Urea compound and use thereof

Abstract

The present invention relates to a urea compound and use thereof and, more specifically, to a urea compound, or a pharmaceutically acceptable salt or stereoisomer thereof, and use thereof as an activator of beta-glucocerebrosidase.

Description

Urea compounds and their uses

[0001] The present invention relates to urea compounds and uses thereof, and more particularly to urea compounds, or pharmaceutically acceptable salts or stereoisomers thereof, and their use as activators of beta-glucocerebrosidase.

[0002] Mutations in beta-glucocerebrosidase (GCase, GBA1) have been reported to be associated with an increased risk of developing Parkinson's disease (PD). The disease manifestations differ depending on the type of beta-glucocerebrosidase mutation. Autosomal recessive mutations cause Gaucher disease, known as a lysosomal storage disease, and heterozygous mutations were previously thought to be unrelated to the pathological process, but studies have shown that the presence or absence of beta-glucocerebrosidase mutations (autosomal recessive or monogenic) increases the risk of Parkinson's disease by approximately 5.43-6.48 times (Sidransky et al, 2009, N. Engl. J. Med.). Studies have shown that 5-10% of patients with Parkinson's disease carry beta-glucocerebrosidase mutations, and this rate may be higher in the Ashkenazi Jewish population. Parkinson's disease caused by beta-glucocerebrosidase mutations is clinically indistinguishable from classic Parkinson's disease, but typically has a slightly earlier age of onset (~5 years) and a higher incidence of cognitive impairment. The pathologic and imaging features, as well as the response to pharmacological treatment, are identical to those of classic Parkinson's disease. Beta-glucocerebrosidase mutations result in reduced enzyme activity and trapping of the mutant protein in the endoplasmic reticulum (ER), which induces protein aggregation, ER-associated degradation, and stress. Both of these mechanisms are important in the pathogenesis of Gaucher disease and Parkinson's disease and lead to lysosomal dysfunction.

[0003] In Parkinson's disease brains, decreased beta-glucocerebrosidase activity and increased alpha-synuclein have been reported. Conversely, in typical Parkinson's disease brains, alpha-synuclein accumulation and decreased beta-glucocerebrosidase activity have been reported. Furthermore, beta-glucocerebrosidase mutations are also associated with an increased risk of Lewy body dementia and other synucleinopathies (Schapira, 2015, Mol. Cell Neurosci.).

[0004] The present invention aims to prevent, alleviate or treat diseases such as Parkinson's disease, Gaucher disease, Lewy body dementia and other synucleinopathies by increasing the activity of beta-glucocerebrosidase and reducing the level of alpha-synuclein.

[0005] The present invention aims to provide a derivative compound containing pyridine urea or pyrimidine urea as an activator of beta-glucocerebrosidase, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0006] In addition, another object of the present invention is to provide a pharmaceutical composition comprising the above pyridine urea or a derivative compound comprising pyrimidine urea, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

[0007] In order to solve the above technical problem, the present invention provides a compound of the following chemical formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0008] [Chemical Formula 1]

[0009]

[0010]

[0011] In the above chemical formula 1,

[0012] X is N or CH;

[0013] R1 and R3 are each independently -H, halo, alkyl or and here R7 is or , and m is 1 or 2; wherein R8 is -H, alkyl, hydroxyalkyl, haloalkyl, dialkylaminocarbonyloxyalkyl or aryl;

[0014] R2 is -H, halo or alkyl;

[0015] R4 is -H or alkyl;

[0016] R5 is -H, alkyl or cycloalkyl;

[0017] R6 is saturated or partially unsaturated carbocyclyl, aryl or partially unsaturated heterocyclyl; wherein said saturated or partially unsaturated carbocyclyl and aryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and alkoxycarbonylalkyl;

[0018] n is 0 or 1;

[0019] The above partially unsaturated heterocyclyl may contain one or more heteroatoms selected from N, O and S,

[0020] However, at least one of R1 and R3 am.

[0021]

[0022] In defining the compound of the above chemical formula 1 throughout this specification, the concepts defined for the following substituents are used unless otherwise stated.

[0023] In this application, the term “hydroxy” group means -OH.

[0024] As used herein, the term “halo”, when used alone or in combination with other additional terms (e.g., haloalkyl), denotes a radical which is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0025] In this application, the term “carbonyl” group means -C(=O)-.

[0026] As used herein, the term “alkyl,” when used alone or in combination with other additional terms (e.g., haloalkyl), means a radical of a straight or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 or 1 to 5 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0027] As used herein, the term "cycloalkyl" refers to a saturated aliphatic hydrocarbon radical having, for example, 3 to 10 or 3 to 8 carbon atoms in a ring shape. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028] The term “alkoxy” herein means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 or 1 to 5 carbon atoms.

[0029] The term “aryl” herein means an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, including but not limited to, phenyl and naphthyl.

[0030] As used herein, the term “saturated or partially unsaturated carbocyclyl” means a hydrocarbon radical forming a single or fused ring having 5 to 12 or 6 to 12 carbon atoms, which is saturated or partially unsaturated. The saturated or partially unsaturated carbocyclyl may comprise a bridged structure, a fused structure, or a spiro structure.

[0031] The term “partially unsaturated heterocyclyl” herein means a cyclic, for example, 5 to 12-membered or 8 to 12-membered, partially unsaturated hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing group.

[0032]

[0033] The compound of formula 1 according to the present invention can form a pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes both acid or base addition salts and stereochemically isomeric forms thereof. The salt includes any salt that maintains the activity of the parent compound in the subject to which it is administered and does not cause undesirable effects, and is not particularly limited thereto. Such salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idetic acid, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, edicilinic acid, esylinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolylarsanilic acid, methylnitric acid, polygalacturic acid, hexylisorcinonic acid, malonic acid, It may be hydramic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, methanesulfonic acid, camphorsulfonic acid or teoclic acid. In addition, the form of the basic salt includes, for example, alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, salts with organic bases such as benzathine, N-methyl-D-glucamine, hydrabamine salts and salts with amino acids such as arginine and lysine. Additionally, the salt form can be converted into a free form by treatment with a suitable base or acid. The term "additional salt" includes the compound of formula 1 and the solvent compounds with which the salt thereof can be formed.Such solvent compounds are, for example, hydrates, alcoholates. According to one embodiment of the present invention, the pharmaceutically acceptable salt may be a nitrate, a sulfurate, a hydrobromate, a toluenesulfonate, a hydrochloride, a methanesulfonate, or a camphorsulfonate.

[0034]

[0035] The compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or asymmetric plane, and therefore may exist as all optical and stereoisomers, including substantially pure enantiomers such as R and S enantiomers, as well as mixture racemates, and all of these isomers and mixtures are included in the scope of the present invention. With respect to pure enantiomers, the optical purity of the enantiomers may be preferably 60%ee or higher, more preferably 95%ee or higher, and most preferably 98%ee or higher. When the compound of formula 1 according to the present invention is a racemate, the racemate may be separated into each isomer by a conventional separation method, for example, by chiral column chromatography on normal or reversed phase, using a corresponding developing solvent, preferably hexane, ethyl acetate, dichloromethane, methanol, etc., in the normal phase, or by mixing water and acetonitrile, etc., in the reverse phase.

[0036]

[0037] According to another specific example of the present invention, in the chemical formula 1

[0038] X is N or CH;

[0039] R1 and R3 are each independently -H, halo, C1-C7 alkyl or and here R7 is or , m is 1 or 2; wherein R8 is -H, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyloxy-C1-C7 alkyl or C6-C 10 It's aryl;

[0040] R2 is -H, halo or C1-C7 alkyl;

[0041] R4 is -H or C1-C7 alkyl;

[0042] R5 is -H, C1-C7 alkyl or C3-C 10 It is cycloalkyl;

[0043] R6 is saturated or partially unsaturated C5-C 12 Carbocyclyl, C6-C 10 Aryl or partially unsaturated 5 to 12 membered heterocyclyl; wherein said saturated or partially unsaturated carbocyclyl and aryl are halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, halo-C1-C7 alkoxy, C3-C 10 which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl and C1-C7alkoxycarbonyl-C1-C7alkyl;

[0044] n is 0 or 1;

[0045] The above partially unsaturated heterocyclyl may contain 1 to 3 heteroatoms selected from N, O and S,

[0046] However, at least one of R1 and R3 am.

[0047] According to another specific example of the present invention, in the chemical formula 1

[0048] R1 is -H or and here R7 is or , and m is 1 or 2; wherein R8 is -H, C1-C5 alkyl, hydroxy-C1-C5 alkyl, halo-C1-C5 alkyl, di(C1-C5 alkyl)aminocarbonyloxy-C1-C5 alkyl or phenyl;

[0049] R3 is -H, C1-C5 alkyl or and here R7 is or , m is 1 or 2; wherein R8 is -H or C1-C5 alkyl,

[0050] However, at least one of R1 and R3 am.

[0051] According to another specific example of the present invention, in the above chemical formula 1, R2 is -H, halo or C1-C5 alkyl.

[0052] According to another specific example of the present invention, in the above chemical formula 1, R4 is -H or C1-C5 alkyl.

[0053] According to another specific example of the present invention, in the above formula 1, R5 is -H, C1-C5 alkyl or C3-C8 cycloalkyl.

[0054] According to another specific embodiment of the present invention, in the above chemical formula 1, R6 is saturated or partially unsaturated C6-C 12 Carbocyclyl, phenyl or partially unsaturated 8 to 12 membered heterocyclyl, wherein said saturated or partially unsaturated carbocyclyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl and C1-C7 alkoxycarbonyl-C1-C7 alkyl; wherein said phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, halo-C1-C7 alkyl, halo-C1-C7 alkoxy and C3-C 10 It may be optionally substituted with one to three substituents selected from the group consisting of cycloalkyl.

[0055] According to another specific embodiment of the present invention, in the above chemical formula 1, R6 is saturated or partially unsaturated C6-C 12 Carbocyclyl, or a partially unsaturated 8 to 12 membered heterocyclyl, wherein said saturated or partially unsaturated carbocyclyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl and C1-C7 alkoxycarbonyl-C1-C7 alkyl.

[0056] According to another specific embodiment of the present invention, the saturated or partially unsaturated C6-C of R6 12 Carbocyclyl, or partially unsaturated 8 to 12 membered heterocyclyl, may be cyclohexyl, spiro[2.5]octyl, spiro[3.5]nonyl, adamantyl, norbornanyl, indanyl, tetralinyl or chromanyl.

[0057]

[0058] In another specific embodiment according to the present invention, representative examples of the compound of the above formula 1 include, but are not limited to, the compounds listed below.

[0059] 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 1);

[0060] 1-[(2-{1-Ethyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 2);

[0061] 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 3);

[0062] 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 4);

[0063] 2-[(2-{1-methyl-3-[(1s,4s)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 5);

[0064] 1-({2-[3-(4,4-difluorocyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole (compound 6);

[0065] 2-[(2-{1-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 7);

[0066] 2-[(2-{1-methyl-3-[(1r,4r)-4-isopropylcyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 8);

[0067] 1-[(2-{1-methyl-3-(6-spiro[2.5]octyl)ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 9);

[0068] 1-[(2-{1-methyl-3-(7-spiro[3.5]nonyl)ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 10);

[0069] 1-Methyl-3-[(4-methylcyclohexyl)methyl]-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 11);

[0070] 2-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 14);

[0071] 1-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 15);

[0072] 5-Methyl-2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 16);

[0073] 5-Methyl-1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 17);

[0074] 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-2H-tetrazol (Compound 18);

[0075] 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-1H-tetrazol (Compound 19);

[0076] 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-2H-tetrazole (Compound 20);

[0077] 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-1H-tetrazole (Compound 21);

[0078] 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 22);

[0079] {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol (compound 23);

[0080] {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol (Compound 24);

[0081] [2-({2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]pyridin-4-yl}methyl)-2H-1,2,3,4-tetrazol-5-yl]methyl N,N-dimethylcarbamate (Compound 25);

[0082] 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 26);

[0083] 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 27);

[0084] 2-[(5-Fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 28);

[0085] 1-[(5-Fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 29);

[0086] 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 45);

[0087] 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 46);

[0088] 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 47);

[0089] 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 48);

[0090] 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 49);

[0091] 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 50);

[0092] 1-({2-[3-(4,4-dimethylcyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole (Compound 51);

[0093] 3-[(1R)-1-cyclohexylethyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 58);

[0094] 3-[(1,4-dimethylcyclohexyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 59);

[0095] 2-[(1r,4r)-4-(3-methyl-3-{4-[(2H-tetrazol-2-yl)methyl]-2-pyridyl} ureido)cyclohexyl]-2-propanol (Compound 60);

[0096] 2-[(2-{1-methyl-3-[(1r,4r)-4-(1-fluoro-1-methylethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 61);

[0097] 1-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-1H-tetrazole (compound 67);

[0098] 2-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-2H-tetrazole (compound 68);

[0099] 1-(1-adamantyl)-3-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (compound 69);

[0100] 1-(1-adamantyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (Compound 70);

[0101] 3-Methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(2H-1,2,3,4-tetrazol-2-yl)ethyl]pyridin-2-yl}urea (Compound 71);

[0102] 3-Methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(1H-1,2,3,4-tetrazol-1-yl)ethyl]pyridin-2-yl}urea (Compound 72);

[0103] Methyl 2-[1-[[[4-(tetrazol-2-ylmethyl)-2-pyridyl]carbamoylamino]methyl]cyclohexyl]acetate (Compound 73);

[0104] 1-[(2R,4R)-norbornan-2-yl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 74); and

[0105] 1-[1-(1-adamantyl)ethyl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 75).

[0106] In another specific embodiment according to the present invention, representative examples of the compound of the above formula 1 include, but are not limited to, the compounds listed below.

[0107] 3-(4-Cyclopropylphenyl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 12);

[0108] 1-Methyl-3-(4-propylphenyl)-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 13);

[0109] 1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 30);

[0110] 1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 31);

[0111] 1-[4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 32);

[0112] 1-[4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 33);

[0113] 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 34);

[0114] 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 35);

[0115] 1-[6-methyl-4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 36);

[0116] 1-[6-methyl-4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 37);

[0117] 1-[6-methyl-4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 38);

[0118] 1-[6-methyl-4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 39);

[0119] 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 40);

[0120] 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 41);

[0121] 1-Methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 42);

[0122] 1-Methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 43);

[0123] 1-[4-[(5-phenyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 44);

[0124] 3-[Cyclopropyl(phenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 52);

[0125] 3-[(R)-Cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 53);

[0126] 3-[(R)-Cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (Compound 62);

[0127] 1-Ethyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 65); and

[0128] 1-(4-Isopropylphenyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 66).

[0129] In another specific embodiment according to the present invention, representative examples of the compound of the above formula 1 include, but are not limited to, the compounds listed below.

[0130] 3-Indan-2-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 54);

[0131] 3-Indan-1-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 55);

[0132] 1-Methyl-3-tetrazol-1-yl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 56);

[0133] 3-(2,2-dimethylchroman-4-yl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 57);

[0134] 1-methyl-3-[(1S)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 63); and

[0135] 1-Methyl-3-[(1R)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 64).

[0136]

[0137] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease mediated by beta-glucocerebrosidase is provided, comprising a compound of the above chemical formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.

[0138]

[0139] As used herein, “prevention” means reducing or eliminating the possibility of contracting a disease.

[0140] As used herein, “treatment” means stopping, delaying or alleviating the progression of a disease when applied to a subject exhibiting symptoms of the disease.

[0141] As used herein, the term "pharmaceutical composition" may include other chemical components, such as carriers, diluents, excipients, etc., in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof, as needed. Such pharmaceutical compositions facilitate administration of the active compound into a living organism. Various techniques for administering pharmaceutical compositions containing compounds are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterilized, or may further include auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control, and / or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating.

[0142] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of living organisms.

[0143] As used herein, a "diluent" is defined as a compound that not only stabilizes the biologically active form of the target compound but also dilutes the compound in water to dissolve it. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate-buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffering diluents rarely alter the biological activity of a compound.

[0144] As used herein, “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of the compound.

[0145]

[0146] In another specific embodiment according to the present invention, the disease mediated by the beta-glucocerebrosidase may be Parkinson's disease, Gaucher's disease, Lewy body dementia, or synucleinopathy, and may include any disease known to be associated with the activity of beta-glucocerebrosidase.

[0147] In another specific embodiment according to the present invention, an increase in beta-glucocerebrosidase activity can be measured using a wild type or beta-glucocerebrosidase mutant animal model or an animal model overexpressing synuclein accumulation.

[0148] The pharmaceutical composition may be formulated into various oral or parenteral dosage forms. For example, it may be any oral dosage form such as tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, etc. These oral dosage forms may, in addition to the active ingredient, contain, according to the typical composition of each dosage form, pharmaceutically acceptable carriers such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol.

[0149] In addition, when the oral administration formulation is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, may further contain a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an effervescent mixture and / or an absorbent, a coloring agent, a flavoring agent or a sweetening agent.

[0150] The pharmaceutical composition may be formulated as a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, in order to formulate the pharmaceutical composition as a dosage form for parenteral administration, the active ingredient, i.e., the compound of formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and this solution or suspension can be prepared in a unit dosage form of an ampoule or vial.

[0151] In addition, the pharmaceutical composition may be sterilized or may further contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control and / or buffers, and may further contain other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating or coating.

[0152] The above active ingredient, i.e., the compound of the above chemical formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, may be included in the pharmaceutical composition in an effective amount for mammals including humans, for example, 0.1 to 1,000 mg / kg (body weight) per day.

[0153] According to the present invention, a novel pyridine urea or pyrimidine urea derivative compound, or a pharmaceutically acceptable salt or stereoisomer thereof, exhibiting an excellent beta-glucocerebrosidase activator effect can be provided. The pyridine urea or pyrimidine urea derivative compound according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, can be effectively used for the prevention or treatment of diseases mediated by beta-glucocerebrosidase, such as Parkinson's disease, Gaucher disease, dementia with Lewy bodies, and other synucleinopathies.

[0154] In addition, according to the present invention, a method for producing the pyridine urea or pyrimidine urea derivative compound, a pharmaceutical composition comprising the same, and a method for activating beta-glucocerebrosidase using the same and treating a dysfunction of beta-glucocerebrosidase and a disease mediated by beta-glucocerebrosidase can be provided.

[0155] According to the present invention, it is possible to prevent the reduction of synuclein, activation of synuclein-induced behavioral delay, reduction of inflammation, and / or death of neurons.

[0156] The present invention is described in more detail below through examples. However, these examples are intended only to exemplify the present invention and are not intended to limit the scope of the invention.

[0157]

[0158] The definitions of abbreviations used in the manufacturing examples and examples below are as follows.

[0159] DMF: N,N-dimethylformamide

[0160] LiHMDS: lithium bis(trimethylsilyl)amide

[0161] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0162] PyBroP: Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

[0163] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0164] XtalFluor-E: (diethylamino)difluorosulfonium tetrafluoroborate

[0165]

[0166] Manufacturing Example 1: Synthesis of N-methyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0167]

[0168]

[0169] Manufacturing Example 1A: 4-(chloromethyl)-N-methylpyridin-2-amine

[0170]

[0171]

[0172] (2-Fluoropyriin-4-yl)methanol (1 eq.) was dissolved in a sealed tube containing a 40% aqueous methylamine solution (4 eq.) and stirred in a microwave reactor at 100°C for 1 h. The reaction solution was cooled to room temperature and dried to obtain [2-(methylamino)pyridin-4-yl]methanol without further purification. The obtained compound was dissolved in acetonitrile (1.5 M) and thionyl chloride (5 eq.) was added. The reaction solution was stirred at room temperature for 1 h and dried under reduced pressure to obtain the title compound without further purification.

[0173] MS, actual value: 157

[0174]

[0175] Manufacturing Example 1: N-Methyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0176] The compound (1 equivalent) obtained in Preparation Example 1A was dissolved in DMF (0.4 M), and 1H-1,2,3,4-tetrazole (1.2 equivalents) and cesium carbonate (3 equivalents) were added. The reaction solution was stirred at 90°C for 12 hours. The mixture was cooled to room temperature and diluted with water. The reaction solution was then extracted with ethyl acetate and dried. The residue was purified under reduced pressure and subjected to column chromatography to obtain the title compound.

[0177] MS, actual value: 191

[0178] 1H-NMR (CDCl3, 400MHz) δ8.61(s, 1H), δ8.11(d, 1H), δ6.41(d, 1H), δ6.14(s, 1H), δ5.50(s, 2H), δ4.75(br, 2H), δ2.90(d, 3H)

[0179]

[0180] Manufacturing Example 2: Synthesis of N-methyl-4-[(2H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0181]

[0182]

[0183] Using the compound obtained in Manufacturing Example 1A as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as the synthesis method of Manufacturing Example 1.

[0184] MS, actual value: 191

[0185]

[0186] Manufacturing Example 3: Synthesis of N,5-dimethyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0187]

[0188]

[0189] Manufacturing Example 3A: 4-(chloromethyl)-N,5-dimethylpyridin-2-amine

[0190]

[0191]

[0192] The title compound was obtained using the same method as in Preparation Example 1A using (2-fluoro-5-methylpyridin-4-yl)methanol as the starting material.

[0193] MS, actual value: 171

[0194]

[0195] Manufacturing Example 3: N,5-dimethyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0196] The title compound was obtained using the compound obtained in Manufacturing Example 3A as a starting material in the same manner as the synthesis method of Manufacturing Example 1.

[0197]

[0198] Manufacturing Example 4: Synthesis of N,5-dimethyl-4-[(2H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0199]

[0200]

[0201] Using the compound obtained in Manufacturing Example 3A as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as the synthesis method of Manufacturing Example 1.

[0202] MS, actual value: 262

[0203]

[0204] Manufacturing Example 5: Synthesis of N-ethyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0205]

[0206]

[0207] Manufacturing Example 5A: (2-Fluoropyridin-4-yl)methyl methanesulfonate

[0208]

[0209]

[0210] (2-Fluoropyridin-4-yl)methanol (1 eq.) was dissolved in dichloromethane (1.5 M), and methanesulfonyl chloride (1.2 eq.) and triethylamine (2 eq.) were added. The reaction solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with dichloromethane. The residue was then purified by column chromatography under reduced pressure to obtain the title compound.

[0211] MS, actual value: 206

[0212]

[0213] Manufacturing Example 5B: 1-[(3-fluorophenyl)methyl]-1H-1,2,3,4-tetrazole

[0214]

[0215]

[0216] The compound (1 equivalent) obtained in Preparation Example 5A was dissolved in acetonitrile (0.3 M), and 1H-1,2,3,4-tetrazole (1.2 equivalents) and potassium carbonate (3 equivalents) were added. The reaction solution was stirred under reflux for 3 days. The mixture was cooled to room temperature and diluted with water. The reaction solution was then extracted with ethyl acetate. The residue was purified under reduced pressure and subjected to column chromatography to obtain the title compound.

[0217] MS, actual value: 179

[0218]

[0219] Manufacturing Example 5: N-Ethyl-4-[(1H-1,2,3,4-tetrazol-1-yl)methyl]pyridin-2-amine

[0220] The compound (1 equivalent) obtained in Preparation Example 5B was dissolved in a sealed tube containing a 66-72% aqueous ethylamine solution (excess, >10 equivalents) and stirred in a microwave reactor at 100°C for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The residue was purified under reduced pressure to obtain the title compound without further purification.

[0221] MS, actual value: 205

[0222]

[0223] Manufacturing Example 6: Synthesis of N-ethyl-4-[(1H-1,2,3,4-tetrazol-2-yl)methyl]pyridin-2-amine

[0224]

[0225]

[0226] Manufacturing Example 6A: 1-[(3-fluorophenyl)methyl]-1H-1,2,3,4-tetrazole

[0227]

[0228]

[0229] Using the compound obtained in Manufacturing Example 5A as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as the synthesis method of Manufacturing Example 5B.

[0230] MS, actual value: 179

[0231]

[0232] Manufacturing Example 6: N-Ethyl-4-[(1H-1,2,3,4-tetrazol-2-yl)methyl]pyridin-2-amine

[0233] The title compound was obtained using the compound obtained in Manufacturing Example 6A as a starting material in the same manner as the synthesis method of Manufacturing Example 5.

[0234] MS, actual value: 179

[0235]

[0236] [Manufacturing Example Reaction Scheme 1]

[0237]

[0238]

[0239] Each pyridine carboxylate (1 equivalent) was added to ethanol (0.24 M), and sodium borohydride (3 equivalents) was added at room temperature. The reaction solution was stirred under reflux for 2 hours. The mixture was cooled to room temperature, and the reaction was terminated by the addition of 1 N aqueous hydrochloric acid solution. The reaction solution was then extracted with ethyl acetate. The resulting mixture was purified under reduced pressure to obtain the desired compound without further purification.

[0240]

[0241] [Manufacturing Example Reaction Scheme 2]

[0242]

[0243]

[0244] A 40% aqueous methylamine solution was added to each pyridinyl methanol (1 equivalent). The reaction solution was stirred in a microwave reactor at 100°C for 1 hour. The mixture was depressurized, and the desired compound was obtained without further purification.

[0245]

[0246] [Manufacturing Example Reaction Scheme 3]

[0247]

[0248]

[0249] Tetrahydrofuran (3.2 M) was added to each carboxylic acid (1 equivalent), and a 1.0 M borane tetrahydrofuran solution (4 equivalents) was added. The reaction solution was stirred at room temperature for 12 hours and the reaction was quenched with methanol. The mixture was then extracted with dichloromethane. The residue was then reduced in pressure and purified by column chromatography to obtain the target compound.

[0250]

[0251] [Manufacturing Example Reaction Scheme 4]

[0252]

[0253]

[0254] To each pyridinyl methanol (1 eq.), a suitable solvent such as dichloromethane, tetrahydrofuran, and DMF (0.3 M) was added. Imidazole (1.5 eq.) and optionally N,N-dimethylpyridin-4-amine (0.1 eq.) were added to the solution. Tert-butyl(chloro)dimethylsilane (1.1 eq.) was then added to the reaction solution and stirred at room temperature for 30 minutes to 12 hours. Water was added to the mixture to terminate the reaction, and the mixture was extracted with dichloromethane. The residue was purified under reduced pressure and subjected to column chromatography to obtain the desired compound.

[0255]

[0256] [Manufacturing Example Reaction Scheme 5]

[0257]

[0258]

[0259] (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid (2 eq.) was dissolved in toluene (0.5 M), and triethylamine (5 eq.) and {[azido(phenoxy)phosphoryl]oxy}benzene (4 eq.) were added. The mixture was stirred at 100°C for 30 min under nitrogen conditions. Each silane compound (1 eq.) was added to the reaction solution, and the mixture was stirred for 12 h. The reaction solution was quenched with 1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The residue was purified by column chromatography under reduced pressure to obtain the target compound.

[0260]

[0261] [Manufacturing Example Reaction Scheme 6]

[0262]

[0263]

[0264] A urea compound (1 equivalent) was dissolved in methanol (0.12 M) and a 1.25 M methanolic hydrochloric acid solution (10 equivalents) was added. The reaction solution was stirred at room temperature for 12 hours and dried under reduced pressure. Afterwards, a saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The resulting residue was purified under reduced pressure and subjected to column chromatography to obtain the target compound.

[0265]

[0266] [Manufacturing Example Reaction Scheme 7]

[0267]

[0268]

[0269] A urea compound (1 equivalent) was dissolved in dichloromethane (0.3 M), and thionyl chloride (4 equivalents) was added. The reaction solution was stirred at room temperature for 30 minutes, quenched with methanol, and dried under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the resulting solid, and extraction was performed with dichloromethane. The resulting residue was then depressurized and optionally purified by column chromatography to obtain the target compound.

[0270]

[0271] Manufacturing Example 7: Synthesis of 3-[4-(chloromethyl)pyridin-2-yl]-1-[(1r,4r)-4-tert-butylcyclohexyl]urea

[0272]

[0273]

[0274] Manufacturing Example 7A: 4-(chloromethyl)pyridin-2-amine hydrochloride

[0275]

[0276]

[0277] (2-Amino-4-pyridyl)methanol (1 equivalent) was dissolved in acetonitrile (0.5 M) and thionyl chloride (2 equivalents) was added. The reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was then dried under reduced pressure to obtain the title compound without further purification.

[0278] MS, actual value: 143

[0279]

[0280] Manufacturing Example 7: 3-[4-(chloromethyl)pyridin-2-yl]-1-[(1r,4r)-4-tert-butylcyclohexyl]urea

[0281] The title compound was obtained using the compound obtained in Manufacturing Example 7A as a starting material in the same manner as Manufacturing Example Reaction Scheme 5.

[0282] MS, actual value: 324

[0283]

[0284] Manufacturing Example 8: Synthesis of 1-[4-(chloromethyl)-2-pyridyl]-1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]urea

[0285]

[0286]

[0287] The title compound was obtained in the same manner as in Manufacturing Examples 2, 4, 5, 6 and 7 using (2-fluoropyridin-4-yl)methanol as the starting material.

[0288] MS, actual value: 338

[0289]

[0290] Manufacturing Example 9: Synthesis of 1-[4-(chloromethyl)-6-methyl-2-pyridyl]-1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]urea

[0291]

[0292]

[0293] The title compound was obtained in the same manner as in Manufacturing Examples 1, 2, 4, 5, 6 and 7 using methyl 2-chloro-6-methylpyridine-4-carboxylate as the starting material.

[0294] MS, actual value: 352

[0295]

[0296] Manufacturing Example 10: Synthesis of 3-[4-(chloromethyl)-5-fluoro-2-pyridyl]-1-[(1r,4r)-4-(tert-butyl)cyclohexyl]urea

[0297]

[0298]

[0299] The title compound was obtained in the same manner as in Manufacturing Examples 3, 4, 5, 6, and 7 using 2-amino-5-fluoropyridine-4-carboxylic acid as the starting material.

[0300] MS, actual value: 338

[0301]

[0302] [Manufacturing Example Reaction Scheme 8]

[0303]

[0304]

[0305] Dichloromethane (0.29 M) and DMF (0.29 M) were added to each carboxylic acid (1 eq). Oxalyl chloride (1.2 eq) was added dropwise to the solution and stirred at room temperature for 1.5 hours. A 50% alcohol solution of dichloromethane (1.2 M) was added dropwise to the reaction solution. The mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solution was then dried under reduced pressure to obtain the target compound without further purification.

[0306]

[0307] [Manufacturing Example Reaction Scheme 9]

[0308]

[0309]

[0310] Each ester (1 equivalent) was dissolved in dimethyl sulfoxide (0.54 M), and 2 M methylamine tetrahydrofuran solution (2 equivalents) was added. The reaction solution was stirred at 100°C for 4 hours under sealed conditions. The reaction solution was then cooled to room temperature, diluted with water, and extracted with ethyl acetate and a saturated aqueous sodium chloride solution. The residue was then purified by column chromatography under reduced pressure to obtain the target compound.

[0311]

[0312] [Manufacturing Example Reaction Scheme 10]

[0313]

[0314]

[0315] (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid (2 eq.) was dissolved in toluene (0.32 M), and triethylamine (4 eq.) and {[azido(phenoxy)phosphoryl]oxy}benzene (2 eq.) were added. The reaction solution was stirred at 90°C for 1.5 h, and each ester (1 eq.) was added. The reaction solution was then stirred at 120°C for 3 days under sealed conditions. The reaction solution was cooled to room temperature, and the reaction was terminated with saturated aqueous sodium bicarbonate solution. The solution was then extracted with ethyl acetate and saturated aqueous sodium chloride solution. The residue was purified under reduced pressure and subjected to column chromatography to obtain the target compound.

[0316]

[0317] [Manufacturing Example Reaction Scheme 11]

[0318]

[0319]

[0320] Each urea compound (1 equivalent) was dissolved in methanol (0.21 M), and sodium borohydride (5 equivalents) was added. The reaction solution was stirred at room temperature for 3 hours, and the reaction was terminated by the addition of water. The reaction solution was then extracted with ethyl acetate and a saturated aqueous sodium chloride solution. The resulting mixture was then depressurized and purified by column chromatography to obtain the target compound.

[0321]

[0322] [Manufacturing Example Reaction Scheme 12]

[0323]

[0324]

[0325] Each urea compound (1 equivalent) was dissolved in dichloromethane (0.24 M), and triethylamine (2 equivalents) and methanesulfonyl chloride (1.2 equivalents) were added. The reaction solution was stirred at room temperature for 20 minutes, and the reaction was quenched by the addition of water. The mixture was then extracted with dichloromethane. The resulting residue was then reduced in pressure and purified by column chromatography to obtain the desired compound.

[0326]

[0327] Manufacturing Example 11: Synthesis of {2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]pyrimidin-4-yl}methyl methanesulfonate

[0328]

[0329]

[0330] The title compound was obtained in the same manner as in Manufacturing Examples 9, 10, 11 and 12 using ethyl 2-chloropyrimidine-4-carboxylate as the starting material.

[0331] MS, actual value: 399

[0332]

[0333] Manufacturing Example 12: Synthesis of {5-methyl-2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]parimidin-4-yl}methyl methanesulfonate

[0334]

[0335]

[0336] The title compound was obtained in the same manner as in Manufacturing Examples 8, 9, 10, 11 and 12 using 2-chloro-5-methylpyrimidine-4-carboxylic acid as the starting material.

[0337] MS, actual value: 413

[0338]

[0339] Manufacturing Example 13: Synthesis of {6-methyl-2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]parimidin-4-yl}methyl methanesulfonate

[0340]

[0341]

[0342] The title compound was obtained in the same manner as in Manufacturing Examples 9, 10, 11 and 12 using methyl 2-chloro-6-methylpyrimidine-4-carboxylate as the starting material.

[0343] MS, actual value: 413

[0344]

[0345] [Manufacturing Example Reaction Scheme 13]

[0346]

[0347]

[0348] Pyridylmethanol (1 equivalent) was dissolved in thionyl chloride (12 equivalents) at 0°C and stirred at 15-20°C for 3 hours. The reaction solution was dried under reduced pressure, and a saturated aqueous ammonium chloride solution was added, followed by stirring for 30 minutes. The reaction solution was then extracted with dichloromethane. The solution was dried over anhydrous sodium sulfate, filtered, and then purified under reduced pressure to obtain the target compound.

[0349]

[0350] [Manufacturing Example Reaction Scheme 14]

[0351]

[0352]

[0353] Chloromethylpyridine (1 equivalent) was dissolved in 1,2-dichloroethane (0.38 M), and 1-isocyanato-4-(trifluoromethoxy)benzene (1.2 equivalents) was added. The reaction solution was stirred at 15-20°C for 12 hours. The reaction mixture was then filtered, and the solid was washed with dichloromethane to obtain the target compound.

[0354]

[0355] Manufacturing Example 14: Synthesis of 1-[4-(chloromethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0356]

[0357]

[0358] The title compound was obtained in the same manner as in Manufacturing Examples 13 and 14 using (2-amino-4-pyridyl)methanol as the starting material.

[0359] MS, actual value: 346

[0360]

[0361] Manufacturing Example 15: Synthesis of 1-[4-(chloromethyl)-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0362]

[0363]

[0364] Manufacturing Example 15A: (2-chloro-6-methyl-4-pyridyl)methanol

[0365]

[0366]

[0367] 2-Chloro-6-methyl-pyridine-4-carboxylic acid (1 eq) was dissolved in tetrahydrofuran (0.3 M), and 1.0 M borane tetrahydrofuran solution (5 eq) was added dropwise under nitrogen at 0°C. The reaction solution was warmed to 10-20°C and stirred for 18 hours. The reaction solution was cooled to 0°C, and saturated aqueous hydrochloric acid solution was added dropwise while stirring for 30 minutes. The mixture was then adjusted to pH = 8 by adding 50% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The solution was then filtered under reduced pressure and purified by column chromatography to obtain the title compound.

[0368] MS, actual value: 158

[0369]

[0370] Manufacturing Example 15B: (2-amino-6-methyl-4-pyridyl)methanol

[0371]

[0372] The compound (1 eq.) obtained in Preparation Example 15A, Pd2(dba)3 (2 mol%), and XPhos (4 mol%) were dissolved in tetrahydrofuran (0.5 M), and 1 M LiHMDS tetrahydrofuran solution (2 eq.) was added under nitrogen conditions. The reaction solution was stirred at 60°C for 4 hours. Afterwards, the reaction solution was adjusted to pH = 3-4 with 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The aqueous layer was adjusted to pH = 10 with 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate and dichloromethane. The collected organic solvent layer was then dried under reduced pressure to obtain the title compound.

[0373] MS, actual value: 139

[0374]

[0375] Manufacturing Example 15: 1-[4-(chloromethyl)-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0376] The title compound was obtained using the compound obtained in Manufacturing Example 15B as a starting material in the same manner as Manufacturing Example Reaction Schemes 13 and 14.

[0377] MS, actual value: 360

[0378]

[0379] Manufacturing Example 16: Synthesis of (2H-tetrazol-5-yl)methanol

[0380]

[0381]

[0382] Ethyl 2H-tetrazol-5-carboxylate (1 eq) was dissolved in tetrahydrofuran (0.35 M), and lithium aluminum hydride (2 eq) was added at 0°C. Sodium sulfate was added to the reaction solution, and the mixture was stirred at the same temperature for 20 minutes. Anhydrous sodium sulfate was then added to the reaction solution, and the mixture was stirred for 20 minutes. The reaction mixture was filtered, and the solid was triturated with dichloromethane and methanol, and then filtered. The collected organic solvent layer was then dried under reduced pressure to obtain the title compound.

[0383] MS, actual value: 101

[0384]

[0385] Manufacturing Example 17: Synthesis of 4-(tetrazol-2-ylmethyl)pyridin-2-amine

[0386]

[0387]

[0388] The compound obtained in Preparation Example 7A (1 equivalent), 1H-1,2,3,4-tetrazole (1.5 equivalents), and cesium carbonate (1.5 equivalents) were added to DMF (0.17 M) and stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic solvent layer was washed with a saturated aqueous sodium chloride solution. The solution was then filtered under reduced pressure and purified by column chromatography to obtain the title compound.

[0389]

[0390] Manufacturing Example 18: Synthesis of 1-[4-(chloromethyl)-2-pyridyl]-1-methyl-3-[4-(trifluoromethoxy)phenyl]urea

[0391]

[0392]

[0393] The compound (1 equivalent) obtained in Preparation Example 1A was dissolved in tetrahydrofuran (0.3 M), and 1-isocyanato-4-(trifluoromethoxy)benzene (2 equivalents) was added. The reaction solution was stirred at room temperature for 12 hours, and the reaction was quenched with water. The reaction solution was then extracted with ethyl acetate. The solution was then reduced in pressure, filtered, and purified through column chromatography to obtain the title compound.

[0394] MS, actual value: 360

[0395]

[0396] Manufacturing Example 19: Synthesis of 3-[6-(chloromethyl)-2-pyridyl]-1-[(1r,4r)-4-(tert-butyl)cyclohexyl]urea

[0397]

[0398]

[0399] Manufacturing Example 19A: 6-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-2-amine

[0400]

[0401] (6-Amino-2-pyridyl)methanol (1 eq) and imidazole (2.5 eq) were dissolved in DMF (0.15 M), and tert-butyl(chloro)dimethylsilane (1.5 eq) was added at 0°C. The reaction solution was stirred at 25°C for 8 hours. The mixture was diluted with ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The solution was then reduced in pressure, filtered, and purified by column chromatography to obtain the title compound.

[0402]

[0403] Manufacturing Example 19B: Trimethyl{1-methyl-1-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methoxy]ethyl}silane

[0404]

[0405]

[0406] (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid (1 eq.) was dissolved in toluene (0.5 M), and triethylamine (3 eq.) and {[azido(phenoxy)phosphoryl]oxy}benzene (2 eq.) were added at room temperature. The reaction solution was stirred at 0°C for 2 h under nitrogen conditions and referred to as mixture A.

[0407] The compound (1.2 equivalents) obtained in Preparation Example 19A was dissolved in tetrahydrofuran (0.4 M), and LiHMDS (2 equivalents) was added at 0°C. The reaction solution was stirred at 0°C for 1 hour under nitrogen conditions and was referred to as mixture B. Mixture A was cooled to room temperature and slowly added to mixture B at 0°C under nitrogen conditions. The mixture was stirred at 25°C for 5 hours under nitrogen conditions. The reaction solution was quenched with a saturated aqueous sodium bicarbonate solution at 5-10°C under nitrogen conditions. The reaction solution was then extracted with ethyl acetate and washed with a saturated aqueous sodium chloride solution. The solution was then filtered under reduced pressure, and purified through column chromatography to obtain the title compound.

[0408] MS, actual value: 420

[0409]

[0410] Manufacturing Example 19C: (6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methanol

[0411]

[0412]

[0413] The compound (1 equivalent) obtained in Preparation Example 19B was dissolved in methanol (0.04 M), and camphorsulfonic acid (1.08 equivalent) was added under nitrogen conditions at room temperature. The reaction solution was stirred at 50°C for 2 hours. An anion exchange resin was added to the mixture, and the mixture was stirred at 25°C for 1 hour. The mixture was filtered and dried. The obtained mixture was purified through reverse-phase high-performance liquid chromatography to obtain the title compound.

[0414] MS, actual value: 306

[0415]

[0416] Manufacturing Example 19: 3-[6-(chloromethyl)-2-pyridyl]-1-[(1r,4r)-4-(tert-butyl)cyclohexyl]urea

[0417] The compound (1 equivalent) obtained in Preparation Example 19C was dissolved in dichloromethane (0.3 M), and thionyl chloride (4 equivalents) was added. The reaction solution was stirred at room temperature for 2 hours. The mixture was dried and diluted with saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane and dried under reduced pressure to obtain the title compound without further purification.

[0418] MS, actual value: 324

[0419]

[0420] Manufacturing Example 20: Synthesis of 1-(1-adamantyl)-3-[4-(chloromethyl)-2-pyridyl]urea

[0421]

[0422]

[0423] The compound obtained in Preparation Example 7A (1 equivalent), 4-nitrophenyl chloroformate (1 equivalent), and diisopropylethylamine (4 equivalents) were dissolved in dichloromethane (0.3 M), adamantane-1-amine (1 equivalent) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic solvent layer was dried under reduced pressure, and then purified through column chromatography to obtain the title compound.

[0424] MS, actual value: 320

[0425]

[0426] Manufacturing Example 21: Synthesis of 3-[4-(2-hydroxyethyl)pyridin-2-yl]-3-methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]urea

[0427]

[0428]

[0429] Manufacturing Example 21A: 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridine

[0430]

[0431]

[0432] 2-(Pyridin-4-yl)ethan-1-ol hydrochloride (1 eq.) and imidazole (2.5 eq.) were dissolved in tetrahydrofuran (0.2 M), and DMF (0.5 M) was added. tert-Butyl(chloro)dimethylsilane (1.5 eq.) was added to the solution at 0°C, and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The solution was then filtered under reduced pressure, and purified by column chromatography to obtain the title compound.

[0433]

[0434] Manufacturing Example 21B: 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-1-ium-1-oleate

[0435]

[0436]

[0437] The compound (1 equivalent) obtained in Preparation Example 21A and magnesium monoperoxyphthalate (1.5 equivalents) were dissolved in methanol (0.3 M) and stirred at 60°C for 3 hours. The reaction solution was cooled to room temperature and filtered to remove solids. The filtrate was dried, diluted with dichloromethane, and extracted. The solution was then dried under reduced pressure to obtain the title compound without further purification.

[0438]

[0439] Manufacturing Example 21C: 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-methylpyridin-2-amine

[0440]

[0441]

[0442] The compound (1 equivalent) obtained in Preparation Example 21B and PyBroP (1.3 equivalents) were dissolved in a sealed tube containing a 2 M methylamine tetrahydrofuran solution (10 equivalents) and stirred at room temperature for 12 hours. The reaction solution was diluted with dichloromethane and extracted. The solution was then dried under reduced pressure to obtain the title compound without further purification.

[0443]

[0444] Manufacturing Example 21D: 3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-2-yl)-3-methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]urea

[0445]

[0446]

[0447] (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid (1.3 eq) was dissolved in toluene (0.5 M), and triethylamine (3 eq) and {[azido(phenoxy)phosphoryl] oxy}benzene (1.3 eq) were added at room temperature. The reaction solution was stirred at 100°C for 1 h under nitrogen conditions and referred to as mixture A.

[0448] The compound (1 equivalent) obtained in Preparation Example 21C was added to mixture A and stirred at 100°C for 12 hours. The reaction was then quenched with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The resulting mixture was dried under reduced pressure and purified through column chromatography to obtain the title compound.

[0449]

[0450] Manufacturing Example 21: 3-[4-(2-hydroxyethyl)pyridin-2-yl]-3-methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]urea

[0451]

[0452] The compound (1 equivalent) obtained in Preparation Example 21D was dissolved in a 1.25 M hydrochloric acid methanol solution (4 equivalents) and stirred at room temperature for 12 hours. The reaction solution was quenched with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The resulting solution was dried under reduced pressure and purified through column chromatography to obtain the title compound.

[0453] MS, actual value: 333

[0454]

[0455] [Reaction Formula 1]

[0456]

[0457]

[0458] Toluene (0.5 M) was added to each carboxylic acid (2 equivalents). Triethylamine (5 equivalents) and {[azido(phenoxy)phosphoryl]oxy}benzene (4 equivalents) were added to the solution and stirred at 90°C for 2 hours. Each amine (1 equivalent) was added to the reaction solution and stirred at 90°C for 12 hours. The mixture was cooled to room temperature, and the reaction was quenched with saturated aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate, dried under reduced pressure, and purified through column chromatography to obtain the target compound.

[0459]

[0460] Example 1: Synthesis of 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0461]

[0462]

[0463] The title compound was obtained (55% yield) in the same manner as in Scheme 1 using (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 1.

[0464] 1H-NMR (CDCl3, 400MHz) δ9.78(d, 1H), δ8.67(s, 1H), δ8.25(d, 1H), δ6.86(s, 1H), δ6.72(d, 1H), δ5.63(s, 2H), δ3.61(m, 1H), δ3.36(s, 3H), δ2.10(d, 2H), δ1.79(d, 2H), δ1.15(m, 4H), δ1.02(m, 1H), δ0.97(s, 9H)

[0465]

[0466] Example 2: Synthesis of 1-[(2-{1-ethyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0467]

[0468]

[0469] The title compound was obtained (13% yield) in the same manner as in Scheme 1 using (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 5.

[0470] 1H-NMR (CDCl3, 400MHz) δ8.70(s, 1H), δ8.26(d, 1H), δ6.92(s, 1H), δ6.76(d, 1H), δ5.63(s, 2H), δ3.96(q, 2H), δ3.61(m, 1H), δ3.10(s, 7H), δ2.09(d, 2H), δ1.79(d, 2H), δ1.11(m, 10H), δ0.88(s, 10H)

[0471]

[0472] Example 3: Synthesis of 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0473]

[0474]

[0475] The title compound was obtained (12% yield) in the same manner as in Scheme 1 using (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 3.

[0476] 1H-NMR (CDCl3, 400MHz) δ9.53(d, 1H), δ8.58(s, 1H), δ8.13(s, 1H), δ6.68(s, 1H), δ5.59(s, 2H), δ3.60(m, 1H), δ3.30(s, 3H), δ2.25(s, 3H), δ2.10(d, 2H), δ1.89(d, 2H), δ1.24(m, 4H), δ1.19(m, 1H), δ1.12(s, 9H)

[0477]

[0478] Example 4: Synthesis of 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0479]

[0480]

[0481] The title compound was obtained (21% yield) in the same manner as in Scheme 1 using (1r,4r)-4-tert-butylcyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 4.

[0482] 1H-NMR (CDCl3, 400MHz) δ9.66(d, 1H), δ8.56(s, 1H), δ8.10(s, 1H), δ6.74(s, 1H), δ5.79(s, 2H), δ3.59(m, 1H), δ3.30(s, 3H), δ2.32(s, 3H), δ2.11(d, 2H), δ1.78(d, 2H), δ1.14(m, 4H), δ1.07(m, 1H), δ1.00(s, 9H)

[0483]

[0484] Example 5: Synthesis of 2-[(2-{1-methyl-3-[(1s,4s)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0485]

[0486]

[0487] The title compound was obtained (31% yield) in the same manner as in Scheme 1 using (1s,4s)-4-tert-butylcyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 2.

[0488] 1H-NMR (CDCl3, 400MHz) δ10.7(s, 1H), δ8.58(s, 1H), δ8.23(d, 1H), δ6.91(s, 1H), δ8.583(d, 1H), δ5.82(s, 2H), δ4.13(m, 1H), δ3.38(s, 3H), δ1.84(d, 2H), δ1.65(d, 2H), δ1.1.48(t, 2H), δ1.26(m, 2H), δ1.17(m, 1H), δ1.15(s, 9H)

[0489]

[0490] Example 6: Synthesis of 1-({2-[3-(4,4-difluorocyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole

[0491]

[0492]

[0493] The title compound was obtained (12% yield) in the same manner as in Scheme 1 using 4,4-difluorocyclohexane-1-carboxylic acid as a starting material and the compound obtained in Preparation Example 1.

[0494] 1H-NMR (CDCl3, 400MHz) δ10.2(d, 1H), δ8.68(s, 1H), δ8.27(d, 1H), δ6.85(s, 1H), δ6.77(d, 1H), δ5.64(s, 2H), δ3.92(m, 1H), δ3.37(s, 3H), δ2.03(m, 4H), δ1.84(m, 2H), δ1.67(m, 2H)

[0495]

[0496] Example 7: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0497]

[0498]

[0499] The title compound was obtained (24% yield) in the same manner as in Scheme 1 using (1r,4r)-4-(trifluoromethyl)cyclohexanecarboxylic acid as a starting material and the compound obtained in Preparation Example 2.

[0500] 1H-NMR (CDCl3, 400MHz) δ10.1(d, 1H), δ8.58(s, 1H), δ8.23(d, 1H), δ6.90(s, 1H), δ6.83(d, 1H), δ5.82(s, 2H), δ3.66(m, 1H), δ3.37(s, 3H), δ2.18(d, 2H), δ2.01(d, 3H), δ1.47(q, 2H), δ1.41(q, 2H)

[0501]

[0502] Example 8: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-isopropylcyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0503]

[0504]

[0505] The title compound was obtained (19% yield) in the same manner as in Scheme 1 using (1r,4r)-7-hydroxy-p-methan-7-one as a starting material and the compound obtained in Preparation Example 2.

[0506] 1H-NMR (CDCl3, 400MHz) δ9.96(s, 1H), δ8.58(s, 1H), δ8.24(d, 1H), δ6.91(s, 1H), δ6.83(d, 1H), δ5.82(s, 2H), δ3.63(m, 1H), δ3.37(s, 3H), δ2.07(d, 2H), δ1.73(d, 2H), δ1.43(m, 1H), δ1.21(m, 5H), δ1.06(s, 6H)

[0507]

[0508] Example 9: Synthesis of 1-[(2-{1-methyl-3-(6-spiro[2.5]octyl)ureido}-4-pyridyl)methyl]-1H-tetrazole

[0509]

[0510]

[0511] The title compound was obtained (4% yield) in the same manner as in Scheme 1 using spiro[2.5]octane-6-carboxylic acid as a starting material and the compound obtained in Preparation Example 1.

[0512] 1H-NMR (CDCl3, 400MHz) δ9.98(d, 1H), δ8.67(s, 1H), δ8.29(d, 1H), δ6.87(s, 1H), δ6.73(d, 1H), δ5.62(s, 2H), δ3.85(m, 1H), δ3.37(s, 3H), δ1.92(m, 2H), δ1.63(m, 2H), δ1.42(m, 2H), δ1.11(d, 2H), δ0.29(m, 2H), δ0.22(m, 2H)

[0513]

[0514] Example 10: Synthesis of 1-[(2-{1-methyl-3-(7-spiro[3.5]nonyl)ureido}-4-pyridyl)methyl]-1H-tetrazole

[0515]

[0516]

[0517] The title compound was obtained (4% yield) in the same manner as in Scheme 1 using spiro[3.5]nonane-7-carboxylic acid as a starting material and the compound obtained in Preparation Example 1.

[0518] 1H-NMR (CDCl3, 400MHz) δ9.87(s, 1H), δ8.65(s, 1H), δ8.26(d, 1H), δ6.85(s, 1H), δ6.72(d, 1H), δ5.61(s, 2H), δ3.71(m, 1H), δ3.34(s, 3H), δ1.83(m, 4H), δ1.68(m, 6H), δ1.43(m, 2H), δ1.11(m, 2H)

[0519]

[0520] Example 11: Synthesis of 1-methyl-3-[(4-methylcyclohexyl)methyl]-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0521]

[0522]

[0523] The title compound was obtained (32% yield) in the same manner as in Scheme 1 using 2-(4-methylcyclohexyl)acetic acid as a starting material and the compound obtained in Preparation Example 1.

[0524] 1H-NMR (CDCl3, 400MHz) δ10.03-10.01(m, 1H), δ8.68(s, 1H), δ8.28-8.26(m, 1H), δ6.86(s, 1H), δ6.74(d, 1H), δ5.63(s, 2H), δ3.37(s, 3H), δ3.32-3.29(m, 1H), δ3.20(t, 1H), δ1.79-1.65(m, 4H), δ1.54-1.41(m, 3H), δ1.35-1.26(m, 1H), δ1.04-0.86(m, 5H)

[0525]

[0526] Example 12: Synthesis of 3-(4-cyclopropylphenyl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0527]

[0528]

[0529] The title compound was obtained in the same manner as in Scheme 1 using 4-cyclopropylbenzoic acid as a starting material and the compound obtained in Preparation Example 1.

[0530] 1H-NMR (CDCl3, 400MHz) δ12.42(s, 1H), δ8.72(s, 1H), δ8.34(d, 1H), δ7.41(d, 2H), δ7.03(d, 2H), δ6.89(s, 1H), δ6.79(d, 1H), δ5.63(s, 2H), δ3.41(s, 3H), δ1.89(m, 1H), δ1.68(s, 1H), δ1.26(t, 1H), δ0.94(q, 2H), δ0.91(q, 2H)

[0531]

[0532] Example 13: Synthesis of 1-methyl-3-(4-propylphenyl)-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0533]

[0534]

[0535] The title compound was obtained in the same manner as in Scheme 1 using 4-propylbenzoic acid as a starting material and the compound obtained in Preparation Example 1.

[0536] 1H-NMR (CDCl3, 400MHz) δ12.43(s, 1H), δ8.77(s, 1H), δ8.32(d, 1H), δ7.43(d, 2H), δ7.13(d, 2H), δ6.91(s, 1H), δ6.78(d, 1H), δ5.62(s, 2H), δ3.39(s, 3H), δ2.56(t, 2H), δ1.66(q, 2H), δ0.94(t, 3H)

[0537]

[0538] [Reaction Formula 2]

[0539]

[0540]

[0541] The chlorine substituted compound (1 equivalent) was dissolved in DMF, and 1H-1,2,3,4-tetrazole (1.2 equivalents) and cesium carbonate (2 equivalents) were added. The reaction solution was stirred at 90°C for 12 hours. The mixture was cooled to room temperature, and the reaction was quenched with saturated aqueous sodium bicarbonate solution. The reaction solution was then extracted with dichloromethane. The residue was purified under reduced pressure and subjected to column chromatography to obtain the target compound.

[0542]

[0543] Example 14: Synthesis of 2-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0544]

[0545]

[0546] The title compound was obtained (24% yield) in the same manner as in Scheme 2 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 7.

[0547] 1H-NMR (CDCl3, 400MHz) δ9.10(s, 1H), δ8.93(s, 1H), δ8.56(s, 1H), δ8.13(d, 1H), δ6.86(s, 1H), δ6.70(d, 1H), δ5.77(s, 2H), δ3.63(m, 1H), δ2.13(d, 2H), δ1.82(d, 2H), δ1.13(m, 4H), δ0.99(m, 1H), δ0.87(s, 9H)

[0548]

[0549] Example 15: Synthesis of 1-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0550]

[0551]

[0552] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 7, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (34% yield).

[0553] 1H-NMR (CDCl3, 400MHz) δ8.62(m, 1H), δ8.18(d, 1H), δ7.52(s, 1H), δ6.64(m, 2H), δ5.56(s, 2H), δ3.64(m, 1H), δ2.12(d, 3H), δ1.81(d, 3H), δ1.14(m, 8H), δ0.86(m, 11H)

[0554]

[0555] Example 16: Synthesis of 5-methyl-2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0556]

[0557]

[0558] The title compound was obtained (11% yield) in the same manner as in Scheme 2 using 5-methyl-2H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 8.

[0559] 1H-NMR (CDCl3, 400MHz) δ9.86(d, 1H), δ8.21(d, 1H), δ6.89(s, 1H), δ6.80(d, 1H), δ5.70(s, 2H), δ3.64(m, 1H), δ3.36(s, 3H), δ2.54(s, 3H), δ2.10(d, 2H), δ1.78(d, 2H), δ1.56(s, 3H), δ1.12(m, 9H), δ0.99(s, 10H)

[0560]

[0561] Example 17: Synthesis of 5-methyl-1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0562]

[0563]

[0564] Using 5-methyl-2H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 8, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (20% yield).

[0565] 1H-NMR (CDCl3, 400MHz) δ9.75(d, 1H), δ8.22(d, 1H), δ6.77(s, 1H), δ6.61(d, 1H), δ5.49(s, 2H), δ5.49(s, 2H), δ3.62(m, 1H), δ3.35(s, 3H), δ2.50(s, 3H), δ2.11(d, 2H), δ2.01(m, 1H), δ1.79(d, 2H), δ1.57(s, 3H), δ1.11(m, 9H), δ1.03(s, 10H)

[0566]

[0567] Example 18: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-2H-tetrazole

[0568]

[0569]

[0570] The title compound was obtained (16% yield) in the same manner as in Scheme 2 using 5-propyl-2H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 8.

[0571] 1H-NMR (CDCl3, 400MHz) δ9.89(s, 1H), δ8.21(d, 1H), δ6.79(m, 2H), δ5.71(s, 2H), δ3.62(m, 1H), δ3.35(s, 3H), δ2.86(t, 2H), δ2.10(d, 2H), δ1.77(m, 4H), δ1.51(s, 2H), δ1.20(m, 6H), δ1.11(t, 4H), δ1.02(s, 10H)

[0572]

[0573] Example 19: Synthesis of 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-1H-tetrazole

[0574]

[0575]

[0576] Using 5-propyl-2H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 8, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (16% yield).

[0577] 1H-NMR (CDCl3, 400MHz) δ9.80(s, 1H), δ8.22(d, 1H), δ6.75(s, 1H), δ6.61(d, 1H), δ5.49(s, 2H), δ3.63(m, 1H), δ3.34(s, 3H), δ2.72(t, 2H), δ2.10(d, 2H), δ2.01(s, 5H), δ1.76(m, 4H), δ1.42(m, 5H), δ1.21(m, 4H), δ1.15(s, 10H)

[0578]

[0579] Example 20: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-2H-tetrazole

[0580]

[0581]

[0582] The title compound was obtained (48% yield) in the same manner as in Scheme 2 using 5-(trifluoromethyl)-2H-tetrazole as a starting material and the compound obtained in Preparation Example 8.

[0583] 1H-NMR (CDCl3, 400MHz) δ9.78(s, 1H), δ8.26(d, 1H), δ6.97(s, 1H), δ6.86(d, 1H), δ5.83(s, 2H), δ3.63(m, 1H), δ3.39(s, 3H), δ2.11(d, 2H), δ1.79(d, 2H), δ1.55(s, 6H), δ1.17(m, 7H), δ0.98(s, 10H)

[0584]

[0585] Example 21: Synthesis of 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-1H-tetrazole

[0586]

[0587]

[0588] Using 5-(trifluoromethyl)-2H-tetrazole as a starting material and the compound obtained in Preparation Example 8, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (4% yield).

[0589] 1H-NMR (CDCl3, 400MHz) δ9.75(d, 1H), δ8.25(s, 1H), δ6.85(s, 1H), δ6.72(d, 1H), δ5.68(s, 2H), δ3.64(m, 1H), δ3.36(s, 3H), δ2.11(d, 2H), δ1.79(d, 2H), δ1.54(s, 11H), δ1.12(m, 11H), δ0.85(s, 11H)

[0590]

[0591] Example 22: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0592]

[0593]

[0594] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 8, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (34% yield).

[0595] 1H-NMR (CDCl3, 400MHz) δ9.84(d, 1H), δ8.57(s, 1H), δ8.22(d, 1H), δ6.89(s, 1H), δ6.80(d, 1H), δ5.80(s, 2H), δ3.63(m, 1H), δ3.36(s, 3H), δ2.10(d, 2H), δ1.78(d, 2H), δ1.15(m, 5H), δ0.99(t, 1H), δ0.85(s, 10H)

[0596]

[0597] Example 23: Synthesis of {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol

[0598]

[0599]

[0600] The title compound was obtained (12% yield) in the same manner as in Scheme 2 using (2H-tetrazol-5-yl)methanol as a starting material and the compound obtained in Preparation Example 8.

[0601] 1H-NMR (DMSO-d6, 400MHz) δ9.18(d, 1H), δ8.26(d, 1H), δ7.19(s, 1H), δ6.83(d, 1H), δ5.98(s, 1H), δ5.75(s, 2H), δ4.83(s, 2H), δ3.45(m, 1H), δ3.39(s, 3H), δ1.94(d, 2H), δ1.73(d, 2H), δ1.23(m, 2H), δ1.20(m, 3H), δ1.16(s, 9H)

[0602]

[0603] Example 24: Synthesis of {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol

[0604]

[0605]

[0606] Using (2H-tetrazol-5-yl)methanol as a starting material and the compound obtained in Preparation Example 8, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (13% yield).

[0607] 1H-NMR (DMSO-d6, 400MHz) δ9.12(d, 1H), δ8.28(d, 1H), δ7.28(s, 1H), δ6.84(d, 1H), δ5.99(s, 2H), δ5.62(t, 1H), δ4.67(d, 2H), δ3.47(m, 1H), δ3.27(s, 3H), δ1.97(d, 2H), δ1.73(d, 2H), δ1.24(q, 2H), δ1.14(q, 3H), δ1.06(s, 9H)

[0608]

[0609] Example 25: Synthesis of [2-({2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]pyridin-4-yl}methyl)-2H-1,2,3,4-tetrazol-5-yl]methyl N,N-dimethylcarbamate

[0610]

[0611]

[0612] The compound obtained in Example 24 (1 equivalent) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (1.5 equivalents) were dissolved in dichloromethane and stirred at room temperature for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. The solution was dried under reduced pressure and dissolved in tetrahydrofuran. Thereafter, 2M dimethylamine tetrahydrofuran solution (1.5 equivalents) and triethylamine (2 equivalents) were added to the solution, stirred at room temperature for 2 hours, and the reaction was quenched with saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with ethyl acetate and dried. After quenching, the mixture was purified by column chromatography to obtain the title compound (37% yield).

[0613] 1H-NMR (CDCl3, 400MHz) δ9.87(d, 1H), δ8.22(d, 1H), δ6.88(s, 1H), δ6.83(d, 1H), δ5.76(s, 2H), δ5.38(s, 2H), δ3.59(m, 1H), δ3.36(s, 3H), δ2.93(d, 6H), δ2.10(d, 2H), δ1.78(d, 2H), δ1.21(m, 4H), δ1.11(t, 1H), δ1.08(s, 9H)

[0614]

[0615] Example 26: Synthesis of 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0616]

[0617]

[0618] The title compound was obtained (17% yield) in the same manner as in Scheme 2 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 9.

[0619] 1H-NMR (CDCl3, 400MHz) δ9.02(s, 1H), δ7.10(s, 1H), δ6.85(s, 1H), δ5.77(s, 2H), δ3.56(t, 1H), δ3.42(s, 3H), δ2.56(s, 3H), δ2.06(d, 2H), δ1.81(d, 2H), δ1.16(m, 6H), δ0.85(s, 9H)

[0620]

[0621] Example 27: Synthesis of 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0622]

[0623]

[0624] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 9, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (16% yield).

[0625] 1H-NMR (CDCl3, 400MHz) δ10.3(d, 1H), δ8.56(s, 1H), δ6.66(d, 2H), δ5.76(s, 2H), δ3.59(m, 1H), δ3.34(s, 3H), δ2.44(s, 3H), δ2.14(d, 2H), δ1.78(d, 2H), δ1.21(m, 5H), δ0.85(s, 10H)

[0626]

[0627] Example 28: Synthesis of 2-[(5-fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0628]

[0629]

[0630] The title compound was obtained (28% yield) in the same manner as in Scheme 2 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 10.

[0631] 1H-NMR (CDCl3, 400MHz) δ8.59(s, 1H), δ8.33(s, 1H), δ8.09(s, 1H), δ7.18(s, 1H), δ6.54(d, 1H), δ5.86(s, 2H), δ3.60(m, 1H), δ2.10(d, 2H), δ1.80(d, 2H), δ1.10(m, 5H), δ1.03(m, 1H), δ0.86(s, 9H)

[0632]

[0633] Example 29: Synthesis of 1-[(5-fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole

[0634]

[0635]

[0636] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 10, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 2 (31% yield).

[0637] 1H-NMR (CDCl3, 400MHz) δ8.70(s, 1H), δ8.10(m, 2H), δ7.78(s, 1H), δ6.76(s, 1H), δ5.62(s, 2H), δ3.63(m, 1H), δ2.10(d, 2H), δ1.81(d, 2H), δ1.16(m, 5H), δ1.01(m, 1H), δ0.86(s, 10H)

[0638]

[0639] [Reaction Formula 3]

[0640]

[0641]

[0642] Each chlorine substituent (1 eq.), each tetrazole (4 eq.), and cesium carbonate (3.3 eq.) were dissolved in DMF (0.4 M) and stirred at 70°C for 15 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic solvent layer was washed with a saturated aqueous sodium chloride solution. The residue was then purified by column chromatography under reduced pressure to obtain the target compound.

[0643]

[0644] Example 30: Synthesis of 1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0645]

[0646]

[0647] The title compound was obtained in the same manner as in Scheme 3 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 14.

[0648] 1H-NMR (DMSO-d6, 400MHz) δ10.41(s, 1H), δ9.60(m, 2H), δ8.28(d, 1H), δ7.63(d, 2H), δ7.43(s, 1H), δ7.32(d, 2H), δ6.89(d, 1H), δ5.80(s, 2H)

[0649]

[0650] Example 31: Synthesis of 1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0651]

[0652]

[0653] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 14, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3.

[0654] 1H-NMR (DMSO-d6, 400MHz) δ10.30(s, 1H), δ9.50(s, 1H), δ9.09(s, 1H), δ8.28(d, 1H), δ7.61(d, 2H), δ7.43(s, 1H), δ7.32(d, 2H), δ6.90(d, 1H), δ6.06(s, 2H)

[0655]

[0656] Example 32: Synthesis of 1-[4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0657]

[0658]

[0659] The title compound was obtained (27% yield) in the same manner as in Scheme 3 using 5-methyl-1H-tetrazole as a starting material and the compound obtained in Preparation Example 14.

[0660] 1H-NMR (DMSO-d6, 400MHz) δ10.36(s, 1H), δ9.49(s, 1H), δ8.27(d, 1H), δ7.64-7.57(m, 2H), δ7.38-7.28(m, 3H), δ6.87-6.80(m, 1H), δ5.73(s, 2H), δ2.50(s, 3H)

[0661]

[0662] Example 33: Synthesis of 1-[4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0663]

[0664]

[0665] Using 5-methyl-1H-tetrazole as a starting material and the compound obtained in Preparation Example 14, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3 (25% yield).

[0666] 1H-NMR (CDCl3, 400MHz) δ11.64(s, 1H), δ8.27(d, 1H), δ7.61(d, 2H), δ7.22(d, 2H), δ6.89(d, 1H), δ6.70(s, 1H), δ5.72(s, 2H), δ2.57(s, 3H)

[0667]

[0668] Example 34: Synthesis of 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0669]

[0670]

[0671] The title compound was obtained (7% yield) in the same manner as in Scheme 3 using the compounds obtained in Manufacturing Examples 14 and 16 as starting materials.

[0672] 1H-NMR (DMSO-d6, 400MHz) δ10.37(s, 1H), δ9.50(s, 1H), δ8.26(d, 1H), δ7.67-7.55(m, 2H), δ7.41(s, 1H), δ7.31(d, 2H), δ6.84(dd, 1H), δ5.95(t, 1H), δ5.76(s, 2H), δ4.82(d, 2H)

[0673]

[0674] Example 35: Synthesis of 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0675]

[0676]

[0677] Using the compounds obtained in Manufacturing Examples 14 and 16 as starting materials, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3 (9% yield).

[0678] 1H-NMR (DMSO-d6, 400MHz) δ10.34(s, 1H), δ9.52(s, 1H), δ8.28(d, 1H), δ7.64-7.58(m, 2H), δ7.50(s, 1H), δ7.31(d, 2H), δ6.90(dd, 1H), δ5.99(s, 2H), δ5.64(t, 1H), δ4.68(d, 2H)

[0679]

[0680] Example 36: Synthesis of 1-[6-methyl-4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0681]

[0682]

[0683] The title compound was obtained (17% yield) in the same manner as in Scheme 3 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 15.

[0684] 1H-NMR (Acetone, 400MHz) δ11.70(s, 1H), δ9.31(s, 1H), δ8.86(s, 1H), δ7.79-7.71(m, 2H), δ7.30(d, 2H), δ6.91(s, 1H), δ6.86(s, 1H), δ5.84(s, 2H), δ2.55(s, 3H)

[0685]

[0686] Example 37: Synthesis of 1-[6-methyl-4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0687]

[0688]

[0689] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 15, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3 (19% yield).

[0690] 1H-NMR (Acetone, 400MHz) δ11.70(s, 1H), δ8.86(s, 1H), δ8.84(s, 1H), δ7.80-7.71(m, 2H), δ7.30(d, 2H), δ6.95(s, 1H), δ6.87(s, 1H), δ6.00(s, 2H), δ2.56(s, 3H)

[0691]

[0692] Example 38: Synthesis of 1-[6-methyl-4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0693]

[0694]

[0695] The title compound was obtained (34% yield) in the same manner as in Scheme 3 using 5-methyl-1H-tetrazole as a starting material and the compound obtained in Preparation Example 15.

[0696] 1H-NMR (Acetone, 400MHz) δ11.75(s, 1H), δ8.84(s, 1H), δ7.80-7.69(m, 2H), δ7.30(d, 2H), δ6.84-6.76(m, 2H), δ5.72(s, 2H), δ2.57(s, 3H), δ2.56(s, 3H)

[0697]

[0698] Example 39: Synthesis of 1-[6-methyl-4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0699]

[0700]

[0701] Using 5-methyl-1H-tetrazole as a starting material and the compound obtained in Preparation Example 15, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3 (31% yield).

[0702] 1H-NMR (Acetone, 400MHz) δ10.67(s, 1H), δ9.54(s, 1H), δ7.60(d, 2H), δ7.31(d, 2H), δ6.76(s, 1H), δ5.88(s, 2H), δ2.47(s, 3H), δ2.43(s, 3H)

[0703]

[0704] Example 40: Synthesis of 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0705]

[0706]

[0707] The title compound was obtained in the same manner as in Scheme 3 using the compounds obtained in Preparation Examples 15 and 16 as starting materials, and purified through high-performance liquid chromatography for preparation (5% yield).

[0708] 1H-NMR (DMSO-d6, 400MHz) δ10.74(s, 1H), 9.65(s, 1H), δ7.65-7.57(m, 2H), δ7.32(d, 2H), δ7.20(s, 1H), δ6.74(s, 1H), δ5.74(s, 2H), δ4.82(s, 2H), δ2.44(s, 3H)

[0709]

[0710] Example 41: Synthesis of 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0711]

[0712]

[0713] The compounds obtained in Manufacturing Examples 15 and 16 were used as starting materials and synthesized in the same manner as in Scheme 3, and the title compound, which is a positional isomer, was purified through high-performance liquid chromatography for manufacturing (5% yield).

[0714] 1H-NMR (DMSO-d6, 400MHz) δ10.66(s, 1H), δ9.58(s, 1H), δ7.64-7.57(m, 2H), δ7.32(d, 2H), δ7.24(s, 1H), δ6.78(s, 1H), δ5.93(s, 2H), δ4.68(s, 2H), δ2.44(s, 3H)

[0715]

[0716] Example 42: Synthesis of 1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0717]

[0718]

[0719] The title compound was obtained (11% yield) in the same manner as in Scheme 3 using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 18.

[0720] 1H-NMR (CDCl3, 400MHz) δ12.68(s, 1H), δ8.68(s, 1H), δ8.38(d, 1H), δ7.58(d, 2H), δ7.19(d, 2H), δ6.92(s, 1H), δ6.85(d, 1H), δ5.67(s, 2H), δ3.45(s, 3H)

[0721]

[0722] Example 43: Synthesis of 1-methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0723]

[0724]

[0725] Using 1H-1,2,3,4-tetrazole as a starting material and the compound obtained in Preparation Example 18, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 3 (6% yield).

[0726] 1H-NMR (CDCl3, 400MHz) δ12.73(s, 1H), δ8.60(s, 1H), δ8.36(d, 1H), δ7.58(d, 2H), δ7.18(d, 2H), δ6.99(s, 1H), δ6.95(d, 1H), δ5.86(s, 2H), δ3.46(s, 3H)

[0727]

[0728] Example 44: Synthesis of 1-[4-[(5-phenyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0729]

[0730]

[0731] The title compound was obtained in the same manner as in Scheme 3 using 5-phenyl-2H-tetrazole as a starting material and the compound obtained in Preparation Example 18.

[0732] 1H-NMR (DMSO-d6, 400MHz) δ10.43(s, 1H), δ9.55(s, 1H), δ8.31(d, 1H), δ8.09(d, 2H), δ7.62(m, 5H), δ7.48(s, 1H), δ7.32(d, 2H), δ6.98(d, 1H), δ6.11(s, 2H)

[0733]

[0734] [Reaction Formula 4]

[0735]

[0736]

[0737] Each methanesulfonyl intermediate (1 eq.), 1H-1,2,3,4-tetrazole (1.2 eq.), and potassium carbonate (2 eq.) were added to acetonitrile (0.12 M). The reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with saturated aqueous sodium bicarbonate solution. The reaction solution was then extracted with ethyl acetate and saturated aqueous sodium chloride solution. The residue was purified under reduced pressure and subjected to column chromatography to obtain the target compound and its positional isomer.

[0738]

[0739] Example 45: Synthesis of 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole

[0740]

[0741]

[0742] The title compound was obtained (43% yield) in the same manner as in Scheme 4 using the compound obtained in Manufacturing Example 11 as the starting material.

[0743] 1H-NMR (CDCl3, 400MHz) δ9.62(d, 1H), δ8.83(s, 1H), δ8.51(d, 1H), δ6.74(d, 1H), δ5.66(s, 2H), δ3.60(m, 1H), δ3.42(s, 3H), δ2.09(d, 2H), δ1.80(d, 2H), δ1.24(m, 4H), δ1.01(m, 1H), δ0.86(s, 9H)

[0744]

[0745] Example 46: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole

[0746]

[0747]

[0748] Using the compound obtained in Manufacturing Example 11 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 4 (40% yield).

[0749] 1H-NMR (CDCl3, 400MHz) δ9.64(d, 1H), δ8.62(s, 1H), δ8.51(d, 1H), δ6.62(d, 1H), δ5.87(s, 2H), δ3.60(m, 1H), δ3.46(s, 3H), δ2.09(d, 2H), δ1.80(d, 2H), δ1.20(m, 4H), δ1.12(m, 1H), δ1.10(s, 9H)

[0750]

[0751] Example 47: Synthesis of 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole

[0752]

[0753]

[0754] The title compound was obtained (40% yield) in the same manner as in Scheme 4 using the compound obtained in Manufacturing Example 12 as the starting material.

[0755] 1H-NMR (CDCl3, 400MHz) δ9.52(d, 1H), δ8.82(s, 1H), δ8.34(s, 1H), δ5.68(s, 2H), δ3.57(m, 1H), δ3.30(s, 3H), δ2.36(s, 3H), δ2.09(d, 2H), δ1.79(d, 2H), δ1.22(m, 4H), δ1.18(m, 1H), δ1.16(s, 9H)

[0756]

[0757] Example 48: Synthesis of 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole

[0758]

[0759]

[0760] Using the compound obtained in Manufacturing Example 12 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 4 (36% yield).

[0761] 1H-NMR (CDCl3, 400MHz) δ9.51(d, 1H), δ8.58(s, 1H), δ8.36(s, 1H), δ5.87(s, 2H), δ3.56(m, 1H), δ3.32(s, 3H), δ2.33(s, 3H), δ2.06(d, 2H), δ1.80(d, 2H), δ1.22(m, 4H), δ1.14(m, 1H), δ1.12(s, 9H)

[0762]

[0763] Example 49: Synthesis of 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole

[0764]

[0765]

[0766] The title compound was obtained (47% yield) in the same manner as in Scheme 4 using the compound obtained in Manufacturing Example 13 as the starting material.

[0767] 1H-NMR (CDCl3, 400MHz) δ9.93(d, 1H), δ8.82(s, 1H), δ6.59(s, 1H), δ5.60(d, 2H), δ3.60(m, 1H), δ3.42(s, 3H), δ2.46(s, 3H), δ2.13(d, 2H), δ1.80(d, 2H), δ1.20(m, 4H), δ1.12(m, 1H), δ1.09(s, 9H)

[0768]

[0769] Example 50: Synthesis of 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole

[0770]

[0771]

[0772] Using the compound obtained in Manufacturing Example 13 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Scheme 4 (38% yield).

[0773] 1H-NMR (CDCl3, 400MHz) δ9.91(d, 1H), δ8.61(s, 1H), δ6.46(s, 1H), δ5.81(s, 2H), δ3.58(m, 1H), δ3.45(s, 3H), δ2.43(s, 3H), δ2.11(d, 2H), δ1.80(d, 2H), δ1.21(m, 4H), δ1.12(m, 1H), δ1.10(s, 9H)

[0774]

[0775] [Reaction Formula 5]

[0776]

[0777]

[0778] Dichloromethane (0.09 M) was added to each pyridine-2-amine intermediate (1 eq). Triethylamine (1.5 eq) was added to the solution, and triphosgene dichloromethane solution (1.5 eq) was added dropwise at room temperature for 10 minutes. Each amine (1.1 eq) and triethylamine (1.5 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The residue was purified under reduced pressure and then purified by column chromatography to obtain the target compound.

[0779]

[0780] Example 51: Synthesis of 1-({2-[3-(4,4-dimethylcyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole

[0781]

[0782]

[0783] The title compound was obtained (70% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and 4,4-dimethylcyclohexan-1-amine as starting materials.

[0784] 1H-NMR (CDCl3, 400MHz) δ9.96(s, 1H), δ8.66(s, 1H), δ8.28(s, 1H), δ6.86(s, 1H), δ6.73(d, 1H), δ5.62(s, 2H), δ3.75(m, 1H), δ3.36(s, 3H), δ1.81(m, 2H), δ1.50(m, 4H), δ1.42(m, 2H), δ1.31(m, 6H)

[0785]

[0786] Example 52: Synthesis of 3-[cyclopropyl(phenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0787]

[0788]

[0789] The title compound was obtained (90% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and 1-cyclopropyl-1-phenylmethylamine hydrochloride as starting materials.

[0790] 1H-NMR (CDCl3, 400MHz) δ10.63(d, 1H), δ8.67(s, 1H), δ8.32(d, 1H), δ7.39(d, 2H), δ7.32(t, 2H), δ7.25-7.22(m, 1H), δ6.85(s, 1H), δ6.75(d, 1H), δ5.61(s, 2H), δ4.50(t, 1H), δ3.35(s, 3H), δ1.26-1.21(m, 1H), δ0.60-0.55(m, 2H), δ0.49-0.39(m, 2H)

[0791]

[0792] Example 53: Synthesis of 3-[(R)-cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0793]

[0794]

[0795] The title compound was obtained (74% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and (R)-cyclopropyl(2-fluorophenyl)methanamine hydrochloride as starting materials.

[0796] 1H-NMR (CDCl3, 400MHz) δ10.78(d, 1H), δ8.67(s, 1H), δ8.36(s, 1H), δ7.31(t, 1H), δ7.22-7.01(m, 1H), δ6.85(s, 1H), δ5.62(s, 2H), δ4.63(t, 1H), δ3.33(s, 3H), δ1.36-1.31(m, 1H), δ0.62-0.56(m, 1H), δ0.50-0.47(m, 2H), δ0.40-0.37(m, 1H)

[0797]

[0798] Example 54: Synthesis of 3-indan-2-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0799]

[0800]

[0801] The title compound was obtained (83% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and indan-2-amine hydrochloride as starting materials.

[0802] 1H-NMR (CDCl3, 400MHz) δ10.25(d, 1H), δ8.65(s, 1H), δ8.16(d, 1H), δ7.26-7.16(m, 4H), δ6.84(s, 1H), δ6.71(d, 1H), δ5.61(s, 2H), δ4.74-4.69(m, 1H), δ3.41-3.35(m, 5H), δ2.92(dd, 2H)

[0803]

[0804] Example 55: Synthesis of 3-indan-1-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0805]

[0806]

[0807] The title compound was obtained (76% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and indan-1-amine as starting materials.

[0808] 1H-NMR (CDCl3, 400MHz) δ10.33(d, 1H), δ8.67(s, 1H), δ8.17(d, 1H), δ7.35(d, 1H), δ7.23-7.21(m, 1H), δ6.88(s, 1H), δ6.72(d, 1H), δ5.62(s, 2H), δ3.43(s, 3H), δ3.00-2.97(m, 1H), δ2.91-2.89(m, 1H), δ2.71-2.67(m, 1H), δ1.92-1.84(m, 1H)

[0809]

[0810] Example 56: Synthesis of 1-methyl-3-tetrazol-1-yl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0811]

[0812]

[0813] The title compound was obtained (87% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and tetralin-1-amine hydrochloride as starting materials.

[0814] 1H-NMR (CDCl3, 400MHz) δ10.28(d, 1H), δ8.65(s, 1H), δ8.15(d, 1H), δ7.39(d, 1H), δ7.17-7.10(m, 3H), δ6.87(s, 1H), δ6.69(d, 1H), δ5.61(s, 2H), δ5.20-5.18(m, 1H), δ3.43(s, 3H), δ2.86-2.79(m, 2H), δ2.16-2.13(m, 1H), δ1.91-1.83(m, 3H)

[0815]

[0816] Example 57: Synthesis of 3-(2,2-dimethylchroman-4-yl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0817]

[0818]

[0819] The title compound was obtained (83% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and 2,2-dimethylchroman-4-amine as starting materials.

[0820] 1H-NMR (CDCl3, 400MHz) δ10.43(d, 1H), δ8.66(s, 1H), δ8.17(d, 1H), δ7.35(d, 1H), δ7.16(t, 1H), δ6.88-6.81(m, 3H), δ6.74(d, 1H), δ5.63(s, 2H), δ5.32-5.26(m, 1H), δ3.44(s, 3H), δ2.31(dd, 1H), δ1.86-1.80(m, 1H), δ1.44(s, 3H), δ1.37(s, 3H)

[0821]

[0822] Example 58: Synthesis of 3-[(1R)-1-cyclohexylethyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0823]

[0824]

[0825] The title compound was obtained (82% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and (1R)-1-cyclohexylethane-1-amine as starting materials.

[0826] 1H-NMR (CDCl3, 400MHz) δ9.97(d, 1H), δ8.65(s, 1H), δ8.27(d, 1H), δ6.85(s, 1H), δ6.73(d, 1H), δ5.62(s, 2H), δ3.88-3.85(m, 1H), δ3.37(s, 3H), δ1.82-1.60(m, 5H), δ1.47-1.45(m, 1), δ1.26-0.97(m, 8H)

[0827]

[0828] Example 59: Synthesis of 3-[(1,4-dimethylcyclohexyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0829]

[0830]

[0831] The title compound was obtained (41% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 1 and 1-(1-methylcyclohexyl)methanamine as starting materials.

[0832] 1H-NMR (CDCl3, 400MHz) δ10.20(s, 1H), δ8.78(s, 1H), δ8.27(d, 1H), δ6.89(s, 1H), δ6.77(d, 1H), δ5.67(s, 2H), δ3.37(s, 3H), δ3.23(d, 2H), δ1.49-1.39(m, 5H), δ1.35-1.26(m, 5H), δ0.93(s, 3H)

[0833]

[0834] Example 60: Synthesis of 2-[(1r,4r)-4-(3-methyl-3-{4-[(2H-tetrazol-2-yl)methyl]-2-pyridyl} ureido)cyclohexyl]-2-propanol

[0835]

[0836]

[0837] The title compound was obtained (51% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 2 and 2-[(1r,4r)-4-aminocyclohexyl]propan-2-ol as starting materials.

[0838] 1H-NMR (CDCl3, 400MHz) δ9.92(d, 1H), δ8.58(s, 1H), δ8.23(d, 1H), δ6.89(s, 1H), δ6.82(d, 1H), δ5.81(s, 2H), δ3.64(m, 1H), δ3.37(s, 3H), δ2.14(d, 2H), δ1.87(d, 2H), δ1.26(m, 5H), δ1.20(s, 6H)

[0839]

[0840] Example 61: Synthesis of 2-[(2-{1-methyl-3-[(1r,4r)-4-(1-fluoro-1-methylethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole

[0841]

[0842]

[0843] Dichloromethane (0.3 M) was added to the compound (1 equivalent) obtained in Example 60 and cooled to -78°C. 1,8-Diazabicycloundec-7-ene (1.5 equivalents) and XtalFluor-E (1.5 equivalents) were added to the solution and warmed to room temperature. The reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The residue was purified under reduced pressure and then purified by column chromatography to obtain the title compound (9% yield).

[0844] 1H-NMR (CDCl3, 400MHz) δ9.95(d, 1H), δ8.58(s, 1H), δ8.23(d, 1H), δ6.89(s, 1H), δ6.82(d, 1H), δ5.81(s, 2H), δ3.65(m, 1H), δ3.37(s, 3H), δ2.14(s, 2H), δ1.84(d, 2H), δ1.63(s, 1H), δ1.52(m, 3H), δ1.33(s, 3H), δ1.22(m, 4H)

[0845]

[0846] Example 62: Synthesis of 3-[(R)-cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0847]

[0848]

[0849] The title compound was obtained (78% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 2 and (R)-cyclopropyl(2-fluorophenyl)methanamine hydrochloride as starting materials.

[0850] 1H-NMR (CDCl3, 400MHz) δ10.89(d, 1H), δ8.58(s, 1H), δ8.33(d, 1H), δ7.33-7.28(m, 1H), δ7.22-7.18(m, 1H), δ7.09-7.00(m, 2H), δ6.90(s, 1H), δ6.87(d, 1H), δ5.82(s, 2H), δ4.64(t, 1H), δ3.34(s, 3H), δ1.34-1.30(m, 1H), δ0.59-0.56(m, 1H), δ0.50-0.47(m, 2H), δ0.39-0.36(m, 1H)

[0851]

[0852] Example 63: Synthesis of 1-methyl-3-[(1S)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0853]

[0854]

[0855] The title compound was obtained (85% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 2 and (1S)-tetralin-1-amine as starting materials.

[0856] 1H-NMR (CDCl3, 400MHz) δ10.40(d, 1H), δ8.57(s, 1H), δ8.12(d, 1H), δ7.39(d, 1H), δ6.82(d, 1H), δ7.17-7.09(m, 3H), δ6.91(s, 1H), δ6.79(d, 1H), δ5.80(s, 2H), δ5.21-5.18(m, 1H), δ3.43(s, 3H), δ2.85-2.76(m, 2H), δ2.16-2.13(m, 1H), δ1.90-1.83(m, 3H)

[0857]

[0858] Example 64: Synthesis of 1-methyl-3-[(1R)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0859]

[0860]

[0861] The title compound was obtained (72% yield) in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 2 and (1R)-tetralin-1-amine as starting materials.

[0862] 1H-NMR (CDCl3, 400MHz) δ10.40(d, 1H), δ8.57(s, 1H), δ8.12(d, 1H), δ7.39(d, 1H), δ6.82(d, 1H), δ7.18-7.09(m, 3H), δ6.91(s, 1H), δ6.79(d, 1H), δ5.80(s, 2H), δ5.21-5.18(m, 1H), δ3.43(s, 3H), δ2.85-2.76(m, 2H), δ2.18-2.13(m, 1H), δ1.90-1.83(m, 3H)

[0863]

[0864] [Reaction Formula 6]

[0865]

[0866]

[0867] Each amine intermediate (1 equivalent) was dissolved in tetrahydrofuran (0.3 M), and each isocyanate (2 equivalents) was added. The reaction solution was stirred at room temperature for 12 hours and the reaction was quenched with water. The reaction solution was then extracted with ethyl acetate. The resulting residue was then purified under reduced pressure and subjected to column chromatography to obtain the desired compound.

[0868]

[0869] Example 65: Synthesis of 1-ethyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea

[0870]

[0871]

[0872] The title compound was obtained (50% yield) in the same manner as in Scheme 6 using the compound obtained in Preparation Example 6 and 1-isocyanato-4-(trifluoromethoxy)benzene as starting materials.

[0873] 1H-NMR (CDCl3, 400MHz) δ12.77(s, 1H), δ8.60(s, 1H), δ8.34(d, 1H), δ7.58(d, 2H), δ7.18(d, 2H), δ6.98(s, 1H), δ6.92(d, 1H), δ5.86(s, 2H), δ4.05(q, 2H), δ1.31(t, 3H)

[0874]

[0875] Example 66: Synthesis of 1-(4-isopropylphenyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0876]

[0877]

[0878] The title compound was obtained (54% yield) in the same manner as in Scheme 6 using the compound obtained in Preparation Example 17 and 1-isocyanato-4-isopropyl-benzene as starting materials.

[0879] 1H-NMR (CDCl3, 400MHz) δddd(s, 1H), δ8.57(s, 1H), δ8.27(d, 1H), δ7.55(s, 1H), δ7.48(d, 2H), δ7.22(d, 2H), δ6.84(d, 1H), δ6.70(s, 1H), δ5.79(s, 2H), δ2.91(m, 1H), δ1.25(d, 6H)

[0880]

[0881] Example 67: Synthesis of 1-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-1H-tetrazole

[0882]

[0883]

[0884] The compound obtained in Preparation Example 19 (1 equivalent), 1H-1,2,3,4-tetrazole (4 equivalents), and potassium carbonate (2 equivalents) were added to acetonitrile (0.1 M) and stirred at 90°C for 12 hours. The reaction solution was cooled to room temperature and filtered to remove potassium carbonate. The filtrate was dried, diluted with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The residue was purified under reduced pressure and then purified by column chromatography to obtain the title compound (27% yield).

[0885] 1H-NMR (CDCl3, 400MHz) δ8.65(s, 1H), δ8.44(s, 1H), δ7.63(t, 1H), δ6.86-6.78(m, 2H), δ5.61(s, 2H), δ3.67-3.59(m, 1H), δ2.07(d, 2H), δ1.85(d, 2H), δ1.25-1.08(m, 5H), δ0.87(s, 9H)

[0886]

[0887] Example 68: Synthesis of 2-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-2H-tetrazole

[0888]

[0889]

[0890] Using the compound obtained in Manufacturing Example 19 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Example 67 (24% yield).

[0891] 1H-NMR (CDCl3, 400MHz) δ8.78(s, 1H), δ8.56(s, 1H), δ7.60(t, 1H), δ6.89(d, 1H), δ6.70(d, 1H), δ5.81(s, 2H), δ3.68-3.60(m, 1H), δ2.07(d, 2H), δ1.86(d, 2H), δ1.34-1.25(m, 2H), δ1.20-1.04(m, 3H), δ0.88(s, 9H)

[0892]

[0893] Example 69: Synthesis of 1-(1-adamantyl)-3-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea

[0894]

[0895]

[0896] The title compound was obtained in the same manner as in Manufacturing Example 17 using the compound obtained in Manufacturing Example 20 as a starting material.

[0897] 1H-NMR (DMSO-d6, 400MHz) δ9.55(s, 1H), δ8.98(s, 1H), δ8.14(d, 1H), δ7.63(s, 1H), δ7.32(s, 1H), δ6.75(d, 2H), δ5.75(s, 2H), δ2.03(s, 3H), δ1.95(s, 6H), δ1.64(s, 6H)

[0898]

[0899] Example 70: Synthesis of 1-(1-adamantyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0900]

[0901]

[0902] Using the compound obtained in Manufacturing Example 20 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Example 69.

[0903] 1H-NMR (CDCl3, 400MHz) δ9.07(s, 1H), δ8.99(s, 1H), δ8.15(d, 1H), δ7.64(s, 1H), δ7.34(s, 1H), δ6.76(d, 1H), δ5.99(s, 2H), δ2.03(s, 3H), δ1.95(s, 6H), δ1.64(s, 6H)

[0904]

[0905] Example 71: Synthesis of 3-methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(2H-1,2,3,4-tetrazol-2-yl)ethyl]pyridin-2-yl}urea

[0906]

[0907]

[0908] The compound (1 equivalent) obtained in Preparation Example 21 was dissolved in dichloromethane (0.3 M), and thionyl chloride (4 equivalents) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solution was depressurized, dissolved in DMF (0.3 M), and then cesium carbonate (1.5 equivalents) and 1H-1,2,3,4-tetrazole (1.5 equivalents) were added. The reaction solution was stirred at 70°C for 12 hours, the reaction was quenched with water, and then extracted with dichloromethane. The residue was purified by column chromatography under reduced pressure to obtain the title compound (25% yield).

[0909] 1H-NMR (CDCl3, 400MHz) δ9.97(d, 1H), δ8.50(s, 1H), δ8.14(d, 1H), δ6.71(d, 2H), δ4.95(t, 2H), δ3.63(m, 1H), δ3.35(m, 5H), δ2.13(d, 2H), δ1.81(d, 2H), δ1.21(m, 5H), δ1.00(m, 1H), δ0.85(s, 9H)

[0910]

[0911] Example 72: Synthesis of 3-methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(1H-1,2,3,4-tetrazol-1-yl)ethyl]pyridin-2-yl}urea

[0912]

[0913]

[0914] Using the compound obtained in Manufacturing Example 21 as a starting material, the title compound, which is a positional isomer, was purified through column chromatography in the same manner as in Example 71 (19% yield).

[0915] 1H-NMR (CDCl3, 400MHz) δ9.86(d, 1H), δ8.36(s, 1H), δ8.16(d, 1H), δ6.65(m, 2H), δ4.70(t, 2H), δ3.64(m, 1H), δ3.32(m, 5H), δ2.11(d, 2H), δ1.81(d, 2H), δ1.19(m, 6H), δ1.00(m, 1H), δ0.86(s, 9H)

[0916]

[0917] Example 73: Synthesis of methyl 2-[1-[[[4-(tetrazol-2-ylmethyl)-2-pyridyl]carbamoylamino]methyl]cyclohexyl]acetate

[0918]

[0919]

[0920] The title compound was obtained in the same manner as in Scheme 5 using the compound obtained in Preparation Example 17 and methyl 2-[1-(aminomethyl)cyclohexyl]acetate as starting materials.

[0921] 1H-NMR (CDCl3, 400MHz) δ8.60 (s, 1H), δ8.15(m, 1H), δ6.78 (s, 1H), δ5.81(s, 2H), δ3.70(m, 3H), δ3.43(d, 2H), δ2.39(s, 2H), δ1.50-1.47(m, 9H)

[0922]

[0923] Example 74: Synthesis of 1-[(2R,4R)-norbornan-2-yl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0924]

[0925]

[0926] The title compound was obtained in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 17 and (2R,4R)-norbornan-2-amine as starting materials.

[0927] 1H-NMR (CDCl3, 400MHz) δ8.64 (s, 1H), δ8.06(br, 1H), δ6.83(m, 1H), δ5.90(m, 2H), δ4.11(m, 1H), δ2.46(s, 1H), δ2.27(s, 1H) δ2.12(m, 1H), δ1.66-1.27(m, 6H), δ0.97-0.86(m, 2H)

[0928]

[0929] Example 75: Synthesis of 1-[1-(1-adamantyl)ethyl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea

[0930]

[0931]

[0932] The title compound was obtained in the same manner as in Scheme 5 using the compound obtained in Manufacturing Example 17 and 1-(1-adamantyl)ethanamine as starting materials.

[0933] 1H-NMR (DMSO-d6, 400MHz) δ9.15(s, 1H), δ9.08(s, 1H) δ8.17(s, 1H), δ7.82(br 1H), δ7.294(s, 1H), δ6.78(s, 1H), δ6.00(s, 2H), δ3.42(m 1H) δ1.95(m, 4H), δ1.67-1.45(m, 11H), δ0.99-0.97(m, 3H)

[0934]

[0935] Experimental example: Pharmacological activity test

[0936] The efficacy of the compound of the example as a glucocerebrosidase activator was tested as follows.

[0937]

[0938] Cell-free assay using imiglucerase

[0939] 484 μL of phosphatidylserine (Avanti Polar Lipids, Inc Cat. No. SKU840032C) dissolved in 1 mg / mL chloroform solution was aliquoted and evaporated with nitrogen for 1 h. To this, 40 mL of 50 mM citric acid / 176 mM potassium phosphate (pH 4.7) and 7.5 μL of Triton X-100 were added and mixed (vortexed) for 5 minutes to prepare mixed micelles of 0.32 mM Triton and 0.37 mol% phosphatidylserine.

[0940] 0.4 μL of 5 mM test compound was dispensed into a 96-well plate, and 100 μL of 50 nM imiglucerase (provided by Isu Abxis) / Sapocin C (EnzoLifescience, ALX-201-262) dissolved in 1 μM 0.32 M Triton / 0.37 mol% reaction buffer was added to the well and reacted at room temperature for 30 minutes. 25 μL of this reaction was aliquoted, mixed with 25 μL of 4 mM 4-methylumbelliferyl-beta-D-glucopyranoside (4-MU, Sigma-Aldrich M3633), and reacted at room temperature for 15 minutes. After 15 minutes, the reaction was terminated with 150 μL of a stop solution of 1 M glycine pH 12.5, and the reaction was confirmed by measuring the fluorescence intensity (excitation: 365 nm, emission: 440 nm) using a SpectraMax M4 or Flitermax (Molecular Devices) instrument.

[0941]

[0942] Measurement of glucocerebrosidase activity in fibroblasts

[0943] Fibroblasts were seeded at 10,000 cells per well in a 96-well cell culture plate and cultured for 1 day in DMEM (Gibco) containing 15% FBS and penicillin / streptomycin at 37°C and 5% CO2. The following day, test compounds were added to the cells and cultured for 3 days. On the 5th day, the culture medium was replaced and the compounds were treated again. On the 7th day of cell culture, the grown cells were washed with 100 μL 37°C PBS, and 20 μL 0.2 M sodium acetate pH 4.0 buffer, 2 μL 37°C PBS, and 25 μL 4-MU solution were added to each well and cultured in a carbon dioxide incubator at 37°C for 1 hour. 150 μL of 0.2 M glycine pH 12 buffer solution was added per well as a stop solution, placed in a carbon dioxide incubator at 37°C for 5 minutes, and the reaction was confirmed by measuring the fluorescence intensity (excitation: 365 nm, emission: 440 nm) using SpectraMax M4 or Filtermax (Molecular Devices).

[0944]

[0945] result

[0946] The measured leucocerebrosidase activity levels are shown in Table 1 below. The results were tested at 10 μM for both cell-free and cell-based tests, and are expressed based on the following criteria.

[0947] ++++: Activation exceeding 90%

[0948] +++: 60% or more - 90% activation

[0949] ++: Over 30% - 60% activation

[0950] +: Activation less than 30%

[0951] ND (not determined): not measured

[0952]

[0953] [Table 1]

[0954]

[0955]

[0956]

Claims

1. A compound of the following chemical formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof: [Chemical Formula 1] In the above chemical formula 1, X is N or CH; R1 and R3 are each independently -H, halo, alkyl or and here R7 is or , and m is 1 or 2; wherein R8 is -H, alkyl, hydroxyalkyl, haloalkyl, dialkylaminocarbonyloxyalkyl or aryl; R2 is -H, halo or alkyl; R4 is -H or alkyl; R5 is -H, alkyl or cycloalkyl; R6 is saturated or partially unsaturated carbocyclyl, aryl or partially unsaturated heterocyclyl; wherein said saturated or partially unsaturated carbocyclyl and aryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and alkoxycarbonylalkyl; n is 0 or 1; The above partially unsaturated heterocyclyl may contain one or more heteroatoms selected from N, O and S, However, at least one of R1 and R3 am.

2. In paragraph 1, X is N or CH; R1 and R3 are each independently -H, halo, C1-C7 alkyl or and here R7 is or , m is 1 or 2; wherein R8 is -H, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyloxy-C1-C7 alkyl or C6-C 10 It's aryl; R2 is -H, halo or C1-C7 alkyl; R4 is -H or C1-C7 alkyl; R5 is -H, C1-C7 alkyl or C3-C 10 It is cycloalkyl; R6 is saturated or partially unsaturated C5-C 12 Carbocyclyl, C6-C 10 Aryl or partially unsaturated 5 to 12 membered heterocyclyl; wherein said saturated or partially unsaturated carbocyclyl and aryl are halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, halo-C1-C7 alkoxy, C3-C 10 which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl and C1-C7alkoxycarbonyl-C1-C7alkyl; n is 0 or 1; The above partially unsaturated heterocyclyl may contain 1 to 3 heteroatoms selected from N, O and S, However, at least one of R1 and R3 A compound characterized by being, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. In paragraph 1, R1 is -H or and here R7 is or , and m is 1 or 2; wherein R8 is -H, C1-C5 alkyl, hydroxy-C1-C5 alkyl, halo-C1-C5 alkyl, di(C1-C5 alkyl)aminocarbonyloxy-C1-C5 alkyl or phenyl; R3 is -H, C1-C5 alkyl or and here R7 is or , m is 1 or 2; wherein R8 is -H or C1-C5 alkyl, However, at least one of R1 and R3 A compound characterized by being, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A compound according to claim 1, characterized in that R2 is -H, halo or C1-C5 alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A compound according to claim 1, characterized in that R4 is -H or C1-C5 alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A compound according to claim 1, characterized in that R5 is -H, C1-C5 alkyl or C3-C8 cycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. In paragraph 1, R6 is saturated or partially unsaturated C6-C 12 Carbocyclyl, phenyl or partially unsaturated 8 to 12 membered heterocyclyl, wherein said saturated or partially unsaturated carbocyclyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl and C1-C7 alkoxycarbonyl-C1-C7 alkyl; wherein said phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, halo-C1-C7 alkyl, halo-C1-C7 alkoxy and C3-C 10 A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the compound can be optionally substituted with one to three substituents selected from the group consisting of cycloalkyl.

8. In paragraph 7, R6 is saturated or partially unsaturated C6-C 12 A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the compound is a carbocyclyl, or a partially unsaturated 8-12 membered heterocyclyl, wherein the saturated or partially unsaturated carbocyclyl may be optionally substituted with 1-3 substituents selected from the group consisting of halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, and C1-C7 alkoxycarbonyl-C1-C7 alkyl.

9. In the 8th paragraph, the saturated or partially unsaturated C6-C of R6 12 A compound characterized in that the carbocyclyl or partially unsaturated 8-12 membered heterocyclyl is cyclohexyl, spiro[2.5]octyl, spiro[3.5]nonyl, adamantyl, norbornanyl, indanyl, tetralinyl or chromanyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is selected from the following group, or a pharmaceutically acceptable salt or stereoisomer thereof: 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 1); 1-[(2-{1-Ethyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 2); 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 3); 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 4); 2-[(2-{1-methyl-3-[(1s,4s)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 5); 1-({2-[3-(4,4-difluorocyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole (compound 6); 2-[(2-{1-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 7); 2-[(2-{1-methyl-3-[(1r,4r)-4-isopropylcyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 8); 1-[(2-{1-methyl-3-(6-spiro[2.5]octyl)ureido}-4-pyridyl)methyl]-1H-tetrazole (compound 9); 1-[(2-{1-methyl-3-(7-spiro[3.5]nonyl)ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 10); 1-Methyl-3-[(4-methylcyclohexyl)methyl]-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 11); 2-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (compound 14); 1-[(2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol (compound 15); 5-Methyl-2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 16); 5-Methyl-1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 17); 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-2H-tetrazol (Compound 18); 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-propyl-1H-tetrazol (Compound 19); 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-2H-tetrazole (Compound 20); 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-5-(trifluoromethyl)-1H-tetrazole (Compound 21); 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 22); {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol (compound 23); {1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazol-5-yl}methanol (Compound 24); [2-({2-[methyl({[(1r,4r)-4-tert-butylcyclohexyl]carbamoyl})amino]pyridin-4-yl}methyl)-2H-1,2,3,4-tetrazol-5-yl]methyl N,N-dimethylcarbamate (Compound 25); 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 26); 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 27); 2-[(5-Fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 28); 1-[(5-Fluoro-2-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyridyl)methyl]-1H-tetrazole (Compound 29); 1-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 45); 2-[(2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 46); 1-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 47); 2-[(5-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 48); 1-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-1H-tetrazole (Compound 49); 2-[(6-methyl-2-{1-methyl-3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-4-pyrimidinyl)methyl]-2H-tetrazole (Compound 50); 1-({2-[3-(4,4-dimethylcyclohexyl)-1-methylureido]-4-pyridyl}methyl)-1H-tetrazole (Compound 51); 3-[(1R)-1-cyclohexylethyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 58); 3-[(1,4-dimethylcyclohexyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 59); 2-[(1r,4r)-4-(3-methyl-3-{4-[(2H-tetrazol-2-yl)methyl]-2-pyridyl} ureido)cyclohexyl]-2-propanol (Compound 60); 2-[(2-{1-methyl-3-[(1r,4r)-4-(1-fluoro-1-methylethyl)cyclohexyl]ureido}-4-pyridyl)methyl]-2H-tetrazole (Compound 61); 1-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-1H-tetrazole (compound 67); 2-[(6-{3-[(1r,4r)-4-(tert-butyl)cyclohexyl]ureido}-2-pyridyl)methyl]-2H-tetrazole (compound 68); 1-(1-adamantyl)-3-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (compound 69); 1-(1-adamantyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (Compound 70); 3-Methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(2H-1,2,3,4-tetrazol-2-yl)ethyl]pyridin-2-yl}urea (Compound 71); 3-Methyl-1-[(1r,4r)-4-tert-butylcyclohexyl]-3-{4-[2-(1H-1,2,3,4-tetrazol-1-yl)ethyl]pyridin-2-yl}urea (Compound 72); Methyl 2-[1-[[[4-(tetrazol-2-ylmethyl)-2-pyridyl]carbamoylamino]methyl]cyclohexyl]acetate (Compound 73); 1-[(2R,4R)-norbornan-2-yl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 74); and 1-[1-(1-adamantyl)ethyl]-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 75).

11. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is selected from the following group, or a pharmaceutically acceptable salt or stereoisomer thereof: 3-(4-Cyclopropylphenyl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 12); 1-Methyl-3-(4-propylphenyl)-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 13); 1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 30); 1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (compound 31); 1-[4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 32); 1-[4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 33); 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 34); 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 35); 1-[6-methyl-4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 36); 1-[6-methyl-4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 37); 1-[6-methyl-4-[(5-methyltetrazol-1-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 38); 1-[6-methyl-4-[(5-methyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 39); 1-[4-[[5-(hydroxymethyl)tetrazol-1-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 40); 1-[4-[[5-(hydroxymethyl)tetrazol-2-yl]methyl]-6-methyl-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 41); 1-Methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 42); 1-Methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 43); 1-[4-[(5-phenyltetrazol-2-yl)methyl]-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 44); 3-[Cyclopropyl(phenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 52); 3-[(R)-Cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 53); 3-[(R)-Cyclopropyl-(2-fluorophenyl)methyl]-1-methyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (Compound 62); 1-Ethyl-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]-3-[4-(trifluoromethoxy)phenyl]urea (Compound 65); and 1-(4-Isopropylphenyl)-3-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 66).

12. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is selected from the following group, or a pharmaceutically acceptable salt or stereoisomer thereof: 3-Indan-2-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 54); 3-Indan-1-yl-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 55); 1-Methyl-3-tetrazol-1-yl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 56); 3-(2,2-dimethylchroman-4-yl)-1-methyl-1-[4-(tetrazol-1-ylmethyl)-2-pyridyl]urea (Compound 57); 1-methyl-3-[(1S)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 63); and 1-Methyl-3-[(1R)-tetrazol-1-yl]-1-[4-(tetrazol-2-ylmethyl)-2-pyridyl]urea (compound 64).

13. A compound according to claim 1, characterized in that the pharmaceutically acceptable salt is nitrate, sulfuric acid salt, hydrobromide, toluenesulfonate, hydrochloride, methanesulfonate or camphorsulfonate, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. A pharmaceutical composition for preventing or treating a disease mediated by beta-glucocerebrosidase, comprising a compound of formula 1 defined in any one of claims 1 to 13 as an active ingredient, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

15. A pharmaceutical composition according to claim 14, characterized in that the disease mediated by the beta-glucocerebrosidase is Parkinson's disease, Gaucher's disease, Lewy body dementia, or synucleinopathy.

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