, 2.00 equiv) was mixed, Pd ₂ (dba) ₃ (1.00 g, 1.08 mmol, 0.20 equiv) and [(t-Bu) ₃ PH ]BF ₄ (630 mg, 2.17 mmol, 0.4 equiv) was added. The resulting mixture was stirred at 60°C for 8 hours under nitrogen atmosphere and the mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was eluted with PE/EtOAc (1:2) and purified by silica gel column chromatography to give 2,4-dimethoxy-5-[(1E)-3,3,3-trifluoroprop-1-ene- 1-yl]pyrimidine (890 mg, 66%) was obtained as a light yellow solid. MS m/z: 235 [M+H] ⁺ .

Step 2: Synthesis of 2,4-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidine

The compound obtained in step 1 (890 mg, 3.80 mmol, 1.00 equiv) and Pd/C (808 mg, 7.60 mmol, 2.00 equiv) were mixed in MeOH (10 mL) and stirred at 25°C for 10 hours under a hydrogen atmosphere. did. The solid was filtered, and the filtrate was concentrated under reduced pressure to obtain 2,4-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidine (700 mg, 75%) as a white solid. MS m/z: 237 [M+H] ⁺ .

Step 3: Synthesis of 5-(3,3,3-trifluoropropyl)pyrimidine-2,4-diol

The compound obtained in step 2 (650 mg, 2.75 mmol, 1.00 equiv) was stirred and mixed in MeOH (4 mL), and HCl (0.60 mL) was added dropwise at 25°C under nitrogen atmosphere. The mixture was stirred at 25°C for 3 days under a nitrogen atmosphere, and the resulting mixture was concentrated under reduced pressure. The crude product was washed with PE/EtOAc (10:1) to give 5-(3,3,3-trifluoropropyl)pyrimidine-2,4-diol (500 mg, 83%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 10.98 (brs, 2H), 7.45 (s, 1H), 2.44 (s, 4H); MS m/z: 209 [M+H] ⁺ .

Step 4: Synthesis of 2,4-dichloro-5-(3,3,3-trifluoropropyl)pyrimidine

The compound obtained in step 3 (480 mg, 2.30 mmol, 1.00 equivalent) was stirred and mixed in POCl ₃ (5 mL), and DIEA (894 mg, 6.91 mmol, 3.00 equivalent) was added dropwise at 0°C. The resulting mixture was stirred at 100°C for 16 hours. The mixture was poured slowly onto ice and extracted with EtOAc (3×30 mL). The organic layer was collected, 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 yield 2,4-dichloro-5-(3,3,3-trifluoropropyl)pyrimidine (200 mg, 34%). was obtained as a light yellow oil. MS m/z: 245/247/249 [M+H] ⁺ .

Preparation Example 6: 2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine

Step 1: Synthesis of ethyl(2Z)-4,4,4-trifluoro-2-(hydroxymethylidene)butanoate

A solution of ethyl 4,4,4-trifluorobutanoate (5.00 g, 28.80 mmol, 1.00 eq) in THF (50 mL) was stirred and lithium diisopropylamide (LDA) (3.99 mL, 37.20 mmol, 1.00 eq). Equivalent) was added dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred at -40°C for 1 hour under nitrogen atmosphere. Ethyl formate (9.50 mL, 128.19 mmol, 4.00 equiv) was added dropwise to the mixture at -60°C. The resulting mixture was further stirred overnight at room temperature. TLC showed the reaction was complete. The reaction was quenched by adding saturated aqueous NH ₄ Cl (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (3 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl (2Z)-4,4,4-trifluoro-2-(hydroxymethylidene)butanoate (2.5 g, 43.81%) as a yellow oil.

Step 2: Synthesis of 5-(2,2,2-trifluoroethyl)-1,3-dihydropyrimidine-2,4-dione

The compound obtained in step 1 (2.50 g, 12.61 mmol, 1.00 equiv) was stirred in H ₂ SO ₄ (25 mL), and urea (0.76 g, 12.61 mmol, 1.00 equiv) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 70° C. under nitrogen atmosphere. LCMS showed the reaction was complete. The mixture was basified to pH 8 with saturated aqueous NaHCO ₃ solution. The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with CH ₂ Cl ₂ /MeOH (12:1) and purified by silica gel column chromatography to obtain 5-(2,2,2-trifluoroethyl)-1,3- Dihydropyrimidine-2,4-dione (300 mg, 12.25%) was obtained as an off-white solid. MS m/z: 195 [M+H] ⁺ .

Step 3: Synthesis of 2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine

The compound obtained in step 2 (300 mg, 1.54 mmol, 1.00 equiv) was stirred in POCl ₃ (3.00 mL), and DIEA (399 mg, 3.09 mmol, 2.00 equiv) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 110° C. under nitrogen atmosphere. LCMS showed the reaction was complete. The mixture was cooled to room temperature and the mixture was basified to pH 8 with saturated aqueous NaHCO ₃ solution. The resulting mixture was extracted with EtOAc (3*20 mL) and the organic layers were combined, washed with brine (3*20 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine (150 mg, 42.02%) as a yellow oil. MS m/z: 231/233/235 [M+H] ⁺ .

Example 1: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-methoxyphenyl]piperidin-3-ol

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

[Scheme 1]

Step 1: Synthesis of 1-(3-methoxy-4-nitrophenyl)piperidin-3-ol

4-fluoro-2-methoxy-1- in a solution of 3-hydroxypiperidine (142 mg, 1.40 mmol, 1.2 equiv) and DIPEA (0.31 mL, 1.78 mmol, 1.5 equiv) in acetonitrile (4 mL). Nitrobenzene (200 mg, 1.17 mmol) was added and stirred at 80°C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography to obtain the desired product as a bright yellow powder (209 mg, 0.96 mmol, 82% yield). ^1H NMR (400 MHz, Acetone-d ₆ ); δ 7.88 (d, J = 9.6 Hz, 1H), 6.58 (s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 4.8 Hz, 1H), 3.94 (s, 3H) , 3.89-3.85 (m, 1H), 3.77-3.73 (m, 2H), 3.18-3.12(m, 1H), 3.04 (dd, J = 12.8, 4.0 Hz, 1H), 2.04-1.99 (m, 1H) , 1.88-1.85 (m, 1H), 1.61-1.54 (m, 2H).

Step 2: Synthesis of 1-(4-amino-3-methoxyphenyl)piperidin-3-ol

To a solution of the compound (209 mg, 0.96 mmol) obtained in Step 1 above in MeOH (15 mL) was added 10% palladium on carbon (40 mg). The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred under H ₂ at 25° C. for 1 hour. After completion of the reaction, the mixture was filtered through a pad of Celite, and the residue was evaporated and purified by column chromatography to obtain the desired product as a brown solid (158 mg, 0.71 mmol, 74% yield). ^1H NMR (400 MHz, Acetone-d ₆ ); δ 6.57 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 3.94 (brs, 2H), 3.80 (s, 3H), 3.74-3.69 ( m, 2H), 3.38-3.35 (m, 1H), 3.18-3.15(m, 1H), 2.62-2.59(m, 1H), 2.49 (dd, J = 10.8, 2.4 Hz, 1H), 1.91-1.88 ( m, 1H), 1.80-1.77 (m, 1H), 1.62-1.59 (m, 1H), 1.32-1.30 (m, 1H).

Step 3: Synthesis of 1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-3-ol

Zinc chloride (2.2 mL of a 1 M solution in ether, 2.2 equivalents) was added at 0°C. After 1 hour, the compound obtained in step 2 (101 mg, 1.0 equiv) was added, followed by the addition of a solution of triethylamine (0.07 mL, 1.1 equiv) in DCE/t-BuOH (3 mL) dropwise. After stirring for 24 hours, the reaction mixture was concentrated, and the residue was diluted with EtOAc and washed with water and saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous MgSO ₄ , and the residue was evaporated and purified by column chromatography to obtain the desired product as a yellow solid (78.9 mg, 0.20 mmol, 43% yield). ¹ H NMR (400 MHz, CD ₃ OD); δ 8.54 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.57 (s, 1H), 3.88 (s, 3H), 3.82-3.80 (m, 1H), 3.61-3.59 (m, 1H), 3.45-3.42(m, 1H), 2.81 (t, J = 10.0 Hz, 1H), 2.70 (dd, J = 11.2, 2.0 Hz, 1H), 2.01-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.72-1.68 (m, 1H), 1.48-1.42 (m, 1H).

Step 4: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl} Synthesis of amino)-3-methoxyphenyl]piperidin-3-ol (compound of Example 1)

Step 3 above to a solution of (3S,4S)-3,4-difluoropyrrolidine (33.6 mg, 0.24 mmol, 1.2 equiv) and DIPEA (0.05 mL, 0.29 mmol, 1.5 equiv) in acetonitrile (1 mL). The compound obtained in (78.9 mg, 0.20 mmol) was added and stirred at 80°C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography to obtain the desired product (compound of Example 1) as a brown powder (25.6 mg, 0.06 mmol, 29% yield). ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.31 (s, 1H), 8.18 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 1H), 4.78 (brs, 1H), 3.98-3.83 (m, 4H), 3.79 (s, 3H), 3.59-3.56 (m, 2H), 3.47-3.44 (m, 1H) , 2.64 (t, J = 11.2 Hz, 1H), 2.47 (m, 1H), 1.91-1.87 (m, 1H), 1.77-1.74 (m, 1H), 1.56-1.53 (m, 1H), 1.30-1.23 (m, 1H); MS m/z: 474 [M+H] ⁺ .

Example 2: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-ethoxyphenyl]piperidin-3-ol

In the same manner as Example 1, except that 4-fluoro-2-ethoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 2 was obtained as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD); 8.23 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 6.66 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.40 (brs, 1H), 5.27 (brs, 1H) ), 4.58 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.05-3.81 (m, 3H), 3.79-3.77 (m, 2H), 3.56-3.54 (m, 1H), 3.40- 3.37(m, 1H), 2.76 (t, J = 10.0 Hz, 1H), 2.66 (t, J = 11.2 Hz, 1H), 2.00-1.97 (m, 1H), 1.88-1.87 (m, 1H), 1.69 -1.66 (m, 1H), 1.44-1.40 (m, 4H); MS m/z: 488 [M+H] ⁺ .

Example 3: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(propan-2-yloxy)phenyl]piperidin-3-ol

The same method as Example 1, except that 4-fluoro-2-isopropoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 3 was obtained as a light yellow solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.30 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.43 (brs, 1H), 5.29 (brs, 1H), 4.69-4.63 (m, 1H), 4.57 (s, 1H), 4.08-4.00 (m, 4H), 3.82(m, 1H), 3.55-3.52 (m, 1H), 3.39-3.37(m, 1H), 2.76 (t, J = 10.8 Hz, 1H), 2.66 (t, J = 10.4 Hz, 1H), 2.01-1.98 (m, 1H), 1.92-1.89 (m, 1H), 1.74-1.66 (m) , 1H), 1.46-1.44 (m, 1H), 1.41 (d, 6H); MS m/z: 502 [M+H] ⁺ .

Example 4: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(trifluoromethoxy)phenyl]piperidin-3-ol

Same as Example 1, except that 4-fluoro-2-trifluoromethoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. This method gave the compound of Example 4 as a white solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.27 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 6.98-6.96 (m, 2H), 5.32 (brs, 1H), 5.19 (brs, 1H), 4.47 (brs, 1H), 4.04-3.91 (m, 4H), 3.82 (m, 1H), 2.96-2.94 (m, 1H), 2.78-2.75(m, 1H), 2.63 (t, J = 9.6 Hz, 1H), 2.54 (t, J = 9.6 Hz, 1H), 1.88-1.86 (m, 2H), 1.67-1.65 (m, 1H), 1.45-1.38 (m, 1H); MS m/z: 528 [M+H] ⁺ .

Example 5: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(trifluoromethyl)phenyl]piperidin-3-ol

Same as Example 1, except that 4-fluoro-2-trifluoromethyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. This method gave the compound of Example 5 as a brown solid. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.54 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 5.14 (m, 1H), 5.06 (s, 1H), 4.05-3.87 (m, 4H), 3.52-3.49 (m, 1H), 3.18-3.16 (m, 1H), 2.90-2.77(m, 2H), 2.07-2.05 (m, 1H), 1.84 (m, 1H), 1.69-1.61 (m, 2H); MS m/z: 512 [M+H] ⁺ .

Example 6: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-methylphenyl]piperidin-3-ol

Carried out in the same manner as Example 1, except that 4-fluoro-2-methyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 6 was obtained as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.80 (s, 1H), 8.28 (s, 1H), 7.18 (m, 1H), 6.76 (s, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.50 (brs, 1H), 5.37 ( brs, 1H), 4.78 (s, 1H), 3.88-3.77 (m, 4H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 1H), 2.63-2.58(m, 1H), 2.49- 2.43 (m, 1H), 2.14 (m, 3H), 1.90-1.87 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.26-1.23 (m, 1H); MS m/z: 458 [M+H] ⁺ .

Example 7: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-ethylphenyl]piperidin-3-ol

Carried out in the same manner as Example 1, except that 4-fluoro-2-ethyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 7 was obtained as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.21 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.35 (brs, 1H), 5.21 (brs, 1H), 3.96-3.81 (m, 5H), 3.62-3.59 (m, 1H), 3.45-3.42 (m, 1H), 2.77 (t, J = 10.8 Hz, 1H), 2.69-2.59 (m, 3H) , 2.02-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.72-1.69 (m, 1H), 1.44-1.41 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H); MS m/z: 472 [M+H] ⁺ .

Example 8: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-[(propan-2-yl)amino]phenyl]piperidin-3-ol

The same method as Example 1, except that 4-fluoro-2-isopropylamino-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 8 was obtained as a purple solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.30 (s, 1H), 7.10 (brs, 1H), 6.42-6.38 (m, 2H), 5.34 (brs, 1H), 5.20 (brs, 1H), 3.96-3.81 (m, 5H), 3.68-3.57 (m, 2H), 3.43-3.41 (m, 1H), 2.81-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.00-1.89 (m, 2H), 1.73-1.68 (m, 1H) , 1.46-1.38 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H); MS m/z: 501 [M+H] ⁺ .

Example 9: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-2-fluoro-5-methoxyphenyl]piperidin-3-ol

Example 1 and Example 1, except that 1,2-difluoro-4-methoxy-5-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 9 was obtained as a white solid in the same manner. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.39 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 14.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.02-3.86 (m, 4H), 3.82 (s, 3H), 3.64-3.63 (m, 1H), 3.36-3.31 (m, 1H), 3.19 -3.16 (m, 1H), 2.61 (t, J = 11.2 Hz, 1H), 2.45 (t, J = 10.0 Hz, 1H), 1.92-1.90 (m, 1H), 1.77-1.74 (m, 1H), 1.62-1.53 (m, 1H), 1.27-1.23 (m, 1H); MS m/z: 492 [M+H] ⁺ .

Example 10: 1-[2-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-5-(3-hydroxypiperidin-1-yl)phenyl]ethan-1-one

Example 1, except that 1-(5-fluoro-2-nitrophenyl)ethan-1-one was used in Step 1 of Example 1 instead of 4-fluoro-2-methoxy-1-nitrobenzene. The compound of Example 10 was obtained as a light yellow solid in the same manner as above. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.44 (d, J = 9.2 Hz, 1H), 8.23 (s, 1H), 7.41 (s, 1H), 7.21 (d, J = 9.6 Hz, 1H), 5.33 (brs, 1H), 5.19 (brs, 1H), 3.40-3.90 (m, 4H), 3.72 (m, 1H), 3.47-3.44 (m, 1H), 3.31-3.28 (m, 1H), 2.74-2.71 (m, 1H), 2.63-2.58 ( m, 1H), 2.55 (s, 3H), 1.91-1.81 (m, 2H), 1.62-1.59 (m, 1H), 1.35-1.32 (m, 1H); MS m/z: 486 [M+H] ⁺ .

Example 11: 2-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl}amino) -5-(3-hydroxypiperidin-1-yl)benzonitrile

Example 11 in the same manner as Example 1, except that 5-fluoro-2-nitrobenzonitrile was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.46 (s, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.97 (s, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.31 (brs, 1H), 5.25 (brs, 1H), 5.24-5.23 (m, 1H), 4.11-3.98 (m, 4H), 3.56-3.53 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.95 (m, 1H), 2.91- 2.86 (m, 1H), 2.17-2.14 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.78 (m, 2H); MS m/z: 469 [M+H] ⁺ .

Example 12: 1-[3-Chloro-4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidine -2-yl}amino)phenyl]piperidin-3-ol

Carried out in the same manner as Example 1, except that 4-fluoro-2-chloro-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 12 was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.91 (s, 1H), 8.32 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.12 (brs, 1H), 5.38 (brs, 1H), 4.82 (brs, 1H), 3.89-3.78 (m, 4H), 3.59-3.56 (m, 2H), 3.49-3.46 (m, 1H), 2.72 (t, J = 10.8 Hz, 1H), 2.58 (t, J = 11.2 Hz, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.56-1.47 (m, 1H), 1.34-1.29 (m , 1H); MS m/z: 478 [M+H] ⁺ .

Example 13: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[2-methoxy-4-(morpholin-4-yl)phenyl]- 5-(trifluoromethyl)pyrimidin-2-amine

The compound of Example 13 was obtained as a white powder in the same manner as Example 1, except that morpholine was used instead of 3-hydroxypiperidine in Step 1 of Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.32 (s, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 3H), 3.98-3.84 (m, 4H), 3.80 (s, 3H), 3.76-3.74 (m, 4H), 3.12-3.10 (m, 4H); MS m/z: 460 [M+H] ⁺ .

Example 14: 1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-all

The compound of Example 14 was synthesized according to Scheme 2 below.

[Scheme 2]

Step 1: Synthesis of 1-(4-nitrophenyl)piperidin-3-ol

To a solution of 3-hydroxypiperidine (753.6 mg, 7.45 mmol, 1.05 equiv) and DIPEA (1.3 mL, 7.45 mmol, 1.05 equiv) in acetonitrile (14 mL) was added 1-fluoro-4-nitrobenzene (1.0 g). , 7.09 mmol) was added and stirred at 80°C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography (CH ₂ Cl ₂ :methanol = 20:1) to obtain the desired product as a yellow powder (1.54 g, 6.92 mmol, 99% yield). ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.02 (d, J = 9.6 Hz, 2H), 6.96 (d, J = 9.6 Hz, 2H), 4.92 (s, 1H), 3.80-3.77 (m, 1H), 3.73-3.70 (m, 1H), 3.56(m, 1H), 3.16-3.11 (m, 1H), 3.01 (dd, J = 12.8, 4.4 Hz, 1H), 1.89-1.87 (m, 1H), 1.77-1.75 (m, 1H), 1.47- 1.41 (m, 2H).

Step 2: Synthesis of 1-(4-aminophenyl)piperidin-3-ol

To a solution of the compound (577 mg, 2.60 mmol) obtained in Step 1 above in MeOH (15 mL) was added 10% palladium on carbon (80 mg). The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred under H ₂ at 25° C. for 1 hour. After completion of the reaction, the mixture was filtered through a pad of Celite, the residue was evaporated and purified by column chromatography (CH ₂ Cl ₂ :methanol = 20:1) to obtain the desired product as a brown solid (473 mg, 2.31 mmol, 89%). yield). ^1H NMR (400 MHz, DMSO-d ₆ ); δ 6.65 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 4.53 (brs, NH2), 3.59-3.55 (m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12(m, 1H), 2.43-2.38 (m, 1H), 2.29-2.24 (m, 1H), 1.85-1.83 (m, 1H), 1.72- 1.69 (m, 1H), 1.56-1.47 (m, 1H), 1.21-1.16 (m, 1H).

Step 3: Synthesis of 1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-3-ol

Zinc chloride (1 M solution in ether) in a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (500 mg, 2.32 mmol, 1.0 equiv) in CH ₂ Cl ₂ /t-BuOH (1:1, 6 mL). 2.3 mL, 1.0 equiv) was added at 0°C. After 1 hour, the compound obtained in step 2 above (445 mg, 2.32 mmol, 1.0 equiv) was added followed by triethylamine (0.36 mL, 2.55 mmol, 1.1 equiv) in CH ₂ Cl ₂ /t-BuOH (6 mL). ) solution was added dropwise. After stirring for 1.5 hours, the reaction mixture was concentrated, and the residue was diluted with EtOAc and washed with water and saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous MgSO ₄ and the residue was evaporated and purified by column chromatography (CH ₂ Cl ₂ :methanol = 20:1) to give the desired product as a yellow solid (877 mg, 2.30 mmol, 97% yield). did. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 10.40 (s, 1H), 8.70 (s, 1H), 7.45 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H) , 3.60-3.53 (m, 2H), 3.44-3.41(m, 1H), 2.64-2.58 (m, 1H), 2.50-2.44 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.72 ( m, 1H), 1.57-1.48 (m, 1H), 1.30-1.20 (m, 1H).

Step 4: 1-(4-((4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine- Synthesis of 3-ol (compound of Example 14)

To a solution of 2,3-dimethylpyrrolidine hydrochloride (21.5 mg, 0.16 mmol, 1.2 equiv) and DIPEA (0.04 mL, 0.20 mmol, 1.5 equiv) in acetonitrile (1.5 mL) was added the compound obtained in step 3 above (50 mg , 0.13 mmol, 1.0 equivalent) was added and stirred at 60°C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain the desired product (compound of Example 14) as a white powder (32.6 mg, 0.75 mmol, 55% yield). did. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81- 3.77 (m, 1.5H), 3.62-3.60 (m, 1H), 3.53-3.50(m, 1.5H), 3.36-3.33(m, 1H), 2.71 (t, 1H), 2.60 (dd, J = 11.2 , 2.0 Hz, 1H), 2.32-2.21 (m, 0.5H), 2.18-1.80 (m, 4H), 1.70 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H) ), 1.28 (d, J = 6.0 Hz, 1.5H), 1.09-1.06 (m, 4.5H); MS m/z: 436 [M+H] ⁺ .

Examples 15 and 16: (3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino }phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidin-3-ol

The compound of Example 14 was separated and purified to (3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl]amino}phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl) Pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained as a white powder, respectively.

(3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol (compound of Example 15)

¹ H NMR (400 MHz, CD ₃ OD); δ 8.18 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81- 3.76 (m, 1.5H), 3.61-3.60 (m, 1H), 3.53-3.49(m, 1.5H), 3.36-3.35(m, 1H), 2.73 (t, J = 10.4 Hz, 1H), 2.60 ( dd, J = 11.2, 2.0 Hz, 1H), 2.32-2.20 (m, 0.5H), 2.17-1.79 (m, 4H), 1.72-1.66 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12-1.05 (m, 4.5H); MS m/z: 436 [M+H] ⁺ .

(3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol (compound of Example 16)

¹ H NMR (400 MHz, CD ₃ OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.98 (m, 0.5H), 3.81- 3.76 (m, 1.5H), 3.61-3.59 (m, 1H), 3.53-3.50(m, 1.5H), 3.36(m, 1H), 2.71 (t, J = 11.2 Hz, 1H), 2.60 (dd, J = 10.8 Hz, 1H), 2.32-2.20 (m, 0.5H), 2.17-1.79 (m, 4H), 1.70 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12-1.05 (m, 4.5H); MS m/z: 436 [M+H] ⁺ .

Example 17: 1-(4-{[4-(3-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3 -all

The compound of Example 17 was obtained as a white powder in the same manner as Example 14, except that 3-methylpiperidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.21 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.57-4.56 (m, 1H), 3.83-3.78 (m, 2H), 3.54-3.50 (m, 1H), 3.24 (m, 1H), 2.74-2.71 (m, 1H), 2.60 (dd, J = 11.2, 2.0 Hz, 1H), 1.99-1.96 (m, 1H), 1.91- 1.58 (m, 9H), 1.40-1.29 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H); MS m/z: 436 [M+H] ⁺ .

Example 18: 1-(4-{[4-(3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-all

The compound of Example 18 was obtained as a white powder in the same manner as Example 14, except that 3,5-dimethylpiperidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. . ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.45 (brs, 1H), 8.30 (s, 1H), 7.49 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.78 (d, J = 4.4 Hz, 1H) , 4.05-4.01 (m, 2H), 3.61-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.38-3.34 (m, 1H), 2.60-2.48 (m, 3H), 2.42 (dd, J = 11.2, 2.0 Hz, 1H), 1.85 (m, 1H), 1.77-1.72 (m, 2H), 1.66-1.42 (m, 3H), 1.25-1.21 (m, 1H), 0.87 (d, J = 6.8 Hz, 6H), 0.86-0.84 (m, 1H); MS m/z: 450 [M+H] ⁺ .

Example 19: 1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine-3 -all

The compound of Example 19 was obtained as a white powder in the same manner as Example 14, except that 2-methylpyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.83-3.76 (m, 4H), 3.70-3.65 (m, 1H), 3.53-3.49 (m, 1H), 3.22-3.17(m, 1H), 2.71 (m, 1H), 2.63-2.58 (m, 1H), 2.36-2.32 (m, 1H), 2.12-2.11 (m, 1H) ), 2.00-1.96 (m, 1H), 1.90-1.86 (m, 1H), 1.71-1.56 (m, 2H), 1.40 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] ⁺ .

Example 20: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

Example 20 in the same manner as Example 14, except that (3S,4S)-3,4-difluoropyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. The compound was obtained as a white powder. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.52 (brs, 1H), 8.35 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.56 (brs, 1H), 5.42 (brs, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.04-3.85 (m, 4H), 3.59-3.50 (m, 2H), 3.40-3.37 (m, 1H), 2.58 (t, J = 10.8 Hz) , 1H), 2.46-2.41 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.55-1.52 (m, 1H), 1.27-1.20 (m, 1H); MS m/z: 444 [M+H] ⁺ .

Example 21: (3S)-1-(4-{[4-(morpholin-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine-3 -all

The compound of Example 21 was obtained as a white powder in the same manner as Example 14, except that morpholine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.29 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.83-3.78 (m, 5H), 3.62 (m, 4H), 3.56- 3.52 (m, 1H), 3.39-3.36 (m, 1H), 2.73 (t, J = 10.4 Hz, 1H), 2.62 (dd, J = 11.2, 2.4 Hz, 1H), 2.02-1.98 (m, 1H) , 1.92-1.87 (m, 1H), 1.71-1.68 (m, 1H), 1.42-1.39 (m, 1H); MS m/z: 424 [M+H] ⁺ .

Examples 22 and 23: (3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl ]amino}phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl )pyrimidin-2-yl]amino}phenyl)piperidin-3-ol

A racemate was obtained in the same manner as in Example 14, except that 3,3-difluoropyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14, from which (3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol and (3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- [I]amino}phenyl)piperidin-3-ol was separated and purified into white powder.

(3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol (compound of Example 22)

^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.51 (brs, 1H), 8.35 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.76 (d, J = 4.8 Hz, 1H) , 3.96 (t, J = 12.8 Hz, 2H), 3.84-3.81 (m, 2H), 3.60-3.50 (m, 2H), 3.40-3.37 (m, 1H), 2.60-2.52 (m, 3H), 2.46 -2.41 (m, 1H), 1.89-1.86 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.27 (m, 1H); MS m/z: 444 [M+H] ⁺ .

(3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol (compound of Example 23)

¹ H NMR (400 MHz, CD ₃ OD); δ 8.27 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.01-3.90 (m, 4H), 3.81-3.77 (m, 1H), 3.54-3.51 (m, 1H), 3.37-3.34 (m, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.61 (dd, J = 10.4 Hz, 1H), 2.53-2.44 (m, 2H) , 2.00-1.96 (m, 1H), 1.90-1.86 (m, 1H), 1.70-1.67 (m, 1H), 1.41-1.37 (m, 1H); MS m/z: 444 [M+H] ⁺ .

Example 24: (3S,5R)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl ) piperidine-3,5-diol

(3S,5R)-piperidine-3,5-diol was used in place of 3-hydroxypiperidine in Step 1 of Example 14, and 2,3-dimethylpyrrolidine was used in Step 4 of Example 14. The compound of Example 24 was obtained as a gray powder in the same manner as Example 14, except that 2-methylpyrrolidine was used instead of hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.23 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.84-3.78 (m, 4H), 3.70-3.58 (m, 3H), 3.20 (t, J = 9.2 Hz, 1H), 2.51 (t, J = 10.4 Hz, 2H), 2.39-2.29 (m, 2H), 2.13-2.11 (m, 1H), 1.64-1.55 (m, 1H) , 1.41-1.32 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 438 [M+H] ⁺ .

Example 24(R): (3S,5R)-1-(4-{[4-((R)-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidine-3,5-diol

(3S,5R)-piperidine-3,5-diol was used in place of 3-hydroxypiperidine in Step 1 of Example 14, and 2,3-dimethylpyrrolidine was used in Step 4 of Example 14. The compound of Example 24(R) was obtained as a pale yellow powder in the same manner as Example 14, except that (R)-2-methylpyrrolidine was used instead of hydrochloride. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.31 (brs, 1H), 8.27 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.92 (m, 2H), 4.51-4.49 ( m, 1H), 3.58-3.55 (m, 6H), 2.30 (t, J = 11.2 Hz, 2H), 2.18-1.99 (m, 3H), 1.85-1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H), 1.22-1.18 (m, 1H); MS m/z: 438 [M+H] ⁺ .

Example 24(S): (3S,5R)-1-(4-{[4-((S)-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidine-3,5-diol

(3S,5R)-piperidine-3,5-diol was used in place of 3-hydroxypiperidine in Step 1 of Example 14, and 2,3-dimethylpyrrolidine was used in Step 4 of Example 14. The compound of Example 24(S) was obtained as a pale yellow powder in the same manner as Example 14, except that (S)-2-methylpyrrolidine was used instead of hydrochloride. ^1H NMR (400 MHz, Acetone-d ₆ ); δ 8.34 (brs, 1H), 8.25 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.62-4.59 (m, 1H), 4.03 ( m, 1H), 3.83 (m, 2H), 3.66-3.64 (m, 1H), 3.54-3.51 (m, 3H), 2.67 (t, J = 10.4 Hz, 2H), 2.24-2.10 (m, 3H) , 1.93-1.89 (m, 1H), 1.67-1.63 (m, 1H), 1.48-1.44 (m, 1H), 1.28 (d, J = 6.0 Hz, 3H); MS m/z 438 [M+H] ⁺ .

Example 25: 1-[2-({4-[(3S,5R)-3,5-dihydroxypiperidin-1-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidine -4-yl]-3-methylpiperidin-4-one

(3S,5R)-piperidine-3,5-diol was used in place of 3-hydroxypiperidine in Step 1 of Example 14, and 2,3-dimethylpyrrolidine was used in Step 4 of Example 14. The compound of Example 25 was obtained as a yellow solid in the same manner as Example 14, except that 3-methylpiperidin-4-one was used instead of hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.32 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.35-4.32 (m, 2H), 3.82-3.77 (m, 2H), 3.63-3.60 (m, 2H), 3.54-3.48 (m, 1H), 3.10 (t, J = 12.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.65-2.59(m, 1H), 2.53- 2.41 (m, 3H), 2.33-2.30 (m, 1H), 1.40-1.32 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H); MS m/z: 466 [M+H] ⁺ .

Example 26: (3R)-1-(2-{[4-(3-methylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)p Rolidin-3-ol

In Step 1 of Example 14, 3-methylpiperidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, (R)-pyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 26 was obtained as a light pink powder in the same manner as Example 14, except that din-3-ol was used. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 5.04 (d, J = 2.8 Hz, 1H) , 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05(m, 1H), 2.85-2.80(m, 1H), 1.99-1.96 (m, 1H), 1.90-1.88 (m, 1H), 1.80-1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] ⁺ .

Example 27: (3S)-1-(2-{[4-(3-methylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)p Rolidin-3-ol

In Step 1 of Example 14, 3-methylpiperidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, (S)-pyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 27 was obtained as a white powder in the same manner as Example 14, except that din-3-ol was used. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.03 (d, J = 2.4 Hz, 1H) , 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05(m, 1H), 2.85-2.80(m, 1H), 1.99-1.96 (m, 1H), 1.89-1.88 (m, 1H), 1.76-1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] ⁺ .

Example 28: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[4-(3,5-dimethylpiperidin-1-yl)phenyl] -5-(trifluoromethyl)pyrimidin-2-amine

In Step 1 of Example 14, 3,5-dimethylpiperidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3-dimethylpyrrolidine hydrochloride was replaced with (3S,4S ) The compound of Example 28 was obtained as a white powder in the same manner as Example 14, except that -3,4-difluoropyrrolidine was used. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.27 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.39 (brs, 1H), 5.25 (brs, 1H), 4.04-3.96 ( m, 4H), 3.56-3.53 (m, 2H), 2.16 (t, J = 11.2 Hz, 2H), 1.83-1.81 (m, 3H), 0.96 (d, J = 6.0 Hz, 6H), 0.69 (q) , J = 12.4 Hz, 1H); MS m/z: 456 [M+H] ⁺ .

Example 29: (3R,4R)-1-(2-{[4-(3,5-dimethylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidine-4 -1)-4-fluoropiperidin-3-ol

In Step 1 of Example 14, 3,5-dimethylpiperidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3-dimethylpyrrolidine hydrochloride was replaced with (3R,4R ) The compound of Example 29 was obtained as a white powder in the same manner as Example 14, except that -4-fluoropiperidin-3-ol was used. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.26 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.54-4.53 (m, 0.5H), 4.42-4.41 (m, 0.5H) ), 4.12-4.08 (m, 1H), 4.00-3.96 (m, 1H), 3.73-3.71 (m, 1H), 3.54-3.51 (m, 2H), 3.24 (t, J = 11.6 Hz, 1H), 3.07 (dd, J = 13.2, 4.0 Hz, 1H), 2.21-2.12(m, 3H), 1.82-1.70 (m, 4H), 0.95 (d, J = 6.0 Hz, 6H), 0.67 (q, J = 12.4 Hz, 1H); MS m/z: 468 [M+H] ⁺ .

Example 30: 4-methyl-1-(4-{[4-(4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

In Step 1 of Example 14, 4-methylpiperidin-3-ol was used in place of 3-hydroxypiperidine, and in Step 4 of Example 14, 4-methylpiperidine-3-ol was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 30 was obtained as a white powder in the same manner as Example 14, except that methylpiperidine was used. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.21 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.22-4.18 (m, 2H), 3.68-3.66 (m, 1H), 3.65-3.53 (m, 1H), 2.98 (t, J = 12.8 Hz, 2H), 2.61 (t, J = 10.8 Hz, 1H), 2.43 (t, J = 10.8 Hz, 1H), 1.81-1.67 (m , 4H), 1.42-1.40 (m, 2H), 1.29-1.20 (m, 3H), 1.09 (d, J = 4.8 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H); MS m/z: 450 [M+H] ⁺ .

Example 31: (3R)-1-(2-{[4-(morpholin-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3 -all

In Step 1 of Example 14, morpholine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, (R)-pyrrolidine-3- was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 31 was obtained as a white powder in the same manner as Example 14, except that all was used. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.60 (brs, 2H), 6.89 (brs, 2H), 5.03 (brs, 1H), 4.37 (brs, 1H), 3.73-3.65 (m, 7H) ), 3.46-3.44 (m, 1H), 3.04 (m, 4H), 2.00-1.88 (m, 2H); MS m/z: 410 [M+H] ⁺ .

Example 32: (3S)-1-(2-{[4-(morpholin-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3 -all

In Step 1 of Example 14, morpholine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, (S)-pyrrolidine-3- was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 32 was obtained as a white powder in the same manner as Example 14, except that all was used. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.04 (s, 1H), 4.37 (s, 1H), 3.74-3.62 (m, 7H), 3.47-3.44 (m, 1H), 3.05-3.02 (m, 4H), 1.99-1.88 (m, 2H); MS m/z: 410 [M+H] ⁺ .

Example 33: 4-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]morpholin-3-one

In Step 1 of Example 14, morpholin-3-one was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, (3S,4S)- was replaced with 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 33 was obtained as a white powder in the same manner as Example 14, except that 3,4-difluoropyrrolidine was used. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.85 (s, 1H), 8.43 (s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 7.2 Hz, 2H), 5.57 (brs, 1H), 5.44 (brs, 1H), 4.19 (s, 2H), 4.08-3.88 (m, 5H), 3.72-3.69 (m, 2H); MS m/z: 444 [M+H] ⁺ .

Examples 34 and 35: (3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl ) pyrrolidin-3-ol and (3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl] amino}phenyl)pyrrolidin-3-ol

In Step 1 of Example 14, 3-hydroxypyrrolidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 3-methylpyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. Compound 1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- was prepared in the same manner as in Example 14, except that dine was used. [1] amino} phenyl) pyrrolidin-3-ol was prepared.

Isolate 1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-ol Purify (3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidine -3-ol and (3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl) Pyrrolidin-3-ol was obtained as a white powder, respectively.

(3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3 -ol (compound of Example 34)

^1H NMR (400 MHz, DMSO-d ₆ ); δ 8.16 (s, 1H), 8.06 (brs, 1H), 7.34 (d, J = 9.2 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.40 (m, 1H), 3.69 (m, 1H), 3.57-3.55 (m, 1H), 3.42-3.25 (m, 4H), 3.06 (d, J = 9.6 Hz, 1H), 2.97 (m, 0.5H), 2.85 (m, 0.5H), 2.28 -2.25 (m, 1H), 2.06-2.00 (m, 2H), 1.91-1.86 (m, 1H), 1.52-1.48 (m, 1H), 1.03-1.02 (m, 3H); MS m/z: 408 [M+H] ⁺ .

(3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3 -ol (compound of Example 35)

^1H NMR (400 MHz, Acetone-d ₆ ); δ 8.16 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.34 (brs, 1H), 6.52 (d, J = 8.8 Hz, 2H), 4.54 (m, 1H), 4.04 (m, 1H), 3.80-3.55 (m, 2H), 3.51-3.39 (m, 4H), 3.33-3.31 (m, 1H), 3.19-3.17 (m, 1H), 3.10-2.90 (m, 1H), 2.40- 2.25 (m, 1H), 2.14-2.00 (m, 2H), 1.61-1.50 (m, 1H), 1.09-1.07 (m, 3H); MS m/z: 408 [M+H] ⁺ .

Example 36: 1-(2-{[4-(3-methylpyrrolidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)azetidine-3- all

In Step 1 of Example 14, 3-methylpyrrolidine was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, azetidin-3-ol was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 36 was obtained as a white powder in the same manner as Example 14, except that . ^1H NMR (400 MHz, Acetone-d ₆ ); δ 8.26 (brs, 1H), 8.14 (s, 1H), 7.58 (d, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.82 (m, 1H), 4.72 (m, 1H), 4.47- 4.43 (m, 2H), 4.03-4.00 (m, 2H), 3.45-3.41 (m, 1H), 3.35-3.24 (m, 2H), 2.42-2.37 (m, 1H), 2.18-2.12 (m, 1H) ), 1.67-1.58 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 394 [M+H] ⁺ .

Example 37: 1-(2-{[4-(2-methyl-1,4-oxazepan-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)ase Tidin-3-ol

In step 1 of Example 14, 2-methyl-1,4-oxazepane was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, azetidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 37 was obtained as a yellow solid in the same manner as Example 14, except that -3-ol was used. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.08 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 4.64-4.62 (m, 1H), 4.47-4.43 (m, 2H), 4.03-3.83 (m, 6H), 3.43-3.36 (m, 3H), 3.00 (dd, J = 15.2, 4.8 Hz, 1H), 2.15-2.13 (m, 1H), 1.96-1.94 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H); MS m/z: 424 [M+H] ⁺ .

Example 38: 4-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

Step 1: 4-(tert-butoxycarbonylamino)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of 1]amino}phenyl)piperidin-3-ol

In Step 1 of Example 14, tert -butyl (3-hydroxypiperidin-4-yl) carbamate was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3- 4-( tert -butoxycarbonylamino)-1-(4-{[4-(2-) in the same manner as Example 14, except that 2-methylpyrrolidine was used instead of dimethylpyrrolidine hydrochloride. Methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained.

Step 2: 4-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperi Synthesis of din-3-ol (compound of Example 38)

Trifluoroacetic acid (0.33 mL, 4.32 mmol, 20 equivalents) was added to the CH ₂ Cl ₂ (3 mL) solution of the compound (0.22 mmol, 1.0 equivalent) obtained in step 1, and the mixture was stirred at room temperature for 3 hours. It was stirred. The mixture was neutralized with saturated NaHCO ₃ solution and extracted with CH ₂ Cl ₂ . The organic layers were collected, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (CH ₂ Cl ₂ :methanol=10:1) to obtain 4-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 38) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.21 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.85-3.74 (m, 3H), 3.69-3.61 (m, 3H), 3.22 (t, 1H), 2.87(m, 1H), 2.76 (t, J = 9.6 Hz, 1H), 2.57 (dd, J = 11.6, 1.2 Hz, 1H), 2.40-2.30 (m, 1H), 2.19 -2.05 (m, 2H), 1.76-1.73 (m, 1H), 1.64-1.58 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H] ⁺ .

Example 39: 5-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

Step 1: 5-(tert-butoxycarbonylamino)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of 1]amino}phenyl)piperidin-3-ol

In Step 1 of Example 14, tert -butyl (3-hydroxypiperidin-5-yl) carbamate was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3- 5-( tert -butoxycarbonylamino)-1-(4-{[4-(2-) in the same manner as Example 14, except that 2-methylpyrrolidine was used instead of dimethylpyrrolidine hydrochloride. Methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained.

Step 2: 5-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperi Synthesis of din-3-ol (compound of Example 39)

The compound obtained in step 1 was reacted in the same manner as step 2 of Example 38 to produce 5-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 39) was obtained as a pale yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ); δ 9.40 (brs, 1H), 8.27 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 6.91-6.87 (m, 2H), 3.74-3.67 (m, 2H), 3.62-3.40 (m , 4H), 3.21 - 3.06 (m, 2H), 2.82 (m, 1H), 2.67 (m, 1H), 2.31-2.29 (m, 1H), 2.09-2.04 (m, 1H), 1.88-1.68 (m , 1H), 1.57-1.40 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H] ⁺ .

Example 40: 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl) Morpholine-2-carbonitrile

Step 1: tert-Butyl (1-(4-((4-(2-cyanomorpholino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-3-hydroxy Synthesis of cipiperidin-4-yl)carbamate

In Step 1 of Example 14, tert -butyl (3-hydroxypiperidin-4-yl) carbamate was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3- tert -butyl (1-(4-((4-(2-cyanomorpholino)-) in the same manner as Example 14, except that morpholine-2-carbonitrile was used instead of dimethylpyrrolidine hydrochloride. 5-(Trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate was obtained. 1H NMR (400 MHz, CD ₃ OD); δ 8.34 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.90 (s, 1H), 4.04-3.98 (m, 2H), 3.85- 3.83 (m, 2H), 3.73-3.70(m, 2H), 3.57-3.54 (m, 2H), 3.48-3.32 (m, 3H), 2.76-2.70 (m, 1H), 2.58 (dd, J = 10.8 Hz, 1H), 2.03-2.01 (m, 1H), 1.65-1.58 (m, 1H), 1.46 (s, 9H).

Step 2: 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)mor Synthesis of polyline-2-carbonitrile (compound of Example 40)

The compound obtained in step 1 was reacted in the same manner as step 2 of Example 38 to obtain 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino} -5-(Trifluoromethyl)pyrimidin-4-yl)morpholine-2-carbonitrile (compound of Example 40) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.33 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.89 (m, 1H), 4.02-3.95 (m, 2H), 3.85- 3.73 (m, 4H), 3.70-3.58(m, 2H), 3.44-3.41 (m, 1H), 2.85 (m, 1H), 2.74 (m, 1H), 2.55 (dd, J = 11.2 Hz, 1H) , 2.03-2.02 (m, 1H), 1.72-1.68 (m, 1H); MS m/z: 464 [M+H] ⁺ .

Example 41: (3R,4R)-4-fluoro-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl]amino}phenyl)piperidin-3-ol

In Step 1 of Example 14, (3R,4R)-4-fluoropiperidin-3-ol was used instead of 3-hydroxypiperidine, and in Step 4 of Example 14, 2,3-dimethylpiperidine was used. The compound of Example 41 was obtained as a white powder in the same manner as Example 14, except that 2-methylpyrrolidine was used instead of rollidine hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.50-4.42 (m, 0.5H), 4.36-4.28 (m, 0.5H) ), 3.83-3.76 (m, 3H), 3.69-3.58 (m, 2H), 3.52-3.49 (m, 1H), 3.19 (t, J = 9.6 Hz, 1H), 2.83 (t, J = 11.6 Hz, 1H), 2.69 (t, J = 11.2 Hz, 1H), 2.34-2.31(m, 1H), 2.17-2.10 (m, 2H), 1.87-1.82 (m, 1H), 1.61-1.56 (m, 1H) , 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 440 [M+H] ⁺ .

Examples 42 and 43: (3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2 -yl]amino}phenyl)-4-methylpyrrolidin-3-ol (compound of Example 42) and (3R,4S)-1-(4-{[4-(3,3-difluoropy) Rolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (compound of Example 43)

The compound of Preparation Example 1 (150 mg, 521.53 umol, 1 equivalent) and the compound of Preparation Example 2 (120.32 mg, 625.83 umol, 1.2 equivalent) were mixed in IPA (2 mL) and added to DIPEA (134.81 mg, 1.04 mmol, 181.68 uL, 2 equivalents) was added and stirred at 90°C for 12 hours. TLC (petroleum ether: ethyl acetate = 1:1, desired product Rf = 0.6) showed the reaction was complete. LCMS (t=1.095) showed the desired product. The mixture was cooled to 20°C and concentrated under reduced pressure at 40°C. The residue was poured into ethyl acetate (w/w = 1/1) (20 mL), washed with water (30 mL), and concentrated under reduced pressure at 40°C. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1) to obtain 1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoro Romethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (87 mg, 37.6% yield) was obtained as a yellow solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.30 (s, 1 H), 7.30-7.41 (m, 2 H), 6.93-7.10 (m, 1 H), 6.46-6.59 (m, 2 H), 4.06-4.20 (m, 1 H), 3.85-4.03 (m, 4 H), 3.57-3.68 (m, 2 H), 3.25 (dd, J = 10.2, 4.0 Hz, 1 H), 2.98 (dd, J = 8.8, 5.2 Hz, 1 H), 2.25-2.50 (m, 3 H), 1.71-1.80 (m, 1 H), 1.06-1.17 (m, 3 H); LCMS: Rt = 1.095 min, MS m/z: 444.1 [M+H] ⁺ .

The obtained compound was applied to prep-SFC (INC_ETOH (DEA) _5_40_2,8ML_8MIN.M). The two enantiomers were each concentrated under reduced pressure and then freeze-dried to form (3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoropyrrolidin-1-yl) Romethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (compound of Example 42) (23 mg, 51.87 umol, 27.06% yield) and (3R,4S)- 1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-4-methylp Rollidin-3-ol (compound of Example 43) (27 mg, 60.89 umol, 31.76% yield, Rt = 3.005 min) was obtained as a yellow solid, respectively (their absolute structures are arbitrarily assigned).

(3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )-4-methylpyrrolidin-3-ol (compound of Example 42)

¹ H NMR (400 MHz, CDCl ₃ )δ ppm 8.30 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.98 (br s, 1 H), 6.53 (d, J = 8.4 Hz) , 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.25-3.23 (m, 1 H), 3.09-2.93 (m) , 1 H), 2.45-2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.092 min, MS m/z = 444.1 [M+H] ⁺ ; HPLC: Purity = 97.6% (area%); Chiral SFC: ee% = 100% (area%).

(3R,4S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )-4-methylpyrrolidin-3-ol (compound of Example 43)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.31 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.96 (br s, 1 H), 6.54 (d, J = 8.4 Hz) , 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.27-3.23 (m, 1 H), 3.00-2.96 (m) , 1 H), 2.44-2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.095 min, MS m/z = 444.2 [M+H] ⁺ ; HPLC: Purity = 96.7% (area%); Chiral SFC: ee% = 97.2% (area%).

Example 44: N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5 -(trifluoromethyl)pyrimidin-2-amine

The compound of Example 44 was synthesized according to Scheme 3 below.

[Scheme 3]

Step 1: Synthesis of 3-chloro-1-(4-nitrophenyl)piperidine

4-Fluoronitrobenzene (100 mg, 0.70 mmol, 1.00 equiv) and 3-chloropiperidine hydrochloride (99 mg, 0.63 mmol, 0.90 equiv) were stirred mixed in ACN (3 mL) and DIEA (366 mg, 2.83 mmol, 4.00 equivalent) was added. The resulting mixture was stirred at 100° C. for 16 hours and the mixture was cooled to room temperature. The mixture was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography to give 3-chloro-1-(4-nitrophenyl)piperidine (65 mg, 31.63%) as a yellow solid. MS m/z: 241/243 [M+H] ⁺ .

Step 2: Synthesis of 4-(3-chloropiperidin-1-yl)aniline

The compound obtained in step 1 (65 mg, 0.27 mmol, 1.00 equiv) and Pd/C (10 mg, 10%) were stirred and mixed in MeOH (5 mL) and stirred for 40 minutes at 25°C under a hydrogen atmosphere. . The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and used directly in the next step. MS m/z: 211/213 [M+H] ⁺ .

Step 3: N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5- Synthesis of (trifluoromethyl)pyrimidin-2-amine (compound of Example 44)

The compound of Preparation Example 3 (54 mg, 0.19 mmol, 1.00 equivalent) was stirred and mixed in n-BuOH (2 mL), and the compound obtained in Step 2 (40 mg, 0.19 mmol, 1.00 equivalent) and HCl (1 drop) were added. ) was added. The resulting mixture was stirred at 80° C. for 1 hour and the mixture was cooled to room temperature. The mixture was eluted with CH ₂ Cl ₂ /MeOH (10:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 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 (55% Phase B, up to 68% in 10 min); Detector, UV 254 nm. The collected fractions were lyophilized to N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl. ]-5-(Trifluoromethyl)pyrimidin-2-amine (compound of Example 44; 9 mg, 10.21%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.58 (s, 1H), 8.36 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.28-4.22 (m, 1H), 4.04-3.84 (m, 4H), 3.69-3.65 (m, 1H) , 3.35-3.34 (m, 1H), 2.99-2.93 (m, 1H), 2.92-2.83 (m, 1H), 2.18-2.07 (m, 1H), 1.86-1.81 (m, 1H), 1.73-1.61 ( m, 2H); MS m/z: 462/464 [M+H] ⁺ .

Example 45: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[4-(3-fluoropiperidin-1-yl)phenyl]- 5-(trifluoromethyl)pyrimidin-2-amine

The compound of Example 45 was prepared as a white solid (5.6 mg, 6.01 mg) in the same manner as Example 44, except that 3-fluoropiperidine hydrochloride was used instead of 3-chloropiperidine hydrochloride in Step 1 of Example 44. %) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.57 (s, 1H), 8.36 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 5.56-5.43 (m, 2H), 4.86-4.71 (m, 1H), 4.04-3.84 (m, 4H), 3.39-3.36 (m, 1H), 3.17-3.01 (m, 3H), 1.93-1.81 (m, 2H), 1.80-1.56 (m, 2H); MS m/z: 446 [M+H] ⁺ .

Example 46: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidine-3-carbonitrile

The compound of Example 46 was prepared as a white solid (7.8 mg, 8.23%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.59 (s, 1H), 8.36 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.04-3.85 (m, 4H), 3.30-3.24 (m, 2H), 3.16-3.11 (m, 2H), 3.05-3.00 (m, 1H), 1.87-1.72 (m, 3H), 1.71-1.63 (m, 1H); MS m/z: 453 [M+H] ⁺ .

Example 47: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-{4-[3-(morpholin-4-yl)azetidin-1- yl]phenyl}-5-(trifluoromethyl)pyrimidin-2-amine

The compound of Example 47 was prepared as a yellow-white solid in the same manner as Example 44, except that 4-(azetidin-3-yl)morpholine hydrochloride was used instead of 3-chloropiperidine hydrochloride in Step 1 of Example 44. (12.3 mg, 12%) was obtained. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 9.47 (s, 1H), 8.33 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 9.0 Hz, 2H), 5.58-5.56 (m, 1H), 5.42-5.40 (m, 1H), 4.05-3.85 (m, 6H), 3.60-3.52 (m, 6H), 3.26-3.18 (m, 1H), 2.32 (s, 4H); MS m/z: 485 [M+H] ⁺ .

Example 48: 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl ]amino}phenyl)piperidin-3-ol

The compound of Example 48 was synthesized according to Scheme 4 below.

[Scheme 4]

Step 1: Synthesis of (2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetic acid

Uracil (100 g, 892.15 mmol, 1.00 eq) was stirred mixed in AcOH (500 mL) and oxo(phosphanyl)borane (53 g, 892.15 mmol, 1.00 eq) was added. The resulting mixture was stirred at 100°C for 48 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (500 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetic acid (10 g, crude) as an off-white solid. MS m/z: 171 [M+H] ⁺ , 169 [MH] ^- .

Step 2: Synthesis of ethyl 2-(2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetate

The compound obtained in Step 1 (10 g, 58.78 mmol, 1.00 equiv) was stirred and mixed in EtOH (150 mL), and H ₂ SO ₄ (15 mL, 281.40 mmol, 4.79 equiv) was added dropwise at 0°C. The resulting mixture was stirred at 100° C. for 16 hours and the mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum and the mixture was neutralized with NaHCO ₃ . The residue was eluted with PE/EtOAc (1:10) and purified by silica gel column chromatography to obtain ethyl 2-(2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetate (2.0g, 15.45 %) was obtained as an off-white solid. MS m/z: 199 [M+H] ⁺ .

Step 3: Synthesis of ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate

The compound obtained in step 2 (2.00 g, 10.09 mmol, 1.00 equiv) was mixed with stirring in POCl ₃ (20 mL), and DIEA (3.91 g, 30.25 mmol, 3.00 equiv) was added dropwise at 0°C. The resulting mixture was stirred at 100°C for 16 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water/ice (100 mL). The resulting mixture was extracted with EtOEt (2×100 mL), and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:3) and purified by silica gel column chromatography to obtain ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate (1.1 g, 44.05 %) was obtained as a light yellow oil. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.82 (s, 1H), 4.18-4.11 (m, 2H), 3.91 (s, 2H), 1.24-1.17 (m, 3H); MS m/z: 235/237/239 [M+H] ⁺ .

Step 4: Synthesis of ethyl 2-[2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate

The compound obtained in step 3 (800 mg, 3.40 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (488 mg, 3.40 mmol, 1.00 equiv) were dissolved in ACN (20 mL). The mixture was stirred and mixed, and DIEA (1.32 g, 10.20 mmol, 3.00 equivalent) was added. The resulting mixture was stirred at 80° C. for 2 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give ethyl 2-[2-chloro-4-[(3S,4S)-3,4- Difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate (850 mg, 75.16%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.02 (s, 1H), 5.55-5.52 (m, 1H), 5.38-5.36 (m, 1H), 4.15-4.10 (m, 2H) ), 4.08-3.84 (m, 6H), 1.20-1.16 (m, 3H); MS m/z: 306/308 [M+H] ⁺ .

Step 5: Ethyl 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropy Synthesis of rolidin-1-yl]pyrimidin-5-yl]acetate

The compound obtained in Step 4 (850 mg, 2.78 mmol, 1.00 equivalent) and the compound of Preparation Example 4 (1.18 g, 4.17 mmol, 1.50 equivalent) were stirred and mixed in n-BuOH (20 mL), and concentrated hydrochloric acid (10 drops) was added. ) was added. The resulting mixture was stirred at 80° C. for 6 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The crude product was eluted with PE/EtOAc (1:10) and purified by silica gel column chromatography to give ethyl 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino) -4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate (800 mg, 44.33%) was obtained as an off-white solid. MS m/z: 552 [M+H] ⁺ .

Step 6: 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropyrroli Synthesis of din-1-yl]pyrimidin-5-yl]ethanol

The compound obtained in step 5 (700 mg, 1.269 mmol, 1.00 eq) was stirred mixed in THF (20 mL) and diisobutylaluminum hydride (DIBAL_H) (1M in THF, 5.08 mL, 5.08 mmol, 4.00 eq). was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 3 hours under nitrogen atmosphere. The reaction was quenched with HCl (1M) (5 mL) at 0°C. The resulting mixture was concentrated under reduced pressure, and the residue was eluted with CH ₂ Cl ₂ /MeOH (10:1) and purified by silica gel column chromatography to obtain 2-[2-([4-[3-(benzyloxy)piperidine. -1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]ethanol (400 mg, 55.67%) Obtained as an off-white solid. MS m/z: 510 [M+H] ⁺ .

Step 7: N-[4-[3-(benzyloxy)piperidin-1-yl]phenyl]-5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoro Synthesis of ropyrrolidin-1-yl]pyrimidin-2-amine

The compound obtained in step 6 (80 mg, 0.15 mmol, 1.00 equiv) was stirred mixed in DCM (5.00 mL), and SOCl ₂ (186 mg, 1.57 mmol, 10.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16 hours under nitrogen atmosphere. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1) to give N-[4-[3-(benzyloxy)piperidine-1- yl]phenyl]-5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-amine (60 mg, 65.14% ) was obtained as an off-white solid. MS m/z: 528/530 [M+H] ⁺ .

Step 8: 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl] Synthesis of amino}phenyl)piperidin-3-ol (compound of Example 48)

The compound obtained in step 7 (60 mg, 0.11 mmol, 1.00 equiv) and BBr3 (1M) were stirred in DCM (3.00 mL) at 25° C. under nitrogen atmosphere for 1 hour. The reaction was quenched with MeOH (1 mL) at 0°C. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 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 (32% Phase B, up to 62% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to produce 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine- 2-yl]amino}phenyl)piperidin-3-ol (compound of Example 48; 9.9 mg, 19.06%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.96 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 5.55-5.53 (m, 1H), 5.39-5.37 (m, 1H), 4.77-4.76 (m, 1H), 4.03-3.87 (m, 4H), 3.72-3.44 (m, 4H) , 3.36-3.33 (m, 1H), 3.11-2.95 (m, 2H), 2.42-2.35 (m, 2H), 1.90-1.84 (m, 1H), 1.77-1.70 (m, 1H), 1.55-1.51 ( m, 1H), 1.22-1.19 (m 1H); MS m/z: 438/440 [M+H] ⁺ .

Example 49: 1-(4-{[5-(2-bromoethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine-2- yl]amino}phenyl)piperidin-3-ol

The compound of Example 48 (40 mg, 0.091 mmol, 1.00 equiv) was stirred mixed in acetone (5.00 mL) and NaBr (94 mg, 0.91 mmol, 10.00 equiv) was added. The resulting mixture was stirred at 80°C for 48 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3×20 mL), and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 19×150 mm, 5 um; Mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ ·H ₂ O) and ACN (44% Phase B, up to 48% in 10 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to produce 1-(4-{[5-(2-bromoethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine. -2-yl]amino}phenyl)piperidin-3-ol (compound of Example 49; 5.0 mg, 10.55%) was obtained as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.87 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.55-5.37 (m, 2H), 4.77 (d, J = 4.8 Hz, 1H), 4.28-3.82 (m, 4H), 3.61-3.45 (m, 4H), 3.36-3.32 (m) , 1H), 3.25-3.08 (m, 2H), 2.49-2.35 (m, 2H), 1.88-1.84 (m, 1H), 1.78-1.72 (m, 1H), 1.60-1.50 (m, 1H), 1.28 -1.15 (m, 1H); MS m/z: 482/484 [M+H] ⁺ .

Example 50: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2-iodoethyl)pyrimidine-2- 1}amino)phenyl]piperidin-3-ol

The compound of Example 48 (50 mg, 0.11 mmol, 1.00 equiv) was stirred mixed in acetone (5.00 mL) and NaI (171 mg, 1.14 mmol, 10.00 equiv) was added. The resulting mixture was stirred at 100° C. for 48 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions: column, XBridge Prep OBD C18 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 (33% Phase B, up to 63% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to produce 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2-iodoethyl)pyrimidine. -2-yl}amino)phenyl]piperidin-3-ol (compound of Example 50; 14.0 mg, 23.07%) was obtained as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.72 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 5.20-4.70 (m, 3H), 3.91-3.80 (m, 1H), 3.77-3.40 (m, 7H), 3.92-2.86 (m, 1H), 2.60-2.55 (m, 1H) , 2.40-2.33 (m, 1H), 1.89-1.84 (m, 1H), 1.76-1.70 (m, 1H), 4.59-1.51 (m, 1H), 1.26-1.15 (m, 1H); MS m/z: 530 [M+H] ⁺ .

Example 51: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl) pyrimidin-2-yl}amino)phenyl]piperidin-3-ol

The compound of Example 51 was synthesized according to Scheme 5 below.

[Scheme 5]

Step 1: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl)pyrimidine

The compound of Preparation Example 5 (100 mg, 0.40 mmol, 1.00 equivalent) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (100 mg, 0.40 mmol, 1.00 equivalent) were added to ACN (3 mL). Stirring to mix, DIEA (158 mg, 1.22 mmol, 3.00 equiv) was added dropwise. The mixture was stirred at 60°C for 3 hours under a nitrogen atmosphere, and the resulting mixture was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (2:1) and purified by silica gel column chromatography to obtain 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5. -(3,3,3-trifluoropropyl)pyrimidine (100 mg, 74%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.09 (s, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.12-4.02 (m, 1H), 3.99- 3.94 (m, 2H), 3.01-2.89 (m, 2H), 2.67-2.58 (m, 2H); MS m/z: 312/314 [M+H] ⁺ .

Step 2: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl)pyri Synthesis of midin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 51)

The compound obtained in step 1 (80 mg, 0.25 mmol, 1.00 equiv) and 1-(4-aminophenyl)piperidin-3-ol (73 mg, 0.38 mmol, 1.50 equiv) were dissolved in n-BuOH (2 mL). After stirring and mixing, HCl (1 drop) was added. The resulting mixture was stirred at 80°C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by Prep _{- HPLC} under the following conditions: (Column _: H ₂ O), mobile phase B: ACN and THF; gradient: 50% B to 80% B in 9 min; RT1 (min): 7.23. The collected fractions were lyophilized to produce 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluorophenol Propropyl)pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 51; 13.6 mg, 11%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.86 (s, 1H), 7.89 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.53-5.52 (m, 1H), 5.41-5.39 (m, 1H), 4.77 (d, J = 4.8 Hz, 1H), 4.05-3.84 (m, 4H), 3.68-3.55 (m) , 1H), 3.49-3.42 (m, 1H), 3.39-3.32 (m, 1H), 2.86-2.78 (m, 2H), 2.56-2.50 (m, 1H), 2.49-2.39 (m, 3H), 1.89 -1.85 (m, 1H), 1.75-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.23-1.19 (m, 1H); MS m/z: 472 [M+H] ⁺ .

Example 52: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

1-[4-({ 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3- All (compound of Example 52; 14.2 mg, 15.2%) was obtained as an off-white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm): δ 9.41 (s, 1H), 7.58 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 5.57-5.46 (m, 2H), 4.78 (d, J = 4.8 Hz, 1H), 4.19-3.72 (m, 4H), 3.66-3.46 (m, 2H), 3.39-3.36 (m , 1H), 2.56-2.53 (m, 1H), 2.44-2.38 (m, 1H), 1.95-1.81 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.26 -1.21 (m, 1H); MS m/z: 444 [M+H] ⁺ .

Example 53: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

1-[4-({ 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3- All (compound of Example 53; 7.9 mg, 10.18%) was obtained as an off-white solid. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 9.54 (s, 1H), 8.35 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.59-5.58 (m, 1H), 5.42-5.40 (s, 1H), 4.79-4.78 (m, 1H), 4.06-3.82 (m, 4H), 3.62-3.49 (m, 2H), 3.41-3.37 (m, 1H), 2.61-2.53 (m, 1H), 2.49-2.39 (m, 1H), 1.90-1.85 (m, 1H), 1.77-1.72 (m, 1H), 1.60-1.50 (m) , 1H), 1.28-1.18 (m, 1H); MS m/z: 444 [M+H] ⁺ .

Example 54: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2,2,2-trifluoroethyl) pyrimidin-2-yl}amino)phenyl]piperidin-3-ol

1-[4-({4-[(3S,4S)-3, 4-difluoropyrrolidin-1-yl]-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (Example 54 Compound (7.3 mg, 9.54%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (br s, 1H), 8.02 (s, 1H), 7.66-7.57 (m, 2H), 7.25-7.12 (m, 2H), 5.58 (s) , 1H), 5.45 (s, 1H), 4.45-4.00 (m, 4H), 3.96-3.71 (m, 3H), 3.59-3.48 (m, 2H), 2.93-2.67 (m, 2H), 1.92-1.87 (m, 2H), 1.70-1.60 (m, 1H), 1.45-1.35 (m, 1H); MS m/z: 458 [M+H] ⁺ .

Example 55: 1-(4-{[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine -2-yl]amino}phenyl)piperidin-3-ol

The compound of Example 55 was synthesized according to Scheme 6 below.

[Scheme 6]

Step 1: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-iodopyrimidine

2,4-dichloro-5-iodopyrimidine (300 mg, 1.09 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (188 mg, 1.31 mmol, 1.20 equivalent) was stirred and mixed, and DIEA (423 mg, 3.27 mmol, 3.00 equivalent) was added. The resulting mixture was stirred at 80° C. for 3 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to produce 2-chloro-4-[(3S,4S)-3,4-difluoropyrroli. Din-1-yl]-5-iodopyrimidine (300 mg, 75.57%) was obtained as an off-white solid. MS m/z: 346/348 [M+H] ⁺ .

Step 2: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-[(Z)-2-ethoxyethenyl]pyrimidine

The compound obtained in step 1 (300 mg, 0.86 mmol, 1.00 equivalent) and tributyl[(Z)-2-ethoxyethenyl]stannane (470 mg, 1.30 mmol, 1.50 equivalent) were dissolved in DMF (5.00 mL). The mixture was stirred and mixed, and Pd(PPh ₃ ) ₂ Cl ₂ (121.89 mg, 0.17 mmol, 0.20 equivalent) was added. The resulting mixture was stirred at 80° C. for 3 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (3×30 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to produce 2-chloro-4-[(3S,4S)-3,4-difluoropyrroli. Din-1-yl]-5-[(Z)-2-ethoxyethenyl]pyrimidine (120 mg, 42.94%) was obtained as an off-white solid. MS m/z: 290/292 [M+H] ⁺ .

Step 3: Synthesis of 2-[2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetaldehyde

The compound (120 mg) obtained in step 2 above was stirred and mixed in THF (3.00 mL), and HCl (4M) in H ₂ O (3.00 mL) was added dropwise. The resulting mixture was stirred at 60° C. for 7 hours under nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:10) and purified by silica gel column chromatography to obtain 2-[2-chloro-4-[(3S,4S)-3,4-difluoro. Lopyrrolidin-1-yl]pyrimidin-5-yl]acetaldehyde (50 mg, 41.52%) was obtained as an off-white solid. MS m/z: 262/264 [M+H] ⁺ .

Step 4: Synthesis of 2-chloro-5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine

The compound obtained in step 3 (50 mg, 0.19 mmol, 1.00 equivalent) was stirred and mixed in DCM (5.00 mL), and diethylaminosulfur trifluoride (DAST) (61 mg, 0.38 mmol, 2.00 equivalent). ) was added dropwise. The resulting mixture was stirred at 25°C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give 2-chloro-5-(2,2-difluoroethyl)-4-[( 3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine (35 mg, 58.12%) was obtained as a light yellow solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.09 (s, 1H), 6.49-6.09 (m, 1H), 5.56-5.54 (m, 1H), 5.39-5.37 (m, 1H) ), 4.07-4.05 (m, 2H), 4.00-3.93 (m, 2H), 3.47-3.36 (m, 2H); MS m/z: 284/286 [M+H] ⁺ .

Step 5: 1-(4-[[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine- Synthesis of 2-yl]amino]phenyl)piperidin-3-ol

The compound obtained in step 4 (35.00 mg, 0.123 mmol, 1.00 equivalent) was stirred and mixed in n-BuOH (2 mL), and 1-(4-aminophenyl)piperidin-3-ol (35 mg, 0.18 mmol, 1.50 equivalent) and concentrated hydrochloric acid (1 drop) were added. The resulting mixture was stirred at 80°C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the resulting mixture was diluted with MeOH (1 mL). The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C18 ExRS, 30×250 mm, 5 um; Mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ ·H ₂ O) and ACN (40% Phase B, up to 60% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to produce 1-(4-{[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl. ]pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 55; 10.3 mg, 18.58%) was obtained as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 9.90 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.35-5.97 (m, 1H), 5.54-5.53 (m, 1H), 5.37-5.35 (m, 1H), 4.77-4.76 (m, 1H), 4.09-3.90 (m, 4H) , 3.63-3.36 (m, 2H), 3.27-3.14 (m, 2H), 2.42-2.26 (m, 3H), 1.95-1.82 (m, 1H), 1.80-70 (m, 1H), 1.65-1.48 ( m, 1H), 1.25-1.18 (m, 1H); MS m/z: 440 [M+H] ⁺ .

Experimental Example 1. Confirmation of LRRK2 enzyme inhibition effect

It was confirmed whether the compounds prepared in the examples had LRRK2 enzyme inhibitory activity. LRRK2 enzyme inhibitory activity was obtained from Nat Biotechnol. It was performed according to the method described in 2011 Oct 30;29(11):1039-45.

Compounds were dissolved in 100% DMSO to prepare stock solutions. To determine the 50% inhibitory concentration (half maximal inhibitory concentration: IC ₅₀ ), the compound was set to a maximum concentration of 10 μM and diluted three-fold to prepare 10 different 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).

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

IC ₅₀ (LRRK2 G2019S) Standard (IC ₅₀ ) <50nM 50-500nM >500nM display value +++ ++ +

LRRK2 antagonistic activity
(IC ₅₀ , nM) LRRK2 antagonistic activity
(IC ₅₀ , nM) Example 1 +++ Example 28 +++ Example 2 ++ Example 29 ++ Example 3 ++ Example 30 ++ Example 4 + Example 31 +++ Example 5 + Example 32 +++ Example 6 +++ Example 33 +++ Example 7 +++ Example 34 + Example 8 ++ Example 35 + Example 9 +++ Example 36 ++ Example 10 ++ Example 37 +++ Example 11 + Example 38 +++ Example 12 +++ Example 39 +++ Example 13 +++ Example 40 ++ Example 14 +++ Example 41 +++ Example 15 +++ Example 42 +++ Example 16 +++ Example 43 ++ Example 17 +++ Example 44 +++ Example 18 +++ Example 45 +++ Example 19 +++ Example 46 +++ Example 20 +++ Example 47 +++ Example 21 +++ Example 48 + Example 22 +++ Example 49 + Example 23 +++ Example 50 + Example 24 +++ Example 51 + Example 24(R) +++ Example 52 + Example 24(S) +++ Example 53 +++ Example 25 +++ Example 54 + Example 26 +++ Example 55 + Example 27 +++

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

Claims (18)

Compounds represented by the following formula (1), stereoisomers, solvates or pharmaceutically acceptable salts thereof:
[Formula 1]

In Formula 1,
R ¹ is C _1-6 alkyl substituted with halogen;
R ² is halogen; CN; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _1-6 alkylcarbonyl; and mono- or di-C _1-6 alkylamino; is selected from the group consisting of,
Ring A is and ring B is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
The rings A and B are each independently halogen; OH; CN; oxo; Amino; or may be optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl;
n is an integer from 0 to 3. According to paragraph 1,
R ¹ is a C _1-3 alkyl substituted with 1 to 3 halogen atoms each independently selected from the group consisting of F, Cl, Br and I, a compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof. According to paragraph 1,
n is an integer from 0 to 2. The compound, stereoisomer, solvate or pharmaceutically acceptable salt thereof. delete delete delete delete delete delete According to paragraph 1,
The compound of Formula 1 is the following compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof:

A pharmaceutical composition for preventing or treating diseases or conditions mediated by or related to LRRK2 (Leucine-rich repeat kinase 2), comprising the compound of claim 1, its stereoisomer, solvate, or pharmaceutically acceptable salt. ,
The disease or disorder mediated by or related to LRRK2 is selected from the group consisting of degenerative brain disease, dyskinesia, central nervous system disorder, cancer, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, and tuberculosis. Composition. delete According to clause 11,
The degenerative brain diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, and multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich's gait 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: According to clause 11,
A pharmaceutical composition wherein the degenerative brain disease is Parkinson's disease. delete delete delete delete