RU2788740C2 - 2-cyanopyrimidine-4-yl carbamate, or a urea derivative, or its salt and a pharmaceutical composition containing them - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry, namely to a compound of formula 1 or to a compound selected from a group consisting of 1-(4-(2-cyanopyrimidine-4-yl)tetrahydro-2H-piran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea and 1-(1-(2-cyanopyrimidine-4-yl)cyclohexyl)-3-(4'-ethyl-[1,1'-diphenyl]-4-yl)urea, their pharmaceutically acceptable salts, pharmaceutical composition and reagent based on them. In formula 1, A is a chemical bond, -CH₂- or -C(CH₃)₂-, L is -(CH₂)m-O-, -(CH₂)_n-NH-, -CH(CH₃)-NH- or -N(CH₃)-, m is 1 or 2, n is 0, 1 or 2, Ar is an aromatic ring selected from a group consisting of phenyl, phenoxyphenyl, pyridinylphenyl, indazolylphenyl, morphololphenyl, piperazinylphenyl, piperidinylphenyl, pyrazolylphenyl, benzyl-phenyl, phenylaminophenyl, diphenyl, piperazinyl-diphenyl, morpholinyl-diphenyl, naphthyl, benzodioxolyl, furanyl, indazolyl, quinoxalinyl and indanyl, and the aromatic ring is selectively replaced by substituents in the amount of one to three, selected from a group consisting of halogen, cyano, hydroxy, trifluoromethyl, C₁~C₄ alkyl, C₃~C₆ cycloalkyl, C₁~C₄ alkoxy, hydroxy- C₁~C₄ alkyl, C₁~C₄ alkoxy- C₁~C₄ alkyl, hydroxycarbonyl- C₁~C₄ alkyl, C₁~C₄ alkoxycarbonyl C₁~C₄ alkyl, C₁~C₄ alkoxy- C₁~C₄ alkoxy alkyl, alkylcarboxylic- C₁~C₄ alkyl, amino-C₁~C₄ alkoxy, mono - or di- C₁~C₄ alkylamino C₁~C₄ alkoxy, aminosulfonyl, C₁~C₄ alkyl-sulfonyl, trifluoromethysulfonyl, C₃~C₆ cycloalkylcarbonyl, mono - or di- C₁~C₄ alkylamino, C₁~C₄ alkylcarbonylamino, methanesulfonylamido, C₁~C₄ alkylarbonyl, hydroxycarbonyl, mono- or di- C₁~C₄ alkylaminocarbonyl, oxolanyl- C₁~C₄ alkylaminocarbonyl, di- C₁~C₄ alkylamino- C₁~C₄ alkylaminocarbonyl, imidazolyl- C₁~C₄ alkylaminocarbonyl, C₁~C₄ alkoxy- C₁~C₄ alkylaminocarbonyl, C₃~C₆ cycloalkylcarbonyl, pyrrolidinylcarbonyl, triazolyl- C₁~C₄ alkylaminocarbonyl, C₁~C₄ alkoxycarbonyl alkynyl, hydroxycarbonyl- C₂~C₄ alkynyl, hydroxy- C₁~C₄ alkylphenyl- C₁~C₄ alkynyl and C₁~C₄ alkoxy- C₁~C₄ alkylphenoxymethyl.

EFFECT: derivatives of 2-cyanopyrimidine-4-ilcarbamate and urea derivatives that selectively inhibit cathepsin K and can be used in the treatment of osteoporosis.

<Formula 1>

12 cl, 7 tbl, 192 ex

Description

FIELD OF TECHNOLOGY

This invention relates to 2-cyanopyrimidin-4-ylcarbamate, or urea derivatives, or a salt thereof, and a pharmaceutical composition containing them.

BACKGROUND OF THE INVENTION

It is known that cathepsins are lysosomal proteases belonging to the family of papain-like cysteine proteases, including cathepsin B, C, F, H, L, O, S, V, X, W, etc. Among them, cathepsin K is a protease having a pronounced collagenase activity and plays an important role in bone resorption. Cathepsin K is predominantly expressed in osteoclasts, while its expression level is very low in other tissues or cells. In the case of osteoclasts, cathepsin K is approximately 100-fold or more overexpressed compared to other cathepsins L or S.

Cathepsin K is down-regulated by estrogen and up-regulated by nuclear factor kappa B activator receptor ligand (RANKL), nerve growth factor (TNF), vitamin D, parathyroid hormone (PTH), interleukin, and the like. Cathepsin K breaks down type I collagen, which makes up the organic bone matrix. In addition to collagen, cathepsin K also cleaves a number of other proteins in bone or cartilage, such as osteonectin, aggrecan, insulin-like growth factor (IGF)-1, and others, and thus the development of selective inhibitors of cathepsin K may be useful as therapeutic agents. for the treatment of osteoporosis ). For example, International Publication Nos. WO 03/075836, WO 04/076455 and the like disclose cathepsin K inhibitors useful in the treatment of, for example, osteoporosis.

DETAILED DISCLOSURE OF THE INVENTION

TECHNICAL PROBLEM

The present inventors have found that 2-cyanopyrimidin-4-ylcarbamate or a urea derivative or a pharmaceutically acceptable salt has a selective inhibitory activity against cathepsin K, and thus can be successfully used to prevent or treat osteoporosis.

Thus, the object of this invention is the development of 2-cyanopyrimidin-4-ylcarbamate, or a urea derivative, or a pharmaceutically acceptable salt thereof, a method for their preparation and a pharmaceutical composition containing them.

Another object of this invention is the development of a reagent for the inhibition of cathepsin K, containing 2-cyanopyrimidin-4-ylcarbamate, or a urea derivative, or a pharmaceutically acceptable salt thereof.

TECHNICAL SOLUTION

According to an aspect of the present invention, 2-cyanopyrimidin-4-ylcarbamate or a urea derivative or a pharmaceutically acceptable salt thereof is provided.

According to another aspect of the present invention, there is provided a process for the preparation of said compound, or a pharmaceutically acceptable salt thereof.

According to yet another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of osteoporosis, comprising said compound or a pharmaceutically acceptable salt thereof as an active ingredient.

According to yet another aspect of the present invention, a reagent for inhibiting cathepsin K is provided, comprising said compound or a salt thereof.

BENEFICIAL EFFECTS OF THE INVENTION

According to the present invention, it has been found that the compound of the present invention, i. 2-cyanopyrimidin-4-ylcarbamate or a urea derivative or a pharmaceutically acceptable salt thereof has selective cathepsin K inhibitory activity. 2-cyanopyrimidin-4-ylcarbamate or a urea derivative or a pharmaceutically acceptable salt thereof can be successfully used in the prevention or treatment of osteoporosis.

BEST MODE FOR CARRYING OUT THE INVENTION

This invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof:

<Formula 1>

wherein

A represents a chemical bond, -CH ₂ -, -O- or -C (CH ₃ ) ₂ -,

L is -(CH ₂ ) _m -O-, -(CH ₂ ) _n -NH-, -CH(CH ₃ )-NH- or -N(CH ₃ )-,

m is 1 or 2,

n is 0, 1 or 2,

Ar is an aromatic ring selected from the group consisting of phenyl, phenoxyphenyl, pyridinylphenyl, indazolylphenyl, morpholinylphenyl, piperazinylphenyl, piperidinylphenyl, pyrazolylphenyl, benzylphenyl, phenylaminophenyl, diphenyl, piperazinylbiphenyl, morpholinylbiphenyl, naphthyl, benzodioxolyl, furanyl, indanylinoxalinyl, and indaninoxalinyl and

the aromatic ring is optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, C ₁ ~C ₄ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₄ alkoxy, hydroxy-C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy-C ₁ ~C ₄ alkyl, hydroxycarbonyl-C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxycarbonyl-C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy- C ₁ ~C ₄ alkoxy-C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkylcarbonylamino-C ₁ ~C ₄ alkyl, amino-C ₁ ~C ₄ alkoxy, mono- or di-C ₁ ~C ₄ alkylamino-C ₁ ~C ₄ alkoxy, aminosulfonyl, C ₁ ~C ₄ alkylsulfonyl, trifluoromethylsulfonyl, C ₃ ~C ₆ cycloalkylaminosulfonyl, mono- or di-C ₁ ~C ₄ alkylamino, C ₁ ~C ₄ alkylcarbonylamino, methanesulfonylamino, C ₁ ~ C ₄ alkylcarbonyl, hydroxycarbonyl, mono- or di-C ₁ ~C ₄ alkylaminocarbonyl, oxolanyl-C ₁ ~C ₄ alkylaminocarbonyl, di-C ₁ ~C ₄ alkylamino-C ₁ ~C ₄ alkylaminocarbonyl, imidazolyl-C ₁ ~C ₄ alkylaminocarbonyl, C ₁ ~C ₄ alkoxy-C ₁ ~C ₄ alkylaminocarbonyl, C ₃ ~C ₆ cycloalk ylaminocarbonyl, pyrrolidinylcarbonyl, triazolyl-C ₁ ~C ₄ alkylaminocarbonyl, C ₁ ~C ₄ alkoxycarbonyl-C ₂ ~C ₄ alkynyl, hydroxycarbonyl-C ₂ ~C ₄ alkynyl, hydroxy-C ₁ ~C ₄ alkylphenyl-C ₂ ~C ₄ alkynyl and C ₁ ~C ₄ alkoxy-C ₁ ~C ₄ alkyl-phenoxymethyl.

Preferably, in the compound or pharmaceutically acceptable salt thereof, in accordance with this invention, the aromatic ring in is selectively substituted with one to three substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, C ₁ ~C ₄ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₄ alkoxy, hydroxymethyl, methoxymethyl, hydroxycarbonylmethyl, hydroxycarbonylethyl, methoxycarbonylmethyl, methoxyethoxymethyl, acetylaminomethyl, aminoethoxy, methylaminoethoxy, dimethylaminoethoxy, aminosulfonyl, methanesulfonyl, trifluoromethylsulfonyl, cyclopropylaminosulfonyl, mono- or di- _C1- ~ C ₄ alkylamino, acetylamino, methanesulfonylamino, acetyl, hydroxycarbonyl, dimethylaminocarbonyl, oxolanylmethylaminocarbonyl, dimethylaminoethylaminocarbonyl, imidazolylethylaminocarbonyl, methoxyethylaminocarbonyl, cyclopropylaminocarbonyl, pyrrolidinylcarbonyl, triazolylethylaminocarbonyl, methoxycarbonylbutynyl, hydroxymethylcarbonyl, hydroxycarbonyl silt and methoxyethylphenoxymethyl. More preferably, the aromatic ring is substituted with one or two substituents selected from the group consisting of halogen, C ₁ ~C ₄ alkyl and acetyl.

More preferably, in a compound or pharmaceutically acceptable salt thereof according to the invention, A is -CH ₂ -, L is -(CH ₂ ) _n -NH-, n is 0, Ar is an aromatic ring selected from the group, consisting of diphenyl, piperazinyl-biphenyl and morpholinyl-biphenyl, and the aromatic ring is substituted with one or two substituents selected from the group consisting of halogen, C ₁ ~C ₄ alkyl and acetyl.

Particularly preferred in the compound or pharmaceutically acceptable salt thereof according to the invention, A is -CH ₂ -, L is -(CH ₂ ) _n -NH-, n is 0, Ar is a piperazinyl-diphenyl group substituted with one or two substituents selected from the group consisting of halogen and C ₁ ~C ₄ alkyl.

In the compound of this invention, preferred compounds or pharmaceutically acceptable salts thereof include the following compounds:

benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

phenethyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-methoxybenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-cyanobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

3-(trifluoromethyl)benzyl-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-(trifluoromethyl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-methoxybenzyl 1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-(trifluoromethyl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-methoxybenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

naphthalen-1-ylmethyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

4-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

2-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate;

(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)methyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

(4'-(methylsulfonyl)-[1,1'-diphenyl]-3-yl)methyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

(4'-morpholino-[1,1'-diphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

(4'-morpholino-[1,1'-diphenyl]-3-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

4-(6-fluoropyridin-3-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

4-(1-methyl-1H-indazol-6-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-(6-fluoropyridin-3-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

3-(1-methyl-1H-indazol-6-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(ortho-toluyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(meta-toluyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(para-toluyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-fluorobenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-phenylurea;

1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea;

1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-phenoxyphenyl)urea;

4-(2-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)ethyl)benzenesulfonamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methylbenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methylbenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methylbenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethoxybenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-dimethylphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-phenylethyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(piperazin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(furan-3-ylmethyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-fluorobenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-1-ylmethyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)benzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)benzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)benzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethylphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,5-dimethylphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dimethylphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-difluorophenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(5-fluoro-2-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxybenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxybenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxybenzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-hydroxyphenyl)urea;

4-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)benzenesulfonamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-hydroxyphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-1-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-2-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-methyl-1H-indazol-5-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(quinoxalin-6-yl)urea;

1-(benzo[d][1,3]dioxol-5-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxyphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxyphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxyphenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dihydro-1H-inden-5-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea;

1-(4-(2-cyanopyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-phenylurea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,5-dimethylphenyl)urea;

1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)benzyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)phenyl)urea;

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-methylphenyl)urea;

1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;

2-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-4-(trifluoromethyl)benzoic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea;

1-(4-benzylphenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(phenylamino)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-hydroxyphenyl)urea;

1-(2,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-methyl-1-phenylurea;

3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,4-difluoro-5-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(methoxymethyl)-5-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(hydroxymethyl)-5-(trifluoromethyl)phenyl)urea;

1-(3-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(4-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-([1,1'-diphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)urea;

1-([1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-morpholino-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-indazol-6-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-4-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-fluoro-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-fluoro-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-fluoropyridin-3-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-methoxypyridin-3-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-3-yl)phenyl)urea;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1'-diphenyl]-4-carboxamide;

3-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)propanoic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea;

1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(4-bromo-2-fluorophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)benzoic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodo-3-(trifluoromethyl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-fluoro-4-iodophenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-morpholinophenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(piperazin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;

1-(4-(4-(tert-butyl)piperazin-1-yl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclostexyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperidin-1-yl)phenyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1'-diphenyl]-4-carboxamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-biphenyl]-4-sulfonamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-carboxamide;

1-(3'-chloro-4'-(pyrrolidin-1-carbonyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea ;

N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methyl)acetamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

methyl 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetate;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((2-methoxyethoxy)methyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1'-diphenyl]-4-carboxamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1'-diphenyl]-4-carboxamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-carboxylic acid;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)acetamide;

N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)methyl)acetamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-sulfonamide;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methanesulfonamide;

methyl 5-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)pent-4-inoate;

1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2,3'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl) urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-sulfonamide;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)methanesulfonamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)methyl)urea ;

5-(4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)phenyl)pent-4-ic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)urea;

N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide;

N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide;

N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1' -diphenyl]-4-carboxamide;

N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-diphenyl]-4-carboxamide;

N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-diphenyl]-4-carboxamide;

N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1, 1'-diphenyl]-4-carboxamide;

1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; and

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(methylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea.

In the compound according to the invention, more preferred compounds, or pharmaceutically acceptable salts thereof, include the following compounds:

1-([1,1'-diphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)urea;

1-([1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-morpholino-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-fluoro-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-fluoro-[1,1'-diphenyl]-4-yl)urea;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1'-diphenyl]-4-carboxamide;

3-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)propanoic acid;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1'-diphenyl]-4-carboxamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-biphenyl]-4-sulfonamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-carboxamide;

1-(3'-chloro-4'-(pyrrolidin-1-carbonyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea ;

N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methyl)acetamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

methyl 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetate;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((2-methoxyethoxy)methyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1'-diphenyl]-4-carboxamide;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1'-diphenyl]-4-carboxamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetic acid;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-carboxylic acid;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)acetamide;

N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)methyl)acetamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1'-diphenyl]-4-yl) urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-sulfonamide;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methanesulfonamide;

methyl 5-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)pent-4-inoate;

1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2,3'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl) urea;

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-sulfonamide;

N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)methanesulfonamide;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)methyl)urea ;

N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide;

N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide;

N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1' -diphenyl]-4-carboxamide;

N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-diphenyl]-4-carboxamide;

N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-diphenyl]-4-carboxamide;

N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1, 1'-diphenyl]-4-carboxamide;

1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; and

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(methylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea.

In the compound of the present invention, even more preferred compounds, or pharmaceutically acceptable salts thereof, include the following compounds:

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; and

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea.

In the compound according to the invention, particularly preferred compounds, or pharmaceutically acceptable salts thereof, include the following compounds:

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea;

1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea.

The compound of formula 1 according to this invention may be in the form of a pharmaceutically acceptable salt. The salt may be a conventional acid addition salt form, including, for example, salts derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; and salts derived from organic acids such as citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid or aspartic acid. The salt may also be in the form of a conventional metal salt, which includes, for example, salts derived from an alkali metal such as lithium, sodium or potassium; or an alkaline earth metal such as calcium or magnesium. The metal salt form also includes a chromium salt. In addition, the salt may be a salt derived from an organic ligand, such as a quaternary ammonium salt; an amine salt, for example a dicyclohexylamine salt or an N-methyl-D-glucamine salt; or an amino acid salt derived from arginine, lysine, etc.

This invention also provides a process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof. For example, a compound of Formula 1 or a pharmaceutically acceptable salt thereof can be prepared according to the following Reaction Scheme 1.

<Reaction scheme 1>

In Reaction Scheme 1, A, L and Ar are the same as defined above.

In Scheme 1, the starting materials 2,4-dichloropyrimidine and ethyl acetoacetate are commercially available. The reaction between 2,4-dichloropyrimidine and ethyl acetoacetate to obtain a compound of formula 2 can be carried out in the presence of a base such as sodium hydride. This reaction can also be carried out in the presence of one or more solvents selected from the group consisting of tetrahydrofuran and toluene. The reaction can be carried out, for example, at the reflux temperature of the solvent used, but is not limited thereto.

A compound of formula 2 may be reacted with a compound of formula 3 to give a compound of formula 4. The reaction of a compound of formula 2 and a compound of formula 3 may be carried out in the presence of a base such as sodium hydride. This reaction can also be carried out in the presence of one or more solvents selected from the group consisting of dimethylformamide, tetrahydrofuran and toluene. This reaction can be carried out at a temperature in the range from 20°C to 80°C, preferably at a temperature in the range from 50°C to 70°C.

The compound of formula 4 can be subjected to hydrolysis and then subjected to a reaction with a compound of formula 5 to give a compound of formula 6. Hydrolysis can be carried out by reacting a compound of formula 4 with sodium hydroxide, potassium hydroxide, and the like. The hydrolysis can also be carried out in a mixture of alcohol (such as 2-propanol) and water. The reaction between the hydrolysis product and the compound of formula 5 can be carried out in the presence of a base such as diphenylphosphorazidate (DPPA) and triethylamine. This reaction can be carried out in a solvent such as toluene at a temperature in the range from 80°C to 130°C, preferably at a temperature in the range from 100°C to 120°C.

The compound of Formula 6 can be reacted with an alkali metal cyanide such as sodium cyanide to give a compound of Formula 1. This reaction can be carried out in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane (DABCO). This reaction can also be carried out in a solvent such as dimethyl sulfoxide at a temperature in the range from 50°C to 150°C, preferably at a temperature in the range from 50°C to 100°C.

Optionally, Reaction Scheme 1 can additionally carry out a Suzuki reaction, a Sonogashira reaction, an amide coupling reaction, and/or a Mitsunobu reaction.

In addition, a compound of Formula 1 or a pharmaceutically acceptable salt thereof can be prepared according to the following Reaction Scheme 2.

<Reaction scheme 2>

In Scheme 2, A, L and Ar are as defined above and Bn is benzyl.

The compound of formula 4 can be prepared in the same manner as in Reaction Scheme 1.

The compound of formula 4 can be subjected to hydrolysis and then reacted with phenylmethanol and diphenylphosphorazidate to obtain the compound of formula 7. Hydrolysis can be carried out by reacting the compound of formula 4 with sodium hydroxide, potassium hydroxide, and the like. The hydrolysis can also be carried out in a mixture of alcohol (such as 2-propanol) and water. The reaction between the hydrolysis product and diphenylphosphorazidate can be carried out in the presence of a base such as diphenylphosphorazidate (DPPA) and triethylamine. This reaction can be carried out in a solvent such as toluene at a temperature in the range from 80°C to 130°C, preferably at a temperature in the range from 100°C to 120°C.

The compound of formula 7 can be reacted with hydrobromic acid to give the compound of formula 8. This reaction can be carried out in a solvent such as acetic acid at a temperature in the range of 0° C. to 80° C., preferably at a temperature in the range of 0° C to 50°C.

The compound of formula 8 can be reacted with an alkali metal cyanide such as sodium cyanide to give a compound of formula 9. This reaction can be carried out in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane (DABCO). This reaction can also be carried out in a solvent such as dimethyl sulfoxide at a temperature in the range from 50°C to 150°C, preferably at a temperature in the range from 50°C to 100°C.

The compound of formula 9 can be reacted with a compound of formula 10 to obtain a compound of formula 1. The reaction between the compound of formula 9 and the compound of formula 10 can be carried out in a solvent such as pyridine, dichloromethane, and the like at a temperature of in the range from 0°C to 100°C, preferably at a temperature in the range from 0°C to 50°C.

Optionally, Reaction Scheme 2 can additionally carry out a Suzuki reaction, a Sonogashira reaction, an amide coupling reaction, and/or a Mitsunobu reaction.

This invention provides a pharmaceutical composition for the prevention or treatment of osteoporosis containing a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutically effective amount refers to an amount sufficient to effect the prevention or treatment of osteoporosis. For example, a therapeutically effective amount may be from about 1 mg/kg to about 300 mg/kg per day. However, the therapeutically effective amount may be varied according to the age, body weight, susceptibility, symptoms of the patient, or the activity of the compound.

The pharmaceutical composition may contain a pharmaceutically acceptable carrier such as diluents, disintegrants, sweeteners, lubricants or flavoring agents commonly used in the art. The pharmaceutical composition may be in an oral form such as tablets, capsules, powders, granules, suspensions, emulsions or syrups; or in a dosage form for parenteral use, such as injection, in accordance with conventional methods. The dosage form may be in various forms, for example, dosage forms for single use or for multiple use.

The pharmaceutical composition according to this invention may contain, for example, a diluent (eg lactose, corn starch, etc.); a lubricant (eg, magnesium stearate, etc.); emulsifying agent; suspending agent; stabilizer; and/or an isotonic agent. If necessary, the composition additionally contains sweeteners and/or flavor additives.

The composition according to this invention can be used orally or parenterally, including by intravenous, intraperitoneal (intraperitoneal), subcutaneous, rectal and topical application. Thus, the composition according to this invention can be included in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of oral tablets, carriers such as lactose, corn starch and lubricants such as magnesium stearate are commonly used. In the case of oral capsules, lactose and/or dried cornstarch can be used as a diluent. If an aqueous suspension is required for oral administration, the active ingredient may be combined with emulsifying and/or suspending agents. If necessary, you can use some sweeteners and/or flavoring additives. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared; at the same time, it is necessary to adjust the pH of these solutions accordingly and buffer them. When administered intravenously, it is necessary to control the total concentration of solutes to make the drug isotonic. The composition according to this invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, such as saline solution, the pH level of which is 7.4. These solutions can be injected into the patient's bloodstream intramuscularly by local bolus injection.

The compound of formula 1 or a salt thereof can also be used as a reagent for inhibiting cathepsin K activity. Thus, the present invention also provides a reagent for inhibiting cathepsin K containing said compound of formula 1 or a salt thereof.

The following examples and experimental examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

Analyzes of the compounds obtained in the examples below were performed as described below: Analysis of the nuclear magnetic resonance (NMR) spectrum was performed on a Bruker 400 MHz spectrometer and the results of the analysis of chemical shifts are expressed in µg/g (ppm). Analysis by liquid chromatography with mass spectroscopy (LC-MS) was performed using a Shimadzu 2020 system. Column chromatography was performed using a CombiFlash Rf system. The starting materials in each example are known compounds that were synthesized according to the literature or obtained from Sigma-Aldrich, Alfa Aesar or TCI.

Example 1: Benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to LTP ctetrahydrofuran, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (MPLC) to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ =200.45

Stage 2: ethyl 1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (4.9 g, 24.4 mmol) obtained in step 1 was added to dimethylformamide (500 ml) and the resulting mixture was cooled to below 0°C . While maintaining the temperature below 0°C, 60% NaH (2.149 g, 53.7 mmol) and 1,4-dibromobutane (3.21 ml, 26.9 mmol) were added to the mixture. The reaction mixture was stirred at 60° C. for 2 hours and then water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by MPLC (100% hexane-8:2=hexane:ethyl acetate) to give 4.3 g of the title compound (yield: 70%). [M+1] ⁺ =255.

Stage 3: 1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylic acid

Ethyl 1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylate (1.24 g, 4.87 mmol) obtained in step 2 was dissolved in 2-propanol (25 ml) and then 1 M NaOH solution (25 ml) was added ). The reaction mixture was stirred for 100 minutes and then distilled under reduced pressure. The resulting residue was added to a 10% citric acid solution (5 ml) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Stage 4: benzyl-(1-(2-chloropyrimidin-4-yl)cyclopentyl)carbamate

1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylic acid (0.85 g, 3.75 mmol) obtained in step 3, phenylmethanol (2.48 g, 22.5 mmol) and triethylamine (0.862 g, 1.5 mmol) 18 mmol) were added successively to toluene (37.5 ml), after which diphenyl phosphorazidate (1.39 d, 4.88 mmol) was slowly added to the mixture. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and then ice water was added thereto to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 0.56 g of the title compound (yield: 45%).

Stage 5: benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

Benzyl (1-(2-chloropyrimidin-4-yl)cyclopentyl)carbamate (117 mg, 0.354 mmol) obtained in step 4 and NaCN (27 mg, 0.531 mmol) were dissolved in dimethyl sulfoxide (1 ml). DABCO (8 mg, 0.071 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 12 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure to obtain 86.58 mg of the title compound (white solid, yield: 76%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 8.70 (s, 1H), 7.53 (s, 1H), 7.35 (s, 5H), 5.25 (s, 1H), 5, 04 (s, 2H), 2.38-2.30 (m, 2H), 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

Low Resolution Mass Spectrometry (LSMS) (electrospray ionization (ESI)): m/z = 323 [M+H]+

The compounds of examples 2-9 were prepared according to the same procedures as in example 1, using the appropriate substituted alcohol or substituted phenol derivatives instead of phenylmethanol used in step 4 of example 1.

Example 2 4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.72 (d, 1H, J=4.4 Hz), 7.54-7.49 (m, 3H), 7.22 (d, 2H, J = 7.2 Hz), 5.27 (s, 1H), 4.99 (s, 2H), 2.38-2.3 (m, 2H), 2.19-2.13 (m, 2H) , 1.97-1.93 (m, 4H)

Purity by HPLC = 98%

MSNR (ESI): m/z = 402 [M+H]+

Example 3 3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=4.8 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 7.49-7.46 (m, 2H), 7.26-7.25 (m, 2H), 5.22 (s, 1H), 4.99 (s, 2H), 2.38-2.3 (m, 2H), 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 402 [M+H]+

Example 4 phenethyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

¹ H NMR (400 MHz, CDCl ₃ ): 6 8.68 (s, 1H), 7.42 (d, J=5.2 Hz, 1H), 7.31 (m, 2H), 7.25- 7.23(m, 2H), 5.12(s, 1H), 4.27(t, J=6.8Hz, 2H), 2.95-2.92(m, 2H), 2.38 -2.3 (m, 2H), 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 98%

MSNR (ESI): m/z = 337 [M+H]+

Example 5 3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.52 (d, J=3.2 Hz, 1H), 7.24 (s, 1H), 7.14-7 .12 (m, 3H), 5.25 (s, 1H), 4.99 (s, 2H), 2.34 (s, 3H), 2.38-2.3 (m, 2H), 2. 19-2.13(m, 2H), 1.97-1.93(m, 4H)

Purity by HPLC = 98%

MSNR (ESI): m/z = 337 [M+H]+

Example 6 3-methoxybenzyl (1-(2-cyanopyrimidin-4-yl) cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.53 (d, J=4 Hz, 1H), 7.26 (s, 1H), 6.89-6.84 (m, 3H), 5.27 (s, 1H), 4.99 (s, 2H), 3.79 (s, 3H), 2.38-2.3 (m, 2H), 2.19- 2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 353 [M+H]+

Example 7 3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.53 (d, J=5.2 Hz, 1H), 7.32-7.31 (m, 1H), 7 .09-6.98(m, 3H), 5.29(s, 1H), 5.01(s, 2H), 2.38-2.3(m, 2H), 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 341 [M+H]+

Example 8 3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (bs, 1H), 7.52 (d, J=5.2 Hz, 1H), 7.31-7.28 (m, 3H), 7 .19 (s, 1H), 5.28 (s, 1H), 4.99 (s, 2H), 2.38-2.3 (m, 2H), 2.19-2.13 (m, 2H ), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 357 [M+H]+

Example 9 3-cyanobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl) carbamate

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=5 Hz, 1H), 7.6 (d, J=7.8 Hz, 2H), 7.53 (d, J=5 .4 Hz, 2H), 7.49-7.45 (m, 1H), 5.32 (s, 1H), 5.04 (s, 2H), 2.38-2.3 (m, 2H) , 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 348 [M+H]+

Example 10: Benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to tetrahydrofuran (THF, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ =200.45

Stage 2: ethyl 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (4.9 g, 24.4 mmol) obtained in step 1 was added to dimethylformamide (488 ml) and the resulting mixture was cooled to below 0° FROM. While maintaining the temperature below 0°C, 60% NaH (2.149 g, 53.7 mmol) and 1,5-dibromopentane (3.73 ml, 26.9 mmol) were added to the mixture. The reaction mixture was stirred at 60°C for 2 hours and then cooled to room temperature. Water was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 3.8 g of the title compound (yield: 60%). [M+1] ⁺ =269.

Stage 3: 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylic acid

Ethyl 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylate (3.8 g, 14.14 mmol) was dissolved in 2-propanol (70.7 ml) and then 1 M NaOH solution (70.7 ml) was added. The reaction mixture was stirred for 100 minutes and then distilled under reduced pressure. The resulting residue was added to a 10% citric acid solution (15 ml) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Stage 4: benzyl (1-(2-chloropyrimidin-4-yl)cyclohexyl)carbamate

1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylic acid (3.40 g, 14.14 mmol) obtained in step 3, phenylmethanol (9.17 g, 85 mmol) and triethylamine (1.860 g, 18.38 mmol ) was added successively to toluene (141 ml), after which diphenyl phosphorazidate (7.74 d, 31.8 mmol) was slowly added to the mixture. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and then ice water was added thereto to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 3.6 g of the title compound (yield: 74%). [M+1] ⁺ =345.70.

Stage 5: benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate

Benzyl (1-(2-chloropyrimidin-4-yl)cyclohexyl)carbamate (37 mg, 0.108 mmol) obtained in step 4 and NaCN (8 mg, 0.162 mmol) were dissolved in dimethyl sulfoxide (1 ml). DABCO (2.5 mg, 0.022 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 12 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure. The resulting residue was purified by MPLC (100% hexane - 6:4=hexane:ethyl acetate) to give 19.6 g of the title compound (white solid, yield: 54%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.54 (s, 1H), 7.40-7.30 (m, 5H), 5.20 (s, 1H) , 5.02 (s, 2H), 2.12-2.08 (m, 2H), 2.00-1.90 (m, 2H), 1.75-1.57 (m, 4H), 1 .32-1.24 (m, 2H)

Purity by HPLC = 98%

MSNR (ESI): m/z = 337 [M+H]+

The compounds of examples 11-28 were prepared according to the same procedures as in example 10, using the appropriate substituted alcohol or substituted phenol derivatives instead of phenylmethanol used in step 4 of example 10.

Example 11 4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

22.69 mg of the title compound (white solid, yield: 63%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=3.4 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 7.49 (d, J = 8 Hz, 2H), 7.21 (bs, 2H), 5.22 (s, 1H), 4.97 (s, 2H), 2.12-2.08 (m, 2H), 1.91 -1.84(m, 2H), 1.67-1.57(m, 4H), 1.35-1.25(m, 2H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 416 [M+H]+

Example 12 3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

20.37 mg of the title compound (white solid, yield: 46%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (d, J=4 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.47-7.45 (m , 2H), 7.26-7.25 (m, 2H), 5.22 (s, 1H), 4.99 (s, 2H), 2.12-2.08 (m, 2H), 1, 91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 97%

MSNR (ESI): m/z = 416 [M+H]+

Example 13 3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

19.53 mg of the title compound (white solid, yield: 53%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.54 (s, 1H), 7.26 (s, 2H), 7.15-7.14 (m, 2H) , 5.18 (s, 1H), 4.98 (s, 2H), 2.36 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1.84 (m , 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 94%

MSNR (ESI): m/z = 351 [M+H]+

Example 14 3-(trifluoromethyl)benzyl-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate

18.04 mg of the title compound (white solid, yield: 42%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.57-7.56 (m, 2H), 7.54-2.49 (m, 3H), 5.22 ( s, 1H), 5.06 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 98%

MSNR (ESI): m/z = 405 [M+H]+

Example 15 3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

9.16 mg of the title compound (white solid, yield: 26%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.36-7.31 (m, 1H), 7 .1-7.09 (m, 1H), 7.04-7.00 (m, 2H), 5.22 (s, 1H), 5.01 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 94%

MSNR (ESI): m/z = 355 [M+H]+

Example 16 3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

23.1 mg of the title compound (white solid, yield: 59%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=3.5 Hz, 1H), 7.54 (d, J=5.2 Hz, 1H), 7.3 (d, J =4.1 Hz, 3H), 7.2 (bs, 1H), 5.22 (s, 1H), 5.00 (s, 2H), 2.12-2.08 (m, 2H), 1 .91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 96%

MSNR (IER): m/z=371 [M+H] ⁺

Example 17 2-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

21.28 mg of the title compound (white solid, yield: 61%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.54 (s, 1H), 7.27-7.2 (m, 4H), 5.2 (s, 1H) , 5.05 (s, 2H), 2.34 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1 .57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=351 [M+H] ⁺

Example 18 2-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

19.29 mg of the title compound (white solid, yield: 54%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.54 (d, J=4.7 Hz, 1H), 7.36-7.3 (m, 2H), 7 .15 (t, J=7.26 Hz, 1H), 7.07 (t, J=8.84 Hz, 1H), 5.19 (s, 1H), 5.1 (s, 2H), 2 .12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=355 [M+H] ⁺

Example 19 2-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

25.77 mg of the title compound (white solid, yield: 68%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.58-7.56 (m, 2H), 7.36-7.34 (m, 2H), 7.22- 7.18 (m, 1H), 5.25 (s, 1H), 5.12 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 95%

MSNR (IER): m/z=416 [M+H] ⁺

Example 20 2-(trifluoromethyl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate

20.16 mg of the title compound (white solid, yield: 65%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.59-7.52 (m, 3H), 7 .44 (t, J=7.7 Hz, 1H), 5.23 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 405 [M+H] ⁺

Example 21 2-methoxybenzyl (1-(2-cyanopyrimidin-4-yl) cyclohexyl) carbamate

17.00 mg of the title compound (white solid, yield: 62%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 7.55 (s, 1H), 7.34-7.29 (m, 2H), 6.97-6.88 ( m, 2H), 5.18 (s, 1H), 5.09 (s, 2H), 3.83 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1 .84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (ESI): m/z = 367 [M+H] ⁺

Example 22 4-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

19.53 mg of the title compound (white solid, yield: 74%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.21-7.18 (m, 4H), 5 .16 (s, 1H), 4.98 (s, 2H), 2.36 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H ), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 96%

MSNR (IER): m/z=351 [M+H] ⁺

Example 23 4-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

23.47 mg of the title compound (white solid, yield: 55%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.53 (d, J=5.1 Hz, 1H), 7.39-7.30 (m, 2H), 7 .30-7.19(m, 2H), 5.20(s, 1H), 4.98(s, 2H), 2.12-2.08(m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 98%

MSNR (IER): m/z=371 [M+H] ⁺

Example 24 4-(trifluoromethyl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate

18.60 mg of the title compound (white solid, yield: 51%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=3.9 Hz, 1H), 7.63 (d, J=7.8 Hz, 2H), 7.54 (d, J =5.3 Hz, 1H), 7.45(bs, 2H), 5.24(s, 1H), 5.08(s, 2H), 2.12-2.08(m, 2H), 1 .91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=405 [M+H] ⁺

Example 25 4-methoxybenzyl (1-(2-cyanopyrimidin-4-yl) cyclohexyl) carbamate

15.60 mg of the title compound (white solid, yield: 43%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.7 (bs, 1H), 7.52 (bs, 1H), 7.31-7.29 (m, 2H), 6.91-6.9 ( m, 2H), 5.14 (s, 1H), 4.95 (s, 2H), 3.81 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1 .84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=367 [M+H] ⁺

Example 26 Naphthalene-1-ylmethyl (1-(2-cyanopyrimidin-4-yl) cyclohexyl)carbamate

26.53 mg of the title compound (white solid, yield: 74%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (bs, 1H), 8.00 (bs, 1H), 7.91-7.85 (m, 3H), 7.91-7.85 ( m, 2H), 7.5 (d, J=41.7 Hz, 5H), 5.50 (s, 2H), 5.18 (s, 1H), 2.12-2.08 (m, 2H ), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=387 [M+H] ⁺

Example 27 4-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

12.05 mg of the title compound (white solid, yield: 33%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.53 (d, J=5.1 Hz, 1H), 7.31 (s, 2H), 7.05 (t , J=8.4 Hz, 2H), 5.18 (s, 1H), 4.98 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 ( m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 99%

MSNR (IER): m/z=355 [M+H] ⁺

Example 28 2-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl) carbamate

4.67 mg of the title compound (white solid, yield: 9%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.56 (s, 1H), 7.38 (s, 2H), 7.34-7.27 (m, 2H) , 5.24 (s, 1H), 5.14 (s, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1 .57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC = 97%

MSNR (IER): m/z=371 [M+H] ⁺

Example 29: (4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

4-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate (18.66 mg, 0.047 mmol) obtained in Example 2 was dissolved in a mixed solvent of dimethylformamide and water (1:0.02). To this solution were added potassium phosphate (29.6 mg, 0.140 mmol), (4-(methylsulfonyl)phenyl)boronic acid (27.9 mg, 0.140 mmol) and Pd(PPh ₃ ) ₄ (1.343 mg, 0.00465 mmol); and the reaction was carried out at 75° C. overnight. Thereafter, the reaction mixture was cooled to room temperature, water and ethyl acetate were added thereto to quench the reaction, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by column chromatography (methylene chloride/pentanol) and preparative HPLC to obtain 4.82 mg of the title compound (white solid, yield: 22%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=4.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.63 (d, J=7.2 Hz, 2H), 7.57 (d, J=4.8 Hz, 1H), 7.47 (d, J=6 .8 Hz, 2H), 5.34 (s, 1H), 5.11 (s, 2H), 3.11 (s, 3H), 2.38-2.3 (m, 2H), 2.19 -2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC = 96%

MSNR (IER): m/z=477 [M+H] ⁺

Example 30: (4'-(methylsulfonyl)-[1,1'-diphenyl]-3-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (2.001 mg) was prepared according to the same procedures as in Example 29, starting from 3-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate prepared in example 3 (white solid, yield: 9%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 8.02 (d, J=6.6 Hz, 2H), 7.76 (d, J=6.08 Hz, 2H ), 7.59-7.51 (m, 4H), 7.42 (m, 1H), 5.31 (s, 1H), 5.12 (s, 2H), 3.11 (s, 3H) , 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90-1.89 (m, 4H)

Purity by HPLC = 99%

MSNR (IER): m/z=477 [M+H] ⁺

Example 31: (4'-morpholino-[1,1'-diphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (5.58 mg) was prepared following the same procedures as in Example 29 using PdCl ₂ (dppf)-CH ₂ Cl ₂ and (4-morpholinophenyl)boronic acid instead of Pd(PPh ₃ ) ₄ and (4-(methylsulfonyl)phenyl)boronic acid, respectively (white solid, yield: 28%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (bs, 1H), 7.56-7.52 (m, 5H), 7.39 (bs, 2H), 6.99 (d, J= 6.96 Hz, 2H), 5.27 (s, 1H), 5.07 (s, 2H), 3.89 (t, J=3.8 Hz, 4H), 3.22 (t, J= 3.8 Hz, 4H), 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90-1.89 (m, 4H)

Purity by HPLC = 96%

MSNR (IER): m/z=484 [M+H] ⁺

Example 32: (4'-morpholino-[1,1'-diphenyl]-3-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (3.99 mg) was prepared following the same procedures as in Example 29 starting from 3-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate and PdCl ₃ (dppf)-PdCl ₂ (dppf)-CH ₂ Cl ₂ and (4-morpholinophenyl)boronic acid instead of Pd(PPh ₃ ) ₄ and (4-(methylsulfonyl)phenyl)boronic acid, respectively (brown oil, yield: 21%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.52-7.51 (m, 5H), 7.4 (s, 1H), 6.99-6.95 ( m, 3H), 5.36 (s, 1H), 5.09 (s, 2H), 4.02 (s, 3H), 3.89 (t, J=3.84 Hz, 4H), 3, 22 (t, J=3.86 Hz, 4H), 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90-1.89 (m, 4H)

Purity by HPLC = 95%

MSNR (IER): m/z=484 [M+H] ⁺

Example 33 4-(6-Fluoropyridin-3-yl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (6.25 mg) was prepared following the same procedures as in Example 29 starting from 4-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate, obtained in example 2; and using (6-fluoropyridin-3-yl)boronic acid instead of (4-(methylsulfonyl)phenyl)boronic acid (white solid, yield: 38%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (m, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.98 (td, J=2.4 Hz, 4 Hz, 1H), 7.58-7.54 (m, 3H), 7.46-7.45 (m, 2H), 7.02 (dd, J=2.8 Hz, 8.4 Hz, 1H ), 5.33 (s, 1H), 5.10 (s, 2H), 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90- 1.89 (m, 4H)

Purity by HPLC = 99%

MSNR (IER): m/z=418 [M+H] ⁺

Example 34 4-(1-methyl-1H-indazol-6-yl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (5.99 mg) was prepared following the same procedures as in Example 29 starting from 4-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate, obtained in example 2; and using (1-methyl-1H-indazol-6-yl)boronic acid instead of (4-(methylsulfonyl)phenyl)boronic acid, (yield: 36%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (m, 1H), 8.01 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (d , J=7.2 Hz, 2H), 7.56 (s, 1H), 7.46-7.45 (m, 1H), 7.4 (dd, J=1.2 Hz, J=8, 4 Hz, 1H), 7.26(s, 1H), 5.32(s, 1H), 5.11(s, 1H), 4.13(s, 3H), 2.29-2.27( m, 2H), 2.18-2.17 (m, 2H), 1.90-1.89 (m, 4H)

Purity by HPLC = 99%

MSNR (IER): m/z=453 [M+H] ⁺

Example 35 3-(6-Fluoropyridin-3-yl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (6.63 mg) was prepared following the same procedures as in Example 29 starting from 3-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate, obtained in example 3; and using (6-fluoropyridin-3-yl)boronic acid instead of (4-(methylsulfonyl)phenyl)boronic acid. (Yield: 44%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71-8.7 (m, 1H), 8.42 (s, 1H), 7.99-7.95 (m, 1H), 7.57 ( d, J=5.2 Hz, 1H), 7.51 (s, 3H), 7.4 (s, 1H), 7.03 (dd, J=3.2 Hz, J=8.4 Hz, 1H), 5.33 (s, 1H), 5.11 (s, 1H), 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90 -1.89 (m, 4H)

Purity by HPLC = 99%

MSNR (IER): m/z=418 [M+H] ⁺

Example 36 3-(1-methyl-1H-indazol-6-yl)benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate

The title compound (6.22 mg) was prepared following the same procedures as in Example 29 starting from 3-bromobenzyl-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate, obtained in example 3; and using (1-methyl-1H-indazol-6-yl)boronic acid instead of (4-(methylsulfonyl)phenyl)boronic acid. (Yield: 38%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.66 (m, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H ), 7.66-7.64 (m, 2H), 7.54 (m, 2H), 7.51-7.48 (m, 1H), 7.39-7.37 (m, 2H), 5.33 (s, 1H), 5.14 (s, 2H), 4.13 (s, 3H), 2.29-2.27 (m, 2H), 2.18-2.17 (m, 2H), 1.90-1.89 (m, 4H)

Purity by HPLC = 99%

MSNR (IER): m/z=453 [M+H] ⁺

Example 37 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(ortho-tolyl)urea

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to tetrahydrofuran (THF, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ = 200.45

Stage 2: ethyl 1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (4.9 g, 24.4 mmol) obtained in step 1 was added to dimethylformamide (500 ml) and the resulting mixture was cooled to below 0°C . While maintaining the temperature below 0°C, 60% NaH (2.149 g, 53.7 mmol) and 1,4-dibromobutane (3.21 ml, 26.9 mmol) were added to the mixture. The reaction mixture was stirred at 60° C. for 2 hours and then water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by MPLC (100% hexane-8:2=hexane:ethyl acetate) to give 4.3 g of the title compound (yield: 70%). [M+1] ⁺ = 255.

Stage 3: (1-(2-chloropyrimidin-4-yl)cyclopentyl)carboxylic acid

Ethyl 1-(2-chloropyrimidin-4-yl)cyclopentanecarboxylate (1.24 g, 4.87 mmol) obtained in step 2 was dissolved in 2-propanol (25 ml) and then 1 M NaOH solution (25 ml). The reaction mixture was stirred for 100 minutes and then distilled under reduced pressure. The resulting residue was added to a 10% citric acid solution (5 ml) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Stage 4: 1-(1-(2-chloropyrimidin-4-yl)cyclopentyl)-3-(ortho-tolyl)urea

The (1-(2-chloropyrimidin-4-yl)cyclopentyl)carboxylic acid (0.20g, 0.882mmol) obtained in Step 3 and triethylamine (0.201g, 1.98mmol) were dissolved in toluene (2mL) at stirring, and then diphenylphosphoryl azide (0.316 g, 1.15 mmol) was added slowly. The reaction mixture was subjected to interaction at 100°C for 2 hours. As the reaction mixture cooled, ortho-toluidine (0.095 g, 0.882 mmol) was added thereto. The reaction mixture was stirred at room temperature. After completion of the reaction, ice water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 88 mg of the title compound (yield: 30%). [M+1] ⁺ =331

Step 5: 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(ortho-tolyl)urea

1-(1-(2-chloropyrimidin-4-yl)cyclopentyl)-3-(ortho-tolyl)urea (84 mg, 0.254 mmol) obtained in step 4 and NaCN (25 mg, 0.508 mmol) were dissolved in dimethyl sulfoxide (2 ml). DABCO (11 mg, 0.102 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 12 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure. The resulting residue was purified by MPLC (100% hexane - 6:4=hexane:ethyl acetate) to give 37 g of the title compound (white solid, yield: 45%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (d, J=5.2 Hz, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.39-7.32 (m, 2H), 7.24-7.17 (m, 2H), 5.93 (s, 1H), 4.99 (s, 1H), 2.27 (s, 3H), 2.26- 2.22 (m, 2H), 2.16-2.11 (m, 2H), 1.89-1.80 (m, 4H)

Purity by HPLC = 93.6%

MSNR (IER): m/z=322 [M+H] ⁺

The compounds of examples 38-83 were prepared according to the same procedures as in example 37, using the appropriate amines instead of ortho-toluidine used in step 4 of example 37.

Example 38 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(meta-tolyl)urea

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=5.2 Hz, 1H), 7.64 (d, J=5.2 Hz, 1H), 7.23-7.19 (m, 2H), 7.02-6.93 (m, 2H), 6.32 (s, 1H), 5.22 (s, 1H), 2.27 (s, 3H), 2.26- 2.22 (m, 2H), 2.18-2.11 (m, 2H), 1.90-1.80 (m, 4H)

15.3 mg (white solid, yield: 44%)

Purity by HPLC = 100%

MSNR (IER): m/z=322 [M+H] ⁺

Example 39 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(para-tolyl)urea

21.6 mg (white solid, yield: 26.8%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=5.2 Hz, 1H), 7.64 (d, J=5.2 Hz, 1H), 7.15-7.10 (m, 4H), 6.21 (s, 1H), 5.13 (s, 1H), 2.30 (s, 3H), 2.28-2.24 (m, 2H), 2.18- 2.13(m, 2H), 1.89-1.83(m, 4H)

Purity by HPLC = 85%

MSNR (IER): m/z=322 [M+H] ⁺

Example 40 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(fluorobenzyl)urea

19.6 mg (white solid, yield: 69.7%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=5.6 Hz, 1H), 7.56 (d, J=5.6 Hz, 1H), 7.14-7.02 (m, 4H), 4.81 (s, 1H), 4.74 (s, 1H), 4.37 (s, 2H), 2.27-2.24 (m, 2H), 2.15- 2.10(m, 2H), 1.89-1.83(m, 4H)

Purity by HPLC = 92%

MSNR (IER): m/z=340 [M+H] ⁺

Example 41 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-phenylurea

¹ H NMR (500 MHz, DMSO) δ 8.89 (d, J=5.4 Hz, 1H), 8.54 (s, 1H), 7.85 (d, J=5.4 Hz, 1H) , 7.30 (d, J=8.0 Hz, 2H), 7.19 (t, J=7.4 Hz, 2H), 6.97 (s, 1H), 6.88 (t, J= 7.3 Hz, 1H), 2.19 - 2.15 (m, 2H), 2.08 - 2.05 (m, 2H), 1.89 - 1.78 (m, 4H). MSNR (IER): m/z=308.1 [M+H] ⁺

Example 42: 1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea

¹ H NMR (500 MHz, DMSO) δ 8.87 (d, J=5.4 Hz, 1H), 7.76 (d, J=5.4 Hz, 1H), 7.33-7.29 ( m, 2H), 7.23-7.20 (m, 3H), 6.76 (s, 1H), 6.88 (m, 1H), 4.15 (d, J=6.0 Hz, 1H ), 2.14 - 2.09 (m, 2H), 2.04 - 2.00 (m, 2H), 1.80 - 1.74 (m, 4H). MSNR (ESI): m/z = 322.2 [M+H] ⁺

Example 43: 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea

¹ H NMR (500 MHz, DMSO) δ 8.86 (d, J=5.4 Hz, 1H), 7.75 (d, J=5.4 Hz, 1H), 6.84 (d, J= 7.9 Hz, 1H), 6.75 (m, 2H), 6.68 (m, 1H), 6.35 (m, 1H), 5.97 (s, 2H), 4.04 (d, J=6.0 Hz, 1H), 2.14-2.09 (m, 2H), 2.04-2.00 (m, 2H), 1.80-1.74 (m, 4H). MSNR (ESI): m/z = 366.2 [M+H] ⁺

Example 44 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-phenoxyphenyl)urea

¹ H NMR (500 MHz, DMSO) δ 8.89 (d, J=5.4 Hz, 1H), 8.87 (s, 1H), 7.85 (d, J=5.4 Hz, 1H) , 7.31 - 7.36 (m, 4H), 7.13 (s, 1H), 7.05 (m, 1H), 6.91 - 6.88 (m, 4H), 2.20 - 2 .14 (m, 2H), 2.09 - 2.05 (m, 2H), 1.85 - 1.77 (m, 4H). MSNR (ESI): m/z=400.2 [M+H] ⁺

Example 45 4-(2-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)ethyl)benzenesulfonamide

¹ H NMR (500 MHz, DMSO) δ 8.86 (d, J=5.4 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.63 (d, J= 5.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.32 (s, 2H), 6.72 (s, 1H), 6.01 (m, 1H) , 3.22-3.18 (m, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.09-2.06 (m, 2H), 1.98-1.76 (m, 2H), 1.76-1.74 (m, 4H). MSNR (ESI): m/z=415.2 [M+H] ⁺

Example 46 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methylbenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5.3 Hz, 1H), 7.60 (d, J=5.3 Hz, 1H), 7.24-7, 12 (m, 5H), 4.83 (s, 1H), 4.55 (t, J=5.7 Hz, 1H), 4.30 (d, J=5.5 Hz, 2H), 2, 30 (s, 3H), 2.28-2.18 (m, 2H), 2.18-2.07 (m, 2H), 1.89-1.78 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 47 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methylbenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.68 (d, J=5.4 Hz, 1H), 7.57 (d, J=5.3 Hz, 1H), 7.23 (d, J=7.6Hz, 1H), 7.07(q, J=7.9Hz, 3H), 4.90(s, 1H), 4.78(t, J=5.8Hz, 1H) , 4.26 (d, J=5.7 Hz, 2H), 2.34 (s, 3H), 2.29 - 2.17 (m, 2H), 2.17 - 2.04 (m, 2H ), 1.92-1.70 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 48 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methylbenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5.4 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 7.16 (s, 4H), 4.80 (s, 1H), 4.68 (t, J=5.8 Hz, 1H), 4.26 (d, J=5.7 Hz, 2H), 2.34 (s, 3H), 2.23 (q, J=7.7, 7.1 Hz, 2H), 2.16-2.05 (m, 3H), 1.91-1.74 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 49 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethoxybenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 6.88-6, 75 (m, 3H), 4.90 (s, 1H), 4.75 (t, J=5.7 Hz, 1H), 4.23 (d, J=5.7 Hz, 2H), 3. 88 (s, 3H), 3.86 (s, 3H), 2.31-2.16 (m, 2H), 2.11 (dq, J=12.6, 4.8, 3.6 Hz, 2H), 1.91-1.70 (m, 4H). MSNR (ESI): m/z=382.2 [M+H] ⁺

Example 50 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-dimethylphenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.73 (d, J=5.3 Hz, 1H), 7.63 (d, J=5.3 Hz, 1H), 7.19 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 5.87 (s, 1H), 4.97 (s, 1H), 2.31 (d, J=26.2 Hz, 7H), 2.19-2.08 (m, 2H), 1.94-1.77 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 51 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-phenylethyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.64 (d, J=5.4 Hz, 1H), 7.46 (d, J=5.4 Hz, 1H), 7.42-7, 35 (m, 2H), 7.35-7.28 (m, 3H), 4.76-4.61 (m, 3H), 2.25-2.10 (m, 2H), 2.08- 1.91 (m, 3H), 1.85-1.71 (m, 2H), 1.71-1.51 (m, 3H), 1.46 (d, J=6.6 Hz, 3H) . MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 52 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(piperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.71 (d, J=5.3 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 6.81 (d, 2H), 6.66 (d, 2H), 5.01 (s, 1H), 3.51 (t, 4H), 3.02 (t, J=5.1 Hz, 4H), 2.37- 2.22 (m, 2H), 2.22-2.08 (m, 3H), 1.98-1.77 (m, 5H). MSNR (ESI): m/z=392.2 [M+H] ⁺

Example 53 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(furan-3-ylmethyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.36 (dd, J=1.8, 0.9 Hz, 1H), 6.33 (dd, J=3.2, 1.9 Hz, 1H), 6.23-6.11 (m, 1H), 4.90 (s, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.30 (d, J=5.7 Hz, 2H), 2.34-2.19 (m, 2H) , 2.19-2.05 (m, 2H), 1.92-1.78 (m, 4H). MSNR (IER): m/z=312.1 [M+H] ⁺

Example 54 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-fluorobenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.71 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.25-7, 20 (m, 2H), 7.10-6.92 (m, 2H), 4.81 (s, 1H), 4.67 (d, J=6.2 Hz, 1H), 4.28 (d , J=5.8 Hz, 2H), 2.31-2.20 (m, 2H), 2.20-2.08 (m, 2H), 1.91-1.78 (m, 4H). MSNR (ESI): m/z=340.2 [M+H] ⁺

Example 55: 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalene-1-ylmethyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.67 (d, J=5.3 Hz, 1H), 8.00-7.93 (m, 1H), 7.92-7.86 (m , 1H), 7.86-7.78 (m, 1H), 7.58 (d, J=5.3 Hz, 1H), 7.56-7.49 (m, 2H), 7.48- 7.39 (m, 2H), 4.77 (d, J=5.6 Hz, 3H), 4.63 (d, J=5.9 Hz, 1H), 2.33-2.20 (m .2H), 2.16-2.05 (m, 2H), 1.91-1.70 (m, 4H).

MSNR (IER): m/z=372.2 [M+H] ⁺

Example 56 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)benzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.68 (d, J=5.4 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.60-7, 48 (m, 3H), 7.39 (t, J=7.5 Hz, 1H), 4.88 (s, 1H), 4.83 (t, J=6.2 Hz, 1H), 4. 53-4.44 (m, 2H), 2.31-2.19 (m, 2H), 2.17-2.06 (m, 2H), 1.90-1.78 (m, 4H). MSNR (IER): m/z=390.1 [M+H] ⁺

Example 57 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)benzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.3 Hz, 1H), 7.53 (dd, J=7.5, 2.0 Hz, 1H), 7.50-7.39 (m, 3H), 5.01 (s, 1H), 4.93 (t, J=6.0 Hz, 1H ), 4.36 (d, J=5.9 Hz, 2H), 2.31-2.18 (m, 2H), 2.18-2.04 (m, 2H), 1.95-1, 75 (m, 4H). MSNR (IER): m/z=390.1 [M+H] ⁺

Example 58 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)benzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.72 (d, J=5.4 Hz, 1H), 7.64-7.56 (m, 3H), 7.37 (d, J=8 .0 Hz, 2H), 4.85 (s, 1H), 4.75 (d, J=5.6 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 2, 29-2.20 (m, 2H), 2.16 (d, J=13.4 Hz, 2H), 1.87 (d, J=7.7 Hz, 4H). MSNR (IER): m/z=390.1 [M+H] ⁺

Example 59 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.72 (d, J=5.4 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.67-7, 57 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 6.53 (s, 1H), 5. 26 (s, 1H), 2.38-2.25 (m, 2H), 2.25-2.11 (m, 2H), 1.98-1.80 (m, 4H). MSNR (ESI): m/z=376.1 [M+H] ⁺

Example 60 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.3 Hz, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H) , 6.57 (s, 1H), 5.23 (s, 1H), 2.37-2.16 (m, 4H), 1.97-1.84 (m, 4H). MSNR (ESI): m/z=376.1 [M+H] ⁺

Example 61 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.4 Hz, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.53 (d, J=8.6Hz, 2H), 7.41(d, J=8.4Hz, 2H), 6.65(s, 1H), 5.29(s, 1H), 2.39-2, 19 (m, 4H), 2.01-1.80 (m, 4H). MSNR (ESI): m/z=376.1 [M+H] ⁺

Example 62 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethylphenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5.4 Hz, 1H), 7.63 (d, J=5.3 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.95 (dd, J=8.1, 2.3 Hz, 1H), 6.30 ( s, 1H), 5.24 (s, 1H), 2.32-2.19 (m, 8H), 2.19-2.10 (m, 2H), 1.95-1.79 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 63 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,5-dimethylphenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.71 (d, J=5.3 Hz, 1H), 7.64 (d, J=5.4 Hz, 1H), 6.87 (s, 2H), 6.77 (s, 1H), 6.31 (s, 1H), 5.25 (s, 1H), 2.29 (m, 8H), 2.21-2.12 (m, 2H ), 1.95-1.79 (m, 4H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 64 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dimethylphenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5.3 Hz, 1H), 7.61 (d, J=5.3 Hz, 1H), 7.20-7, 08 (m, 3H), 6.03 (s, 1H), 4.99 (s, 1H), 2.34 (s, 3H), 2.23 (s, 5H), 2.15-2.04 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.73 (m, 2H). MSNR (ESI): m/z=336.2 [M+H] ⁺

Example 65 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-difluorophenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.3 Hz, 1H), 7.85-7.76 (m, 1H), 7.66 (d, J=5 .4 Hz, 1H), 7.05-6.92 (m, 1H), 6.69-6.55 (m, 2H), 5.25 (s, 1H), 2.38-2.27 ( m, 2H), 2.27-2.18 (m, 2H), 1.96-1.89 (m, 4H). MSNR (ESI): m/z=344.1 [M+H] ⁺

Example 66 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.3 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J=5.4 Hz, 1H), 7.34 (d, J=1.4 Hz, 2H), 6.09 (s, 1H), 5.12 (s, 1H), 2.34 (s, 3H), 2.32- 2.16 (m, 4H), 1.91 (q, J=3.5 Hz, 4H). MSNR (IER): m/z=390.1 [M+H] ⁺

Example 67 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(5-fluoro-2-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.4 Hz, 1H), 7.82 (dd, J=10.9, 2.4 Hz, 1H), 7, 63 (d, J=5.4 Hz, 1H), 7.59-7.50 (m, 1H), 6.83 (t, J=8.2 Hz, 1H), 6.68 (s, 1H ), 5.34 (s, 1H), 2.41-2.28 (m, 2H), 2.28-2.16 (m, 2H), 2.00-1.87 (m, 4H). MSNR (ESI): m/z=394.1 [M+H] ⁺

Example 68 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxybenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.62 (d, J=5.4 Hz, 1H), 7.51 (d, J=5.4 Hz, 1H), 7.31-7, 19 (m, 2H), 6.98-6.86 (m, 2H), 4.95 (s, 1H), 4.92 (t, J=7.2 Hz, 1H), 4.28 (d , J=5.7 Hz, 2H), 3.86 (s, 3H), 2.31-2.20 (m, 2H), 2.14-2.04 (m, 2H), 1.91- 1.72 (m, 4H). MSNR (ESI): m/z=356.2 [M+H] ⁺

Example 69 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxybenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5.4 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 7.31-7, 21 (m, 3H), 6.88-6.75 (m, 3H), 4.87 (s, 1H), 4.76 (t, J=5.9 Hz, 1H), 4.28 (d , J=5.5 Hz, 2H), 3.80 (s, 3H), 2.31-2.19 (m, 2H), 2.15-2.05 (m, 2H), 1.92- 1.71 (m, 4H). MSNR (ESI): m/z=356.2 [M+H] ⁺

Example 70: 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxybenzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.68 (d, J=5.3 Hz, 1H), 7.57 (d, J=5.3 Hz, 1H), 7.18 (d, 2H), 6.88 (d, 2H), 4.89 (s, 1H), 4.75 (t, J=5.6 Hz, 1H), 4.23 (d, J=5.4 Hz, 2H), 3.81 (s, 3H), 2.30-2.18 (m, 2H), 2.15-2.03 (m, 2H), 1.91-1.73 (m, 4H) . MSNR (ESI): m/z=356.2 [M+H] ⁺

Example 71 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-hydroxyphenyl)urea

2.21 mg of the title compound (white solid, yield: 46%)

¹ H NMR (400 MHz, MeOD) δ 8.79(d, J=5.4 Hz, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.04 (t, J= 8.08 Hz, 1H), 6.87 (t, J=2.18 Hz, 1H), 6.72-6.7 (m, 1H), 6.44-6.41 (m, 1H), 2.38-2.3 (m, 2H), 2.19-2.13 (m, 2H), 1.97-1.93 (m, 4H)

Purity by HPLC=94%

MSNR (IER): m/z=324 [M+H] ⁺

Example 72 4-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)benzenesulfonamide

21.60 mg of the title compound (white solid, yield: 47%)

¹ H NMR (400 MHz, MeOD) δ 8.80 (d, J=5.4 Hz, 1H), 7.83 (d, J=5.4 Hz, 1H), 7.80-7.75 ( m, 2H), 7.51-7.45 (m, 2H), 2.40-2.29 (m, 2H), 2.24-2.14 (m, 2H), 2.00-1, 91 (m, 4H)

Purity by HPLC=100%

MSNR (IER): m/z=387 [M+H] ⁺

Example 73 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-hydroxyphenyl)urea

4.03 mg of the title compound (white solid, yield: 13%)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.82 (d, J=5.4 Hz, 1H), 8.00 (s, 1H), 7.77 -7.72 (m, 2H), 7.56 (s, 1H), 6.72 (dd, J=7.9, 1.5 Hz, 1H), 6.64 (td, J=7.6 , 1.7 Hz, 1H), 6.55 (td, J=7.7, 1.5 Hz, 1H), 2.15-2.04 (m, 2H), 2.02-1.94 ( m, 2H), 1.80-1.67 (m, 4H)

Purity by HPLC=99%

MSNR (IER): m/z=324 [M+H] ⁺

Example 74 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalene-1-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.4 Hz, 1H), 8.70 (s, 1H), 8.12 (d, J=8.4 Hz , 1H), 7.95-7.84 (m, 3H), 7.64-7.49 (m, 3H), 7.43 (s, 1H), 7.37 (t, J=7.9 Hz, 1H), 2.31-2.19 (m, 2H), 2.19-2.08 (m, 2H), 1.98-1.79 (m, 4H). 358 [M+H] ⁺

Example 75 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalene-2-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.4 Hz, 1H), 8.82 (s, 1H), 7.97 (d, J=2.1 Hz , 1H), 7.90 (d, J=5.4 Hz, 1H), 7.77 (d, J=8.6 Hz, 2H), 7.70 (d, J=8.2 Hz, 1H ), 7.44-7.28 (m, 3H), 7.12 (s, 1H), 2.29-2.16 (m, 2H), 2.16-2.06 (m, 2H), 1.92-1.77 (m, 4H). 358 [M+H] ⁺

Example 76 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-methyl-1H-indazol-5-yl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.72 (d, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.65 (s, 2H), 7.48- 7.33 (m, 2H), 6.44 (s, 1H), 5.16 (s, 1H), 4.07 (s, 3H), 2.40-2.11 (m, 3H), 2 .06-1.94 (m, 1H), 1.94-1.76 (m, 4H). 362 [M+H] ⁺

Example 77 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(quinoxalin-6-yl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.80-8.73 (m, 3H), 8.03 (d, J=9.6 Hz, 1H), 7.98-7.86 (m , 2H), 7.73 (d, J=5.3 Hz, 1H), 7.26 (s, 1H), 5.78 (s, 1H), 2.44-2.22 (m, 4H) , 2.02-1.87 (m, 4H). 360 [M+N] ⁺

Example 78: 1-(benzo[d][1,3]dioxol-5-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.73 (d, J=5.3 Hz, 1H), 7.65 (d, J=5.3 Hz, 1H), 6.86 (d, J=2.2Hz, 1H), 6.78(d, J=8.2Hz, 1H), 6.67(dd, J=8.3, 2.2Hz, 1H), 6.37( s, 1H), 5.99 (s, 2H), 5.25 (s, 1H), 2.34-2.24 (m, 2H), 2.22-2.12 (m, 2H), 1 .94-1.76 (m, 4H). 352 [M+H] ⁺

Example 79 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxyphenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 7.93 (d, J=8.0 Hz , 1H), 7.83 (d, J=5.5 Hz, 1H), 7.64 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.87 (t , J=7.7 Hz, 1H), 6.77 (t, J=7.7 Hz, 1H), 3.87 (s, 3H), 2.26-2.13 (m, 2H), 2 .11-2.02 (m, 2H), 1.92-1.75 (m, 4H). 338 [M+H] ⁺

Example 80 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxyphenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=5.4 Hz, 1H), 8.62 (s, 1H), 7.85 (d, J=5.4 Hz , 1H), 7.10 (t, J=8.1 Hz, 1H), 7.06-7.00 (m, 2H), 6.87-6.74 (m, 1H), 6.47 ( dd, J=8.2, 2.5 Hz, 1H), 3.68 (s, 3H), 2.24-2.14 (m, 2H), 2.13-2.02 (m, 2H) , 1.89-1.75 (m, 4H). 338 [M+H] ⁺

Example 81 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxyphenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.78 (d, J=5.4 Hz, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.38 (t , J=7.9 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.23-7.14 (m, 2H), 6.87-6.78 (m, 2H), 3.76 (s, 3H), 2.43-2.26 (m, 2H), 2.25-2.11 (m, 2H), 2.04-1.86 (m, 4H) . 338 [M+H] ⁺

Example 82 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dihydro-1H-inden-5-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.4 Hz, 1H), 8.47 (s, 1H), 7.84 (d, J=5.4 Hz , 1H), 7.27 (d, J=1.9 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.00-6.92 (m, 2H), 2 .76 (q, J=7.0 Hz, 4H), 2.24-2.13 (m, 2H), 2.12-2.02 (m, 2H), 1.96 (quintet, J=7 .4 Hz, 2H), 1.82-1.75 (m, 4H). 348 [M+H] ⁺

Example 83: 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.66 (d, J=5.2 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.69 (t , J=5.2 Hz, 1H), 7.25 (s, 1H), 7.22-7.09 (m, 1H), 2.40-2.29 (m, 2H), 2.24- 2.14 (m, 2H), 2.00-1.91 (m, 4H) ppm. Purity by HPLC=99%, MSNR (ESI): m/z 394 [M+H] ⁺

Example 84 1-(1-(2-cyanopyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to tetrahydrofuran (THF, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (MPLC) to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ =200.45

Stage 2: ethyl 1-(2-chloropyrimidin-4-yl)-4,4-dimethylcyclohexanecarboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (448 g, 2.24 mmol) obtained in step 1 was added to dimethylformamide (15 ml) and the resulting mixture was cooled to below 0°C. While maintaining the temperature below 0°C, 60% NaH (179 g, 4.48 mmol) and 1,5-dibromo-3,3-dimethylpentane (607 mg, 2.35 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 15 hours and then water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 46 mg of the title compound (yield: 7%). [M+1] ⁺ =296.

Stage 3: 1-(2-chloropyrimidin-4-yl)-4,4-dimethylcyclohexanecarboxylic acid

Ethyl 1-(2-chloropyrimidin-4-yl)-4,4-dimethylcyclopentanecarboxylate (53 mg, 0.18 mmol) obtained in step 2 was dissolved in 2-propanol (2 ml) and then a 2 M solution was added NaOH (0.45 ml). The reaction mixture was stirred at room temperature for 3 hours, and then water (2 ml) was added thereto. The reaction mixture was acidified by adding 10% acetic acid solution (15 ml) and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Stage 4: 1-(1-(2-chloropyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea

(1-(2-Chloropyrimidin-4-yl)-4,4-dimethylcyclohexanecarboxylic acid (46 mg, 0.17 mmol) obtained in step 3 and triethylamine (38 mg, 0.38 mmol) were dissolved in toluene (1 .5 mL) with stirring, and then diphenylphosphoryl azide (60 mg, 0.22 mmol) was added slowly. The reaction mixture was reacted at 100°C for 2 hours. mg, 0.85 mmol) The reaction mixture was reacted with stirring at room temperature After completion of the reaction, ice water was added to quench the reaction The reaction mixture was extracted with ethyl acetate The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate to remove moisture and then distilled under reduced pressure The resulting residue was purified by HPLC to obtain 6 mg of the title compound (yield: 10%) [M+1] ⁺ =387

Step 5: 1-(1-(2-cyanopyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea

1-(1-(2-Chloropyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea (6 mg, 0.015 mmol) obtained in step 4 and NaCN (1, 5 mg, 0.031 mmol) was dissolved in dimethyl sulfoxide (1 ml). DABCO (0.7 mg, 0.0062 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 15 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 5.4 mg of the title compound (yield: 83%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J=5.4 Hz, 1H), 7.79 (s, 1H), 7.78 (d, J=5.5 Hz , 1H), 7.50-7.41 (m, 1H), 7.07 (s, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.68-6.55 ( m, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.08-2.03 (m, 2H), 1.83-1.68 (m, 2H), 1 .68-1.46 (m, 4H), 0.87 (s, 6H); MS m/z: 378 [M+H] ⁺

Example 85 1-(4-(2-cyanopyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to tetrahydrofuran (THF, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ =200.45

Stage 2: ethyl 4-(2-chloropyrimidin-4-yl)-tetrahydro-2H-pyran-4-carboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (200 mg, 0.997 mmol) obtained in step 1 was added to dimethylformamide (10 ml) and the resulting mixture was cooled to below 0°C. While maintaining the temperature below 0°C, 60% NaH (88 mg, 2.19 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (254 mg, 1.09 mmol) were added to the mixture. The reaction mixture was stirred at 60° C. for 2 hours and then water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 200 mg of the title compound (yield: 72%). [M+1] ⁺ =271

Stage 3: 4-(2-chloropyrimidin-4-yl)-tetrahydro-2H-pyran-4-carboxylic acid

Ethyl 4-(2-chloropyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate (200 mg, 0.718 mmol) obtained in step 2 was dissolved in 2-propanol (4 ml) and then a 1 M solution was added NaOH (4 ml). The reaction mixture was stirred at room temperature for 15 hours, and then water (2 ml) was added thereto. The reaction mixture was acidified by adding 10% acetic acid solution (20 ml) and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Step 4: 1-(4-(2-chloropyrimidin-4-yl)-tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea

(4-(2-Chloropyrimidin-4-yl)-tetrahydro-2H-pyran-4-carboxylic acid (174 mg, 0.718 mmol) obtained in Step 3 and triethylamine (165 mg, 1.61 mmol) were dissolved in toluene (4 ml) with stirring, and then diphenylphosphoryl azide (268 mg, 0.933 mmol) was slowly added.The reaction mixture was reacted at 50°C for 10 minutes.As the reaction mixture was slowly cooled, 4-fluoro-3-(trifluoromethyl )aniline (193 mg, 1.08 mmol) The reaction mixture was reacted at 110°C for 5 hours After completion of the reaction, ice water was added to quench the reaction The reaction mixture was extracted with ethyl acetate The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate to remove moisture, and then distilled under reduced pressure The resulting residue was purified by HPLC to obtain 20 mg of the title compound (yield: 7%) [M+1] ⁺ =419

Step 5: 1-(4-(2-cyanopyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea

1-(4-(2-Chloropyrimidin-4-yl)-tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (20 mg, 0.047 mmol) obtained in step 4, and NaCN (4.5 mg, 0.093 mmol) was dissolved in dimethyl sulfoxide (2 ml). DABCO (21 mg, 0.018 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 15 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 3.20 mg of the title compound (yield: 16%).

¹ H NMR (400 MHz, MeOD) δ 8.85 (d, J=5.4 Hz, 1 H), 7.85 (d, J=5.4 Hz, 1 H), 7.77-7, 72 (m, 1H), 7.54-7.46 (m, 1H), 7.22 (t, J=9.6 Hz, 1H), 3.98-3.89 (m, 2H), 3 .85 (td, J=11.8, 1.9 Hz, 2H), 2.38-2.28 (m, 2H), 2.21-2.12 (m, 2H). Purity by HPLC=97%, MSNR (ESI): m/z 410 [M+H] ⁺

Example 86 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-phenyl urea

Stage 1: ethyl 2-(2-chloropyrimidin-4-yl)acetate

NaH (4.04 g, 100.68 mmol) was added to tetrahydrofuran (THF, 200 ml) followed by stirring at 0°C. Thereafter, ethyl acetoacetate (13.1 g, 100.68 mmol) was added dropwise to the mixture. The reaction mixture was further stirred at room temperature for 30 minutes and then concentrated under reduced pressure. To the resulting residue were added 2,4-dichloropyrimidine (10 g, 67.12 mmol) and toluene (200 ml) with stirring. The reaction mixture was refluxed for about 12 hours. The reaction mixture was extracted twice with ethyl acetate and brine. The combined organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 5.28 g of the title compound (yield: 39%). [M+1] ⁺ =200.45

Stage 2: ethyl 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylate

Ethyl 2-(2-chloropyrimidin-4-yl)acetate (4.9 g, 24.42 mmol) obtained in step 1 was added to dimethylformamide (488 ml) and the resulting mixture was cooled to below 0°C . While maintaining the temperature below 0°C, 60% NaH (2.149 g, 53.7 mmol) and 1,5-dibromopentane (3.73 ml, 26.9 mmol) were added to the mixture. The reaction mixture was stirred at 60°C for 2 hours and then cooled to room temperature. Water was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 3.8 g of the title compound (yield: 60%). [M+1] ⁺ =269.

Stage 3: 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylic acid

Ethyl 1-(2-chloropyrimidin-4-yl)cyclohexanecarboxylate (3.8 g, 14.14 mmol) obtained in step 2 was dissolved in 2-propanol (70.7 ml) and then 1 M NaOH solution ( 70.7 ml). The reaction mixture was stirred for 100 minutes and then distilled under reduced pressure. The resulting residue was added to a 10% citric acid solution (15 ml) and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Stage 4: 1-(1-(2-chloropyrimidin-4-yl)cyclohexyl)-3-phenylurea

(1-(2-Chloropyrimidin-4-yl)cyclohexanecarboxylic acid (61 mg, 0.253 mmol) obtained in step 3 and triethylamine (57 mg, 0.57 mmol) were dissolved in toluene (2 ml) with stirring, and then diphenylphosphoryl azide (90mg, 0.329mmol) was added slowly.The reaction mixture was reacted at 100°C for 2 hours.As the reaction mixture was cooled, aniline (142mg, 1.524mmol) was added thereto.The reaction mixture was reacted with stirring at room temperature After completion of the reaction, ice water was added to quench the reaction.The reaction mixture was extracted with ethyl acetate.The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate to remove moisture, and then distilled under reduced pressure.The resulting residue was purified by HPLC to give 32 mg of the title compound (yield: 38%) [M+1] ⁺ =331

Step 5: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-phenylurea

1-(1-(2-Chloropyrimidin-4-yl)cyclohexyl)-3-phenylurea (32 mg, 0.097 mmol) obtained in step 4 and NaCN (9.5 mg, 0.193 mmol) were dissolved in dimethyl sulfoxide (1 ml ). DABCO (4.3 mg, 0.039 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 12 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 17.7 mg of the title compound (yield: 56%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J=5.4 Hz, 1H), 8.60 (s, 1H), 7.79 (d, J=5.4 Hz , 1H), 7.25-7.19 (m, 2H), 7.17-7.07 (m, 2H), 6.81 (tt, J=7.3, 1.2 Hz, 1H), 6.71 (s, 1H), 2.02 (d, J=13.2 Hz, 2H), 1.77 (td, J=12.9, 4.4 Hz, 2H), 1.67-1 .41 (m, 5H), 1.28-1.18 (m, 1H). [M+H] ⁺ =322.

The compounds of examples 87-110 were prepared according to the same procedures as in example 86, using the appropriate amines instead of the aniline used in step 4 of example 86.

Example 87 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,5-dimethylphenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 8.83 (d, J=5.4 Hz, 1 H), 7.79 (s, 1 H), 7.78 (d, J=5, 5 Hz, 1H), 7.50-7.41 (m, 1H), 7.07 (s, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.68-6, 55 (m, 1H), 2.09 (d, J=4.6 Hz, 6H), 2.03 (d, J=13.3 Hz, 2H), 1.83-1.68 (m, 2H ), 1.68-1.46 (m, 5H), 1.28-1.20 (m, 1H); MC m/z: 350 [M+H] ⁺

Example 88: 1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5.4 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.41-7, 33 (m, 2H), 7.32-7.27 (m, 3H), 4.82 (t, J=5.6 Hz, 1H), 4.75 (s, 1H), 4.31 (d , J=5.5 Hz, 2H), 2.17 (d, J=13.5 Hz, 2H), 1.88 (td, J=13.1, 3.8 Hz, 3H), 1.75 -1.60 (m, 3H), 1.51-1.37 (m, 2H). 336 [M+H] ⁺

Example 89 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.77 (d, J=5.4 Hz, 1H), 7.67 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.31 (s, 1H), 6.93 (s, 1H), 5.29 (s, 1H), 2.31 (d, J=13.5 Hz, 2H), 1.97 (td, J=13.1, 3.7 Hz, 2H), 1, 85-1.70 (m, 4H), 1.69-1.64 (m, 1H), 1.45-1.34 (m, 1H). 390 [M+N] ⁺

Example 90: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.78 (d, J=5.4 Hz, 1H), 7.67 (d, J=5.4 Hz, 1H), 7.55 (d, J=8.2Hz, 2H), 7.42(d, J=8.5Hz, 2H), 6.56(s, 1H), 5.07(s, 1H), 2.32(d, J=13.5 Hz, 2H), 1.98 (td, J=13.3, 3.5 Hz, 2H), 1.85-1.70 (m, 4H), 1.72-1.61 (m, 1H), 1.47-1.36 (m, 1H). 390 [M+N] ⁺

Example 91 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)benzyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.73 (d, J=5.4 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.63-7, 57 (m, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 4.84 (t, J=6.2 Hz, 1H), 4.74 (s, 1H), 4.52 (d, J=5.9 Hz, 2H), 2.22 (d, J=13.5 Hz, 2H), 1.91 ( td, J=13.1, 3.8 Hz, 2H), 1.80-1.64 (m, 4H), 1.54-1.46 (m, 1H), 1.40-1.31 ( m, 1H). 404 [M+N] ⁺

Example 92 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.74 (d, J=5.4 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.66-7, 58 (s, 3H), 7.52 (t, J=7.9 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 5.63 (s, 1H), 2, 26 (d, J=13.6 Hz, 2H), 1.97 (td, J=13.2, 3.8 Hz, 2H), 1.82-1.69 (m, 4H), 1.63 -1.53(m, 1H), 1.47-1.33(m, 1H). 390 [M+H] ⁺

Example 93: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J=5.4 Hz, 1H), 7.79 (s, 1H), 7.78 (d, J=5.5 Hz , 1H), 7.50-7.41 (m, 1H), 7.07 (s, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.68-6.55 ( m, 1H), 2.09 (d, J=4.6 Hz, 6H), 2.03 (d, J=13.3 Hz, 2H), 1.83-1.68 (m, 2H), 1.68-1.46 (m, 5H), 1.28-1.20 (m, 1H). 424 [M+H] ⁺

Example 94 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-methylphenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 8.91 (d, J=5.4 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 7.87 (d , J=5.5 Hz, 1H), 7.82 (dd, J=7.9, 2.1 Hz, 1H), 7.28 (s, 1H), 7.05 (dd, J=11, 6, 8.3 Hz, 1H), 6.74-6.63 (m, 1H), 2.17 (s, 3H), 2.08 (d, J=13.3 Hz, 2H), 1, 83 (td, J=12.9, 4.2 Hz, 2H), 1.73-1.51 (m, 5H), 1.35-1.20 (m, 1H). 354 [M+H] ⁺

Example 95 1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.78 (d, J=5.4 Hz, 1H), 7.94-7.75 (m, 3H), 7.67 (d, J=5 .4 Hz, 1H), 7.45 (s, 1H), 5.76 (s, 1H), 2.30 (d, J=13.5 Hz, 2H), 1.92 (td, J=13 .1, 3.7 Hz, 2H), 1.81-1.74 (m, 4H), 1.67-1.52 (m, 1H), 1.44-1.32 (m, 1H). 458 [M+H] ⁺

Example 96 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.91 (d, J=5.4 Hz, 1H), 7.91-7.82 (m, 2H) , 7.49-7.41(m, 1H), 7.40-7.32(m, 1H), 6.91(s, 1H), 2.14-2.03(m, 2H), 1 .89-1.78 (m, 2H), 1.73-1.50 (m, 5H), 1.34-1.25 (m, 1H), HPLC purity=99%, MSNR (ESI): m/z=408 [M+H] ⁺

Example 97 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.92 (d, J=5.5 Hz, 1H), 8.41 (dd, J=7.5, 2.4 Hz, 1H), 7.90 (d, J=5.5 Hz, 1H), 7.51-7.37 (m, 2H), 7.35-7.25 (m, 1H), 2.10 (d, J=13.3 Hz, 2H), 1.85 (td, J=13.0, 4.1 Hz, 2H), 1.62 (dq, J=26.2, 13, 2 Hz, 5H), 1.37-1.17 (m, 1H). 408 [M+H] ⁺

Example 98 2-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-4-(trifluoromethyl)benzoic acid

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.69 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 8.06 (d, J=8.3 Hz , 1H), 7.69 (d, J=5.4 Hz, 1H), 7.12 (dd, J=8.3, 1.9 Hz, 1H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 434 [M+H] ⁺

Example 99 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J=5.5 Hz, 1H), 8.23 (s, 1H), 8.19 (d, J=1.9 Hz , 1H), 7.88 (d, J=5.5 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.18 (dt , J=7.7, 1.6 Hz, 1H), 2.31 (s, 3H), 2.11 (d, J=13.3 Hz, 2H), 1.86 (td, J=12, 7, 4.6 Hz, 2H), 1.65 (q, J=20.1, 17.3 Hz, 5H), 1.37-1.22 (m, 1H). 404 [M+N] ⁺

Example 100: 1-(4-benzylphenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.78 (d, J=5.4 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.28-7 .13 (m, 7H), 7.08 (d, J=8.5 Hz, 2H), 3.90 (s, 2H), 2.12-2.08 (m, 2H), 1.91- 1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 412 [M+H] ⁺

Example 101 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(phenylamino)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.80 (d, J=5.4 Hz, 1H), 7.83 (d, J=5.5 Hz, 1H), 7.23-7 .12 (m, 4H), 7.06-6.96 (m, 4H), 6.79 (tt, J=7.3, 1.2 Hz, 1H), 2.12-2.08 (m , 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 413 [M+H] ⁺

Example 102 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-hydroxyphenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.88 (d, J=5.48 Hz, 1H), 8.28 (s, 1H), 7.82 (d, J=5.48 Hz, 1H), 7.79 (dd, J=1.58 Hz, J=8.06 Hz, 1H), 7.44 (s, 1H), 6.78 (dd , J=1.5Hz, J=7.9Hz, 1H), 6.68(td, J=3.81Hz, J=13.6Hz, 1H), 6.59(td, J=3 .89 Hz, J=13.84 Hz, 1H), 2.09-2.06 (m, 2H), 1.81 (d, J=29.92 Hz, 2H), 1.69-1.62 (m, 4H), 1.32-1.23 (m, 2H)

Purity by HPLC=98%

MCHP (ESI): m/z=338 [M+H] ⁺

Example 103 1-(2,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.67 (d, J=5.4 Hz, 1H), 8.05-8.03 (m, 1H), 7.7 (d, J=8.28 Hz, 1H), 7.66 (d, J=5.44 Hz, 1H), 7.36 (d, J=8.28 Hz, 1H), 2.11-2.07 (m, 2H), 1.88-1.81 (m, 2H), 1.68-1.53 (m, 4H), 1.33-1.16 (m, 2H), Purity by HPLC=99%, HRMS (ESI) : m/z=458 [M+H] ⁺

Example 104 3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-methyl-1-phenylurea

¹ H NMR (400 MHz, MeOD) δ 8.8 (d, J=5.44 Hz, 1H), 7.77 (d, J=5.44 Hz, 1H), 7.57 (t, J= 7.72 Hz, 2H), 7.48 (d, J=7.32 Hz, 2H), 7.43 (t, J=7.32 Hz, 1H), 5.32 (s, 1H), 3 .21 (s, 3H), 2.11-2.08 (m, 2H), 1.91-1.85 (m, 2H), 1.7-1.64 (m, 4H), 1.36 -1.31 (m, 2H)

Purity by HPLC=96%

MSNR (IER): m/z=336 [M+H] ⁺

Example 105 3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea

¹ H NMR (400 MHz, MeOD) δ 8.8 (d, J=5.44 Hz, 1H), 7.78-7.75 (m, 2H), 7.72-7.69 (m, 1H ), 7.36 (t, J=64.96 Hz, 1H), 3.27 (s, 3H), 2.23-2.2 (m, 2H), 1.95-1.88 (m, 2H), 1.77-1.68 (m, 4H), 1.57-1.47 (m, 2H)

Purity by HPLC=99%

MSNR (IER): m/z=422 [M+H] ⁺

Example 106 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,4-difluoro-5-(trifluoromethyl)phenyl)urea

1H NMR (400 MHz, MeOD) δ 8.69 (d, J=5.44 Hz, 1H), 8.22 (t, J=8.02 Hz, 1H), 7.7 (d, J=5 .44 Hz, 1H), 7.18 (t, J=10.58 Hz, 1H), 2.18-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1 .67-1.57 (m, 4H), 1.35-1.25 (m, 2H), HPLC purity=99%, MSNR (ESI): m/z=426 [M+H] ⁺

Example 107 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(methoxymethyl)-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.79 (d, J=5.44 Hz, 1H), 8.02 (s, 1H), 7.8 (d, J=5.44 Hz, 1H) , 7.45 (d, J=7.92 Hz, 1H), 7.28 (d, J=7.52 Hz, 1H), 4.55 (s, 2H), 3.42 (s, 3H) , 2.24-2.21 (m, 2H), 2.01-1.94 (m, 2H), 1.8-1.71 (m, 4H), 1.43-1.38 (m, 2H), purity by HPLC=99%, MSNR (ESI): m/z=434 [M+H] ⁺

Example 108 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(hydroxymethyl)-5-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.77 (d, J=5.3 Hz, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.67 ( d, J=5.4Hz, 1H), 7.33-7.28(m, 1H), 5.44-5.29(m, 1H), 5.18(s, 1H), 4.76 (s, 2H), 2.30 (d, J=13.4 Hz, 2H), 1.94 (td, J=13.9, 3.9 Hz, 2H), 1.82-1.70 ( m, 4H), 1.69-1.60 (m, 1H), 1.44-1.32 (m, 1H). m/z=420 [M+H] ⁺

Example 109 1-(3-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.67 (d, J=5.44 Hz, 1H), 7.69 (d, J=5.44 Hz, 1H), 7.51 (t, J= 1.7 Hz, 1H), 7.07-6.96 (m, 3H), 2.09-2.06 (m, 2H), 1.9-1.82 (m, 2H), 1.68 -1.55(m, 4H), 1.33-1.18(m, 2H)

Purity by HPLC=97%

MSNR (IER): m/z=401 [M+H] ⁺

Example 110 1-(4-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.80 (d, J=5.5 Hz, 1H), 7.82 (d, J=5.5 Hz, 1H), 7.37 (d , J=8.7 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=98.1%, MSNR (ESI): m/z 401 [M+H] ⁺

Example 111 1-([1,1'-diphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

1-(3-Bromophenyl)-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea (21 mg, 0.052 mmol) obtained in Example 109 was dissolved in 0.6 ml of a mixed solvent of dimethylformamide and water (5:1) To this solution were added potassium phosphate (33 mg, 0.157 mmol), phenylboronic acid (9.60 mg, 0.079 mmol) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (4.28 mg, 0 .00525 mmol); and the reaction was carried out at 80°C using a microwave oven. After completion of the reaction, water and ethyl acetate were added to the reaction mixture, and then the organic layer was separated. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure The resulting residue was purified by preparative HPLC to obtain 3.82 mg of the title compound (yield: 18%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=5.36 Hz, 2H), 7.63 (d, J=5.36 Hz, 2H), 7.52 (t, J =1.74 Hz, 1H), 7.45-7.33 (m, 5H), 7.24 (t, J=1.64 Hz, 1H), 6.59 (s, 1H), 5.21 (s, 1H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1 .25 (m, 2H)

Purity by HPLC=95%

MSNR (IER): m/z=398 [M+H] ⁺

Example 112: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)urea

The compound of example 112 was prepared according to the same procedures as in example 111 using 1-(3-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea (14 .7 mg, 0.037 mmol) obtained in example 109; and using (4-trifluoromethyl)phenyl)boronic acid instead of phenylboronic acid used in Example 111.

¹ H NMR (400 MHz, MeOD) δ 8.69 (d, J=5.44 Hz, 1H), 7.73(d, J=5.44 Hz, 1H), 7.68-7.59 ( m, 5H), 7.27-7.14 (m, 3H), 2.13-2.07 (m, 2H), 1.94-1.85 (m, 2H), 1.7-1, 56 (m, 4H), 1.36-1.19 (m, 2H)

Purity by HPLC=97%

MSNR (IER): m/z=466 [M+H] ⁺

Compounds of examples 113-131 were obtained in accordance with the same methods as in example 111, using as starting material 1-(4-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea obtained in example 110; and using the appropriate boronic acids instead of the phenylboronic acid used in Example 111.

Example 113: 1-([1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.4 Hz, 1H), 8.87 (s, 1H), 7.88 (d, J=5.5 Hz , 1H), 7.59 (d, J=7.0 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.41 (m, 4H), 7.29 (t , J=7.3 Hz, 1H), 6.90 (s, 1H), 2.14-2.03 (m, 2H), 1.89-1.78 (m, 2H), 1.73- 1.50 (m, 5H), 1.34-1.25 (m, 1H) ppm. Purity by HPLC=94.3%, MSNR (ESI): m/z 398 [M+H] ⁺

Example 114 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.5 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 7.78 (d , J=8.2 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 2H), 7.47-7.41 (m, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 ( m, 2H) ppm. Purity by HPLC=95%, MSNR (ESI): m/z 466 [M+H] ⁺

Example 115 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol) δ 8.80 (d, J=5.4 Hz, 1H), 7.83 (d, J=5.4 Hz, 1H), 7.48-7.38 ( m, 4H), 7.38-7.29 (m, 2H), 6.91-6.79 (m, 2H), 2.12-2.08 (m, 2H), 1.91-1, 84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=97%, MSNR (ESI): m/z 414 [M+H] ⁺

Example 116 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.82 (d, J=5.4 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.90-7 .80 (m, 3H), 7.64 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 3.16 (s, 3H), 2 .12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm Purity by HPLC=98%, MSNR (ESI): m/z 476 [M+H] ⁺

Example 117 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-morpholino-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.84 (d, J=5.4 Hz, 1H), 7.87 (d, J=5.5 Hz, 1H), 7.51 (t , J=8.6 Hz, 4H), 7.37 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 3.89-3.84 (m, 4H), 3.22-3.17 (m, 4H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1 .57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 483 [M+H] ⁺

Example 118 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-indazol-6-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.85 (d, J=5.4 Hz, 1H), 8.02 (d, J=0.9 Hz, 1H), 7.89 (d , J=5.5 Hz, 1H), 7.81 (dd, J=8.4, 0.8 Hz, 1H), 7.76 (q, J=1.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 3H), 4.13 (s, 3H), 2.12-2.08 (m, 2H) , 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=99%, MSNR (ESI): m/z 452 [M+H] ⁺

Example 119 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-4-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.4 Hz, 1H), 8.54 (d, J=5.4 Hz, 2H), 7.85 (d , J=5.4 Hz, 1H), 7.75-7.66 (m, 4H), 7.48 (d, J=8.7 Hz, 2H), 6.76 (s, 1H), 2 .12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm Purity by HPLC=98%, MSNR (ESI): m/z 399 [M+H] ⁺

Example 120 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.80 (d, J=5.4 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=5.4 Hz , 1H), 7.75 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 3.92 (s , 3H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)ppm. Purity by HPLC=97%, MSNR (ESI): m/z 402 [M+H] ⁺

Example 121 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-fluoro-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.5 Hz, 1H), 7.85 (d, J=5.4 Hz, 1H), 7.64-7 .53 (m, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.20-7.09 (m, 2H), 2.12-2.08(m, 2H), 1.91-1.84(m, 2H), 1.67-1.57(m, 4H), 1.35-1.25( m, 2H) ppm. Purity by HPLC=99%, MSNR (ESI): m/z 416 [M+H] ⁺

Example 122 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.5 Hz, 1H), 7.85 (d, J=5.4 Hz, 1H), 7.83-7 .73 (m, 4H), 7.61 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=97%, MSNR (ESI): m/z 423 [M+H] ⁺

Example 123: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.4 Hz, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.58-7, 50 (m, 2H), 7.44-7.29 (m, 4H), 7.25-7.22 (m, 1H), 7.07-6.98 (m, 1H), 6.37 ( s, 1H), 2.27 (d, J=13.6 Hz, 2H), 1.95 (td, J=13.3, 3.8 Hz, 2H), 1.78-1.69 (m , 4H), 1.40-1.29 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 416[M+H] ⁺

Example 124 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-fluoro-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, chloroform-d) δ 8.75 (d, J=5.4 Hz, 1H), 7.65 (d, J=5.4 Hz, 1H), 7.57-7, 49 (m, 2H), 7.46-7.26 (m, 4H), 7.25-7.09 (m, 2H), 6.40 (s, 1H), 2.27 (d, J= 13.6 Hz, 2H), 1.95 (td, J=13.3, 3.8 Hz, 2H), 1.78-1.69 (m, 4H), 1.40-1.29 (m , 2H) ppm. Purity by HPLC=99%, MSNR (ESI): m/z 416 [M+H] ⁺

Example 125 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-fluoropyridin-3-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.4 Hz, 1H), 8.41 (dt, J=2.7, 0.8 Hz, 1H), 8 .16 (m, 1H), 7.85 (d, J=5.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.50-7.40 (m, 2H), 7.13 (m, 1H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1, 35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 417 [M+H] ⁺

Example 126 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.95 (d, J=2.2 Hz, 1H), 8.81 (d, J=5.5 Hz, 1H), 8.24 (dd , J=8.2, 2.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1 .35-1.25 (m, 2H) ppm. Purity by HPLC=98%, MSNR (ESI): m/z 467 [M+H] ⁺

Example 127 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-methoxypyridin-3-yl)phenyl)urea

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H), 7.91 (dd , J=8.6, 2.6 Hz, 1H), 7.84 (d, J=5.5 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 2.12-2.08 (m, 2H) , 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H) ppm. Purity by HPLC=99%, MSNR (ESI): m/z 429 [M+H] ⁺

Example 128 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-3-yl)phenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.44 Hz, 1H), 8.77 (d, J=1.88 Hz, 1H), 8.47 (dd, J= 1.44Hz, J=4.84Hz, 1H), 8.05(td, J=1.94Hz, J=8.44Hz, 1H), 7.85(d, J=5.44Hz , 1H), 7.6-7.57 (m, 2H), 7.5 (dd, J=5.18 Hz, J=7.82 Hz, 1H), 7.47-7.45 (m, 2H), 6.73 (s, 1H), 2.24-2.21 (m, 2H), 2.04-2 (m, 2H), 1.77-1.71 (m, 4H), 1 .45-1.26(m, 2H)

Purity by HPLC=96%

MSNR (IER): m/z=399 [M+H] ⁺

Example 129: N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.92 (d, J=5.4 Hz, 1H), 8.76 (s, 1H), 7.89 (d, J=5.4 Hz, 1H), 7.86 (d, J=5.4 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.51 (m , 3H), 7.37 (d, J=8.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64- 1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =455.

Example 130 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide

¹ H NMR (400 MHz, MeOD) δ 8.82 (d, J=5.4 Hz, 1H), 7.84 (m, 2H), 7.69 (d, J=8.6 Hz, 1H) , 7.59 (m, 3H), 7.48 (m, 2H), 7.42 (d, J=8.7 Hz, 2H), 3.13 (s, 3H), 3.07 (s, 3H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 ( m, 2H), [M+1] ⁺ =469.

Example 131 3-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)propanoic acid

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H), 7.50 (m, 4H) , 7.37 (d, J=8.6Hz, 2H), 7.29 (d, J=8.2Hz, 2H), 2.95 (t, J=7.6Hz, 2H), 2 .64 (t, J=7.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m , 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =470.

Example 132 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea

Stage 1: 1-(2-bromopyrimidin-4-yl)cyclohexanamine

Benzyl-(1-(2-chloropyrimidin-4-yl)cyclohexyl)carbamate (15.78 g, 45.6 mmol) obtained in step 4 of Example 10 was dissolved in acetic acid (450 ml) and then added dropwise 33% solution of HBr in acetic acid (75 ml, 456 mmol). The reaction mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, resulting in a precipitate, after which the mixture was filtered. The resulting solid was washed with diethyl ether and then dissolved in water. The solution was made basic with 1N sodium hydroxide solution and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled under reduced pressure to obtain 8.32 g of the title compound (yield: 72%). [M+1] ⁺ =257.50

Step 2: Intermediate 4-(1-aminocyclohexyl)pyrimidine-2-carbonitrile

1-(2-Bromopyrimidin-4-yl)cyclohexanamine (1.53 mg, 5.97 mmol) obtained in step 1 and NaCN (0.453 g, 8.96 mmol) were dissolved in dimethyl sulfoxide (53.3 ml). DABCO (0.135 mg, 1.195 mmol) was added to the resulting solution at room temperature, followed by stirring at 50° C. for about 12 hours. Water was added to quench the reaction, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N NaOH and brine, dried over anhydrous Na ₂ SO ₄ to remove moisture, and then distilled under reduced pressure to obtain 1.1 g of the title compound (yield: 91%). [M+1] ⁺ =202.55

Step 3: 4-nitrophenyl(4-iodophenyl)carbamate

4-Iodaniline (0.500 g, 2.283 mmol) was dissolved in dichloromethane (11.4 ml), and then this solution was cooled to a temperature below 0°C. While maintaining this temperature, pyridine (0.923 ml, 11.41 mmol) was added to the reaction mixture, after which it was stirred for 10 minutes. 4-nitrophenylcarbonchloridate (506 g, 2.51 mmol) was slowly added to the reaction mixture, after which it was stirred at room temperature for 1 hour. Water was added to quench the reaction, and then the reaction mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was used in the next reaction without purification.

Step 4: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea

4-Nitrophenyl(4-iodophenyl)carbamate (0.877 g, 2.28 mmol) from step 3 and intermediate from step 2 i.e. 4-(1-aminocyclohexyl)pyrimidine-2-carbonitrile (0.462 g, 2.28 mmol) was dissolved in pyridine (11.4 ml). The resulting solution was subjected to interaction at 60°C for 1 hour. Ethyl acetate and brine were added to the reaction mixture. The organic layer was extracted with ethyl acetate. The extract was washed with 10% CuSO ₄ solution, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 540 mg of the title compound (yield: 52.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.9 (d, 1 H, J=5.44 Hz), 8.78 (s, 1H), 7.86 (d, 1H, J=5 .44 Hz), 7.5 (d, 2H, J=8.76 Hz), 7.15 (d, 2H, J=8.8 Hz), 6.82 (s, 1H), 2.09- 2.06 (m, 2H), 1.86-1.79 (m, 2H), 1.69-1.55 (m, 4H), 1.29-1.23 (m, 2H) Purity by HPLC \u003d 94%, MSNR (ESI): m / z \u003d 448 [M + H] ⁺

Compounds of examples 133-146 were prepared in accordance with the same procedures as in example 132, using the appropriate amines instead of 4-iodoaniline used in step 3 of example 132. 1-(4-Bromophenyl)-3-(1-(2 The -cyanopyrimidin-4-yl)cyclohexyl)urea of Example 110 can also be prepared according to the same procedures using 4-bromoaniline in place of the 4-iodaniline used in step 3 of Example 132.

Example 133: 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.44 Hz, 1H), 7.86 (d, J=1.96 Hz, 1H), 7.82 (d, J= 5.44Hz, 1H), 7.63(d, J=8.72Hz, 1H), 7.4(dd, J=2Hz, J=8.72Hz, 1H), 2.23-2 .19 (m, 2H), 2.03-1.95 (m, 2H), 1.78-1.65 (m, 4H), 1.45-1.26 (m, 2H)

Purity by HPLC=98%

MSNR (IER): m/z=469 [M+H] ⁺

Example 134 1-(4-bromo-2-fluorophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=5.4 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 7.93 (t , J=8.9 Hz, 1H), 7.85 (d, J=5.4 Hz, 1H), 7.51 (dd, J=11.1, 2.3 Hz, 1H), 7.27 (s, 1H), 7.19 (dt, J=8.9, 1.6 Hz, 1H), 2.10 - 2.02 (m, 2H), 1.82 (td, J=13.3 , 3.7 Hz, 2H), 1.61 (p, J=12.9 Hz, 5H), 1.27 (s, 1 H). [M+H] ⁺ =418.

Example 135 4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)benzoic acid

¹ H NMR (400 MHz, MeOD) δ 8.69 (d, J=5.44 Hz, 1H), 7.79 (d, J=8.84 Hz, 2H), 7.71 (d, J= 5.44 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 2.12-2.08 (m, 2H), 1.94-1.84 (m, 2H), 1.64-1.5 (m, 4H), 1.34-1.19 (m, 2H)

Purity by HPLC=99%, MSNR (ESI): m/z 366 [M+H] ⁺

Example 136 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodo-3-(trifluoromethyl)phenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.85-7.79 ( m, 2H), 7.23 (dd, J=8.6, 2.5 Hz, 1H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H) , 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC=99%, MSNR (ESI): m/z 516 [M+H] ⁺

Example 137 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-fluoro-4-iodophenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.91 (d, J=5.6 Hz, 1H), 7.87 (d, J=5.5 Hz , 1H), 7.61 (dd, J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=11.1, 2.3 Hz, 1H), 6.93 (s, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 2.08 (d, J=13.2 Hz, 2H), 1.83 (td, J=13.1 , 3.9 Hz, 2H), 1.58 (dt, J=26.0, 13.7 Hz, 5H), 1.28 (d, J=11.9 Hz, 1H). [M+H] ⁺ =465.9.

Example 138 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.4 Hz, 1H), 8.41 (s, 1H), 7.85 (d, J=5.4 Hz , 1H), 7.14 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 6.65 (s, 1H), 2.99 (t , J=4.8 Hz, 4H), 2.42 (t, J=4.9 Hz, 4H), 2.20 (s, 3H), 2.06 (d, J=13.4 Hz, 2H ), 1.82 (dt, J=14.5, 7.3 Hz, 2H), 1.71-1.51 (m, 5H), 1.27 (d, J=12.2 Hz, 1H) . [M+H] ⁺ =420.1.

Example 139 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-morpholinophenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.80 (d, J=5.44 Hz, 1H), 7.82 (d, J=5.44 Hz, 1H), 7.35 (d, J= 7.72 Hz, 2H), 7.18 (s, 2H), 3.92 (s, 4H), 2.22 (d, J=13.20 Hz, 2H), 2.03 (m, 2H) , 1.77 (m, 5H), 1.42 (m, 1H). [M+H] ⁺ =407.0.

Example 140 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(piperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.78 (d, J=5.44 Hz, 1H), 7.73 (d, J=5.44 Hz, 1H), 7.28 (d, J= 8.96Hz, 2H), 7.14(d, J=9.0Hz, 2H), 3.63(m, 4H), 3.28(m, 4H), 2.26(d, J= 13.16 Hz, 2H), 2.01(m, 2H), 1.78(m, 5H), 1.44(m, 1H). [M+H] ⁺ =406.0.

Example 141 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea

1H NMR (400 MHz, MeOD) *5 8.80 (d, J=5.44 Hz, 1H), 7.82 (d, J=5.44 Hz, 1 H), 7.35 (s, 2H ), 7.21 (s, 2H), 3.79 (s, 2H), 3.52 (m, 1H), 3.20 (m, 2H), 2.93 (s, 6H), 2.22 (m, 2H), 2.06 (m, 2H), 1.80 (m, 5H), 1.44 (m, 1 H). [M+H]+=448.1.

Example 142 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.79 (d, J=5.44 Hz, 1H), 7.82 (d, J=5.44 Hz, 1H), 7.24 (d, J= 8.92 Hz, 2H), 6.96 (d, J=8.96 Hz, 2H), 3.78 (d, J=13.0 Hz, 2H), 3.60 (m, 3H), 3 .02 (m, 2H), 2.21 (d, J=13.08 Hz, 2H), 2.01 (m, 2H), 1.80 (m.5H), 1.43 (d, J= 6.64 Hz, 7H). [M+H] ⁺ =448.0.

Example 143: 1-(4-(4-(tert-butyl)piperazin-1-yl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=5.44 Hz, 1H), 7.85 (d, J=5.48 Hz, 1H), 7.16 (d , J=8.88 Hz, 2H), 6.80 (d, J=8.96 Hz, 2H), 3.00 (s, 4H), 2.68 (d, J=1.8 Hz, 4H ), 2.08 (d, J=13.12 Hz, 2H), 1.85 (m, 2H), 1.63 (m, 5H), 1.29 (m, 1H), 1.06 (s , 9H). [M+H] ⁺ =462.15.

Example 144 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.44 Hz, 1H), 8.41 (s, 1H), 7.85 (d, J=5.40 Hz, 1H), 7.14 (d, J= 8.84 Hz, 2H), 6.79 (d, J=8.92 Hz, 2H), 6.64 (s, 1H), 2.95 (s, 4H), 2.64 (s, 4H), 2.07 (m, 2H), 1.84 (m, 2Н), 1.62 (m, 5H), 1.28 (m, 1Н), 0.43 (d, J=4.28 Hz, 2Н), 0.32 (d, J=2.52 Hz, 2Н). [M+H] ⁺ =446.05.

Example 145 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperidin-1-yl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.91 (d, J=5.44 Hz, 1H), 7.86 (d, J=5.44 Hz, 1H), 7.43 (s, 4H) , 6.95 (s, 1H), 2.10 (d, J=6.32 Hz, 2H), 1.90 (m, 4H), 1.65 (m, 9H), 1.29 (s, 1H), 0.90 (d, J=6.68 Hz, 6H). [M+H] ⁺ =447.10.

Example 146 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.4 Hz, 1H), 8.45 (s, 1 H), 7.85 (d, J=5.4 Hz, 1H), 7.14 (d, J =8.9 Hz, 2H), 6.79 (d, J=8.9 Hz, 2H), 6.68 (s, 1H), 3.00 (s, 4H), 2.47-2.34 (m, 4H), 2.06 (d, J=12.8 Hz , 2Н), 1.81 (td,J=13.0.4.1 Hz, 2Н), 1.71-1.52 (m, J=32.6, 17.9 Hz, 5Н), 1.33-1.21 (m, J=11.4 Hz, 1H), 1.03 ( t, J=6.9 Hz, 3H), HPLC purity=99%, MSNR (ESI): m/z=434 [M+H] ⁺

Example 147 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1'-diphenyl]-4-carboxamide

Solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (30 mg, 0.067 mmol) prepared in Example 132, cesium carbonate (54.6 mg, 0.168 mmol) , N-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.47 mg, 0.067 mmol) and PdCl ₂ (dppf) (5.48 mg, 0.0671 mmol) in a mixed solvent of dimethylformamide and water (5:1) (0.6 ml) was reacted at 120° C. for 30 minutes using a microwave oven. After completion of the reaction, water and ethyl acetate were added to the mixture, and the organic layer was extracted. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to give 3.4 mg of the title compound (white solid, yield: 10%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J=5.4 Hz, 1H), 8.85 (s, 1H), 8.55 (t, J=5.2 Hz, 1H), 7.93-7.84 (m, 3H), 7.73-7.65 (m, 2H), 7.64-7.56 (m, 2H), 7.45-7.37 (m, 2H), 6.85 (s, 1H), 3.27 (s, 4H), 2.10 (d, J= 13.2 Hz, 2H), 1.84(t, J=13.0 Hz, 2H), 1.63 (q, J=12.8 Hz, 5H), 1.29 (d, J=12.4 Hz, 1 H). [M+H] ⁺ =499.

Compounds of examples 148-161 were obtained in accordance with the same methods as in example 147, using as starting material 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea obtained in example 132; and using the appropriate boronic acid or boronic acid ester instead of N-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide used in Example 147 .

Example 148 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-sulfonamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95-8.85 (m, 2H), 7.93 (d, J=2.6 Hz, 1H), 7.89 (d, J=5.5 Hz, 1H), 7.84 (s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 6.87 (s, 1H), 2.10 (dt, J=10.3, 3.2 Hz, 2H), 1.90- 1.79 (m, 2H), 1.63 (q, J=12.8 Hz, 5H), 1.29 (d, J=11.9 Hz, 1H), 0.49 (td, J=7.0, 6.5, 4.8 Hz, 2H), 0.40 (q , J=4.0 Hz, 2H). [M+H] ⁺ =517.

Example 149 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J=5.4 Hz, 1H), 8.85 (s, 1H), 8.46 (d, J=4.2 Hz, 1H), 7.93-7.80 (m, 3H), 7.74-7.55 (m, 4H), 7.48-7.34 (m, 2H), 6.85 (s, 1H), 2.85 (tq, J=7.6, 4.0 Hz, 1H), 2.14-2.04 (m, 2H) , 1.84 (t, J=11.6 Hz, 2H), 1.63 (q, J=12.9, 12.4 Hz, 5H), 1.31 (s, 1H), 0.70 (td, J=7.1.4.7 Hz, 2H), 0.61- 0.53 (m, 2H). [M+H] ⁺ =481.

Example 150: 1-(3'-chloro-4'-(pyrrolidin-1-carbonyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl) cyclohexyl)urea

¹ H NMR (400 MHz, MeOD) δ 8.82 (d, J=5.4 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.60-7.53 (m, 2H), 7.48-7.39 (m, 3H), 3.64 (t, J=6.9 Hz, 2H), 2.23 (d, J=13.3 Hz, 2H ), 2.07-1.93 (m, 5H), 1.74 (d, J=26.1 Hz, 5H), 1.42 (d, J=11.4 Hz, 1H). [M+H] ⁺ =529.

Example 151: N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methyl)acetamide

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H), 7.54 (m, 4H), 7.35 (m, 4H), 4.39 ( d, J=5.5 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1 ] ⁺ =469

Example 152: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1'-diphenyl]-4 -yl)urea

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.84-7.33 (m, 8H), 7.15 (m, 2H), 6.93 (m, 2H), 5.12 (s, 2H ), 3.59 (m, 2H), 2.81 (m, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H ), [M+1] ⁺ =562.

Example 153: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.4 Hz, 1H), 8.78 (s, 1H), 7.88 (d, J=5.4 Hz, 1H), 7.59-7.55 (m, 2H), 7.50-7.45 (m, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.08-7.03 (m, 2H), 6.84 (s, 1H), 4.33 (t, J=5.0 Hz, 2H ), 2.87 (d, J=3.6 Hz, 6H), 2.10 (d, J=13.2 Hz, 2H), 1.84 (t, J=12.0 Hz, 2H), 1.70-1.58 (m, 5H). [M+H] ⁺ =485.

Example 154 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.4 Hz, 1H), 8.76 (s, 1H), 7.88 (d, J=5.5 Hz, 1H), 7.49 (dd, J= 20.0, 8.8 Hz, 4H), 7.35 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.9 Hz, 2H), 6.83 (s, 1H), 3.91 (d, J=13.1 Hz, 2H) , 3.53 (d, J=12.1 Hz, 2H), 3.17 (t, J=11.2 Hz, 2H), 2.97 (t, J=12.3 Hz, 2H), 2.10 (d, J=13.3 Hz, 2H), 1.88 -1.78 (m, 2H), 1.71-1.56 (m, 5H), 1.30 (d, J=6.6 Hz, 6H). [M+H] ⁺ =524.

Example 155 1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J=5.5 Hz, 1H), 8.72 (s, 1H), 7.86 (d, J=5.5 Hz, 1H), 7.45 (dd, J= 10.3, 8.6 Hz, 4H), 7.33 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.79 (s, 1H), 3.14 (dt, J=27.0, 5.2 Hz, 4Н), 2.11-2.05 (m, 2Н), 2.03 (s, 3Н), 1.83 (td, J=13.0, 4.4 Hz, 2Н), 1.62 (dq, J=22.8, 13.0, 12.2 Hz, 5Н), 1.31 -1.24 (m, 1H). [M+H] ⁺ =523.

Example 156 Methyl 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetate

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=5.5 Hz, 1H), 8.78 (s, 1H), 7.87 (d, J=5.5 Hz, 1H), 7.58-7.46 (m, 4Н), 7.38 (d, J=8.7 Hz, 2Н), 7.29 (d, J=8.0 Hz, 2Н), 6.82 (s, 1Н), 3.69 (s, 2Н), 3.61 (s, 3Н), 2.13- 2.05 (m, 2H), 1.83 (dt, J=13.0, 7.3 Hz, 2H), 1.72-1.53 (m, 5H), 1.28 (d, J=12.1 Hz, 1H). [M+H] ⁺ =470.

Example 157 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((2-methoxyethoxy)methyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=5.4 Hz, 1H), 8.78 (s, 1H), 7.88 (d, J=5.4 Hz, 1H), 7.57 (d, J= 8.2 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.36 (dd, J=12.6, 8.6 Hz, 4H), 6.82 (s, 1H), 4.49 (s, 2H), 3.55 (dd, J=5.8, 3.3 Hz, 2H), 3.48 (dd, J=5.8, 3.3 Hz, 2H), 3.25 (s, 3H), 2.11-2.05 (m, 2H), 1.83 (dt, J=13.2, 6.6 Hz , 2Н), 1.60 (d, J=23.6 Hz, 5Н), 1.30-1.25 (m, 1Н). [M+H] ⁺ =486.

Example 158 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1'-diphenyl]-4- carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=5.5 Hz, 1H), 8.82 (s, 1H), 8.54 (t, J=5.9 Hz, 1H), 7.94-7.83 (m, 3Н), 7.67 (d, J=8.2 Hz, 2Н), 7.58 (d, J=8.7 Hz, 2Н), 7.39 (d, J=8.5 Hz, 2H), 6.83 (s, 1H), 3.96 (p, J=6.2 Hz, 1H), 3.76 (q, J=7.0 Hz, 1H), 3.61 (q, J=7.3 Hz, 1H), 2.08 (d, J=13.1 Hz, 2H), 1.92-1.74 (m, 5H), 1.70-1.50 (m, 6H), 1.28 (s, 1H). [M+H] ⁺ =525.

Example 159 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1'-diphenyl]-4-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J=5.8 Hz, 2H), 8.70 (t, J=5.7 Hz, 1H), 7.95-7.84 (m, 3H), 7.74 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 6.90 (s, 1H), 3.61 (q, J=5.9 Hz, 2H) , 3.27 (q, J=5.8 Hz, 2H), 2.85 (d, J=4.7 Hz, 6H), 2.10 (d, J=13.1 Hz, 2H), 1.84 (td, J=13.0, 4.2 Hz, 2H) , 1.62 (q, J=12.6 Hz, 5H), 1.33-1.26 (m, 1 H). [M+H] ⁺ =512.

Example 160 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, MeOD) δ 8.67 (d, J=5.4 Hz, 1H), 7.71 (d, J=5.4 Hz, 1H), 7.41-7.31 (m, 4H), 7.22 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 3.16-3.07 (m, 4H), 2.60-2.47 (m, 4H), 2.40 (q, J=7.2 Hz, 2H), 2.09 (d , J=13.2 Hz, 2H), 1.87 (td, J=13.1, 4.3 Hz, 2H), 1.63 (dd, J=27.8, 16.3 Hz, 5H), 1.35-1.24 (m, 1H), 1.05 (t, J=7.2 Hz, 3H), HPLC purity=96%, MSNR (ESI): m/z=510 [M+H] ⁺ .

Example 161 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetic acid

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.36 Hz, 1H), 7.85 (d, J=5.40 Hz, 1H), 7.55 (m, 4H), 7.39 (m, 4H), 3.64 ( s, 2Н), 2.23 (d, J=11.96 Hz, 2Н), 2.02 (m, 2Н), 1.76 (m, 5Н), 1.43 (m, 1Н). [M+H] ⁺ =456.05.

The compounds of examples 162 and 163 were obtained in accordance with the same methods as in example 147, using as starting material 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidine- 4-yl)cyclohexyl)urea obtained in example 133; and using (4-(methylsulfonyl)phenyl)boronic acid or 4-boronebenzoic acid instead of N-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) benzamide used in example 147.

Example 162: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 1H), 8.93 (d, J=5.5 Hz, 1H), 8.00-7.95 (m, J=5.4 Hz, 3H), 7.90 (d, J=5.5 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.51 (dd, J=8.4, 2.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.98 (s, 1 H), 3.29 (s, 3H), 2.12-2.08 (m, 2H), 1.91-1.84 (m, 2H), 1.67-1.57 (m, 4H), 1.35-1.25 (m, 2H)

Purity by HPLC=99%

MSNR (IER): m/z=544 [M+H] ⁺

Example 163 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-carboxylic acid

¹ H NMR (400 MHz, MeOD) δ 8.72 (d, J=5.44 Hz, 2H), 7.95 (d, J=8.36 Hz, 2H), 7.77 (d, J=2.2 Hz, 1H), 7.75 (d, J=5.44 Hz, 1H), 7.44 (dd, J=2.12 Hz, J=8.4 Hz, 1H), 7.3 (d, J=8.16 Hz, 2H), 7.16 (d, J=8.44 Hz, 1H), 2.15 -2.12 (m, 2H), 1.94-1.87 (m, 2H), 1.67-1.6 (m, 4H), 1.37-1.24 (m, 2H)

Purity by HPLC=99%

MSNR (IER): m/z=510 [M+H] ⁺

Compounds of examples 164-168 were obtained in accordance with the same methods as in example 147, using as starting material 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-fluoro-4 -iodophenyl)urea prepared in Example 137 and using the corresponding boronic acid instead of N-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide used in example 147.

Example 164 N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)acetamide

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.46 (d, J=7.3Hz, 2H), 7.33(m, 2H), 7.06(dd, J=2.1Hz, J=8.4Hz 1H), 2.12-2.08(m, 2H), 2.15(s, 3H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =473.

Example 165: N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)methyl) acetamide

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.46 (d, J=7.3 Hz, 2H), 7.35 (m, 2H), 7.06 (dd, J=2.1 Hz, J=8.4 Hz 1H), 4.40 (s, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =487.

Example 166 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4 -yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.92 (d, J=5.4 Hz, 1H), 7.88 (d, J=5.5 Hz, 1H), 7.44-7.29 (m, 4Н), 7.13-7.01 (m, 3Н), 6.93 (s, 1Н), 3.93 (d, J=13.1 Hz, 2Н), 3.53(d, J=13.1 Hz, 2Н), 3.18 (q, J=11.5 Hz, 2H), 2.99 (t, J=12.4 Hz, 2H), 2.10 (d, J=13.1 Hz, 2H), 1.84 (t, J=12.8 Hz, 2H), 1.71-1.54 (m, 5H), 1.30 (d, J=6.6 Hz, 6H). [M+H] ⁺ = 542.4.

Example 167 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1 H), 8.93 (d, J=5.4 Hz, 1H), 8.02 -7.95 (m, 2H), 7.89 (d, J=5.5 Hz , 1Н), 7.76 (dd, J=8.4, 1.6 Hz, 2Н), 7.53-7.42 (m, 2Н), 7.13 (dd, J=8.5, 2.1 Hz, 1Н), 6.97 (s, 1Н), 3.25 ( s, 3Н), 2.16-2.05 (m, 2Н), 1.89-1.80 (m, 2Н), 1.74-1.53 (m, 5Н), 1.30 (s, 1Н). [M+H] ⁺ = 494.1.

Example 168: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1'-diphenyl]-4 -yl)urea

¹ H NMR (400 MHz, MeOD) δ 8.82 (d, J=5.44 Hz, 1H), 7.84 (d, J=5.44 Hz, 1H), 7.49 (d, J=7.40 Hz, 2H), 7.36 (m, 4Н), 7.08 (m, 1Н), 3.80 (d, J=12.48 Hz, 2Н), 3.39 (d, J=11.32 Hz, 2Н), 3.01 (m, 1Н), 2.88 (s, 1Н), 2.23 ( t, J=14.54 Hz, 4H), 2.03 (m, 4H), 1.75 (m, 5H), 1.45 (m, 1H), 1.03 (d, J=5.1 Hz, 4H). [M+H] ⁺ =539.30.

Example 169 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea

Step 1: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) urea

A mixture of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (150 mg, 0.335 mmol) prepared in Example 132, bis(pinacolato)diboron (52 mg, 0.503 mmol ), potassium acetate (48.6 mg, 0.495 mmol) and PdCl ₂ (dppf) (27.4 mg, 0.034 mmol) in dimethyl sulfoxide (2 ml) was stirred at 90°C for 4 hours. The reaction mixture was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 75 mg of the title compound (yield: 50%). [M+1] ⁺ =448.

Step 2: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea

A mixture of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea ( 6 mg, 0.013 mmol) obtained in step 1, 1-bromo-4-((trifluoromethyl)sulfonyl)benzene (3.25 mg, 10.73 mmol), cesium carbonate (10.92 mg, 0.034 mmol) and adduct PdCl ₂ (dppf)-CH ₂ Cl ₂ (2.66 mg, 3.25 μmol) in a mixture of dimethylformamide (1000 μl) and water (100 μl) was reacted at 120° C. for 30 minutes using a microwave oven. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 1.5 mg of the title compound (yield: 17%).

¹ H NMR (400 MHz, MeOD) δ 8.70 (d, J=5.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.89 (d, J=9.2 Hz, 2H), 7.73 (d, J=5.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =530.

The compounds of examples 170-175 were prepared according to the same procedures as in example 169 using the appropriate bromides instead of 1-bromo-4-((trifluoromethyl)sulfonyl)benzene used in step 2 of example 169.

Example 170: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, CDCl ₂ ) δ 8.77 (d, J=5.4 Hz, 2H), 7.97 (t, 2H), 7.67 (d, J=5.4 Hz, 1 H), 7.54-7.45 (m, J =14.1, 5.5 Hz, 3H), 7.41-7.33 (m, J=8.6 Hz, 3H), 6.64 (s, 1H), 5.23 (s, 1H), 3.26 (s, 3H), 2.12-2.08 (m , 2Н), 1.91-1.84 (m, 2Н), 1.67-1.57 (m, 4Н), 1.35-1.25 (m, 2Н)

Purity by HPLC=96%

MSNR (ESI): m/z=494 [M+H]+

Example 171: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl) urea

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=5.5 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J= 5.1 Hz, 1H), 7.76 (d, J=8.9 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64- 1.52 (m, 4H), 1.35-1.25 (m, 2H), [M] ⁺ =543.

Example 172 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea

¹ H NMR (400 MHz, MeOD) δ 8.67 (d, J=5.4 Hz, 1H), 7.73 (d, J=5.4 Hz, 1H), 7.64 (d, J=7.8 Hz, 1 H), 7.51 (t , J=7.3 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.25 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 2.12-2.08 (m, 2H), 1.93 -1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =466.

Example 173 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-sulfonamide

¹ H NMR (400 MHz, MeOD) δ 8.82 (d, J=5.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.86 (d, J=5.4 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =477.

Example 174 N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methanesulfonamide

¹ H NMR (400 MHz, pyridine-d ₆ ) δ 8.80 (m, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.86 (d, J=5.4 Hz, 1H), 7.78 (d, J= 8.5 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64- 1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =491.

Example 175 Methyl 5-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)pent-4-inoate

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.4 Hz, 1H), 7.85 (d, J=5.4 Hz, 1H), 7.52 (m, 4H), 7.39 (m, 4H), 2.73 ( t, J=7.6 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35 -1.25 (m, 2H), [M+1] ⁺ =508.

Example 176 1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

Step 1: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 -(trifluoromethyl)phenyl)urea

Mixture of 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea (237 mg, 0.507 mmol) prepared in Example 133, bis(pinacolato) diboron (142 mg, 0.558 mmol), potassium acetate (174 mg, 1.776 mmol) and PdCl ₂ (dppf) (21 mg, 0.025 mmol) in dimethyl sulfoxide (2 ml) was stirred at 120°C for 30 minutes using a microwave . The reaction mixture was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by HPLC to obtain 100 mg of the title compound (yield: 38%). [M+1] ⁺ =516.

Step 2: 1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

A mixture of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-( trifluoromethyl)phenyl)urea (5 mg, 9.70 mmol) obtained in step 1, 1-bromo-2-(trifluoromethyl)benzene (1.211 µl, 8.94 µmol), cesium carbonate (7.90 mg, 0.024 mmol ) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (2.66 mg, 3.25 µmol) in a mixture of dimethylformamide (900 µl) and water (100 µl) were reacted at 120°C for 30 minutes using a microwave ovens. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 1.0 mg of the title compound (yield: 19%).

¹ H NMR (400 MHz, MeOD) δ 8.70 (d, J=5.4 Hz, 1H), 7.74 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.48 (m, 2H), 7.38 ( dd, J=2.0 Hz, J=8.4 Hz 1H), 7.19 (d, J=7.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 2.12-2.08 (m, 2H), 1.93- 1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =534.

The compounds of examples 177-180 were prepared according to the same procedures as in example 176 using the appropriate bromides instead of 1-bromo-2-(trifluoromethyl)benzene used in step 2 of example 176.

Example 177: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)-4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4- silt) urea

¹ H NMR (400 MHz, MeOD) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.81 (d, J=1.8 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.48 (dd, J=1.8 Hz, J=8.4 Hz 1H), 7.21 (d, J=8.4 Hz, 1H), 2.12- 2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ = 598.

Example 178: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2,3'-bis(trifluoromethyl)-[1,1'-diphenyl]-4 -yl)urea

¹ H NMR (400 MHz, MeOD) δ 8.71 (d, J=5.4 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.74 (s, 1H), 7.72 (m, 2H), 7.49 ( dd, J=1.0 Hz, J=9.3 Hz 1H), 7.21 (d, J=8.4 Hz, 1H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =612.

Example 179 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-sulfonamide

¹ H NMR (400 MHz, MeOD) δ 8.71 (d, J=5.4 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.77 (d, J=2.0 Hz 1H), 7.74 (d, J =5.4 Hz, 1H), 7.44 (dd, J=2.0 Hz, J=8.3 Hz 1H), 7.17 (m, 5H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64- 1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =545.

Example 180 N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)methanesulfonamide

¹ H NMR (400 MHz, MeOD) δ 8.71 (d, J=5.4 Hz, 1H), 7.73 (m, 2H), 7.44 (dd, J=2.0 Hz, J=8.3 Hz 1H), 7.35 (d, J =8.2 Hz, 2H), 7.15(d, J=8.4 Hz, 1H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 ( m, 2H), [M+1] ⁺ =559.

Example 181 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) methyl)urea

4-Nitrophenyl 4-iodobenzylcarbamate was prepared according to the same procedures as in Example 132, using (4-iodophenyl)methanamine instead of 4-iodoaniline used in step 3 of Example 132. 4-Nitrophenyl 4-iodobenzylcarbamate was reacted with the intermediate, obtained in stage 2, i.e. 4-(1-Aminocyclohexyl)pyrimidine-2-carbonitrile to give 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(iodobenzyl)urea. The title compound (0.8 mg) was prepared according to the same procedures as in example 147 using 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) piperazine (yield: 1.373%).

¹ H NMR (400 MHz, MeOD) δ 8.78 (d, J=5.40 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J=5.44 Hz, 1H), 7.60 (t, J=8.0 Hz, 4Н), 7.33 (d, J=8.12 Hz, 2Н), 7.13 (d, J=8.84 Hz, 2Н), 4.28 (s, 2Н), 3.98 (d, J=12.68 Hz, 2Н), 3.63 (m, 3Н), 3.15 (m, 2Н), 2.23 (m, 2Н), 1.96 (m, 2Н), 1.72 (m, 5Н), 1.46 (d, J=6.68 Hz, 6Н). [M+H] ⁺ =538.35.

Example 182 5-(4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)phenyl)pent-4-ic acid

1-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (10 mg, 0.011 mmol) prepared in Example 132, bis(triphenylphosphine)palladium(II) chloride (0.392 mg , 1.118 µmol) and copper(I) iodide (0.213 mg, 1.118 µmol) were dissolved in dimethylformamide (1.5 ml). Triethylamine (0.016 ml, 0.112 mmol) was slowly added to this mixture. Pent-4-ic acid (2.193 mg, 0.022 mmol) was added to the reaction mixture, after which it was stirred at 80° C. for 4 hours. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 2 mg of the title compound (yield: 21%).

¹ H NMR (400 MHz, MeOD) δ 8.80 (d, J=5.4 Hz, 1H), 7.81 (d, J=5.4 Hz, 1H), 7.24 (m, 4H), 2.68 (t, J=7.6 Hz, 2Н), 2.58 (t, J=7.6 Hz, 2Н), 2.12-2.08 (m, 2Н), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H) , [M+1] ⁺ =418

Example 183 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)urea

1-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (10 mg, 0.011 mmol) prepared in Example 132, bis(triphenylphosphine)palladium(N) chloride (0.392 mg , 1.118 µmol) and copper(I) iodide (0.213 mg, 1.118 µmol) were dissolved in dimethylformamide (1.5 ml). Triethylamine (0.016 ml, 0.112 mmol) was slowly added to this mixture. (4-ethynylphenyl)methanol (2.95 mg, 0.022 mmol) was added to the reaction mixture, after which it was stirred at 80° C. for 4 hours. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 0.5 mg of the title compound (yield: 5%).

¹ H NMR (400 MHz, MeOD) δ 8.80 (d, J=5.4 Hz, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.38 (m, 6H), 4.63 (s, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1 ] ⁺ =452

Example 184: N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl ]-4-carboxamide

Stage 1: 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-carboxylic acid

Solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (30 mg, 0.067 mmol) prepared in Example 132, cesium carbonate (54.6 mg, 0.168 mmol) , 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (11 mg, 0.067 mmol) and PdCl ₂ (dppf) (5.48 mg, 0.0671 mmol) in a mixed solvent of dimethylformamide and water (5:1) (0.6 ml) was reacted at 120° C. for 30 minutes using a microwave oven. After completion of the reaction, water and ethyl acetate were added to the mixture, and the organic layer was extracted. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to give 3.5 mg of the title compound (white solid, yield: 10%).

Step 2: N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl ]-4-carboxamide

4'-(3-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-carboxylic acid (3 mg, 6.80 µmol) prepared in Step 1 , was dissolved in dimethylformamide (1 ml). 2-(1H-imidazol-4-yl)ethanamine dihydrochloride (1.251 mg, 6.80 µmol), 2-(3H-[1.2.3]triazolo[4,5-b]pyridine-3- yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (3.10 mg, 8.15 µmol) and Hunig's base (5.93 µl, 0.034 mmol). The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 2 mg of the title compound (yield: 55%).

¹ H NMR (400 MHz, MeOD) δ 8.83 (d, J=5.4 Hz, 1H), 8.81 (s, 1H), 7.85 (m, 3H), 7.69 (d, J=8.5 Hz, 2H), 7.59 ( d, J=8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.38 (s, 1H), 3.73 (t, J=6.7 Hz, 2H), 3.06 (t, J=5.5 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =535

Example 185: N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl ]-4-carboxamide

4'-(3-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-carboxylic acid (3 mg, 6.80 µmol) prepared in Step 1 example 184, was dissolved in dimethylformamide (1 ml). 2-(1H-imidazol-1-yl)ethanamine (0.755 mg, 6.80 µmol), 2-(3H-[1.2.3]triazolo[4,5-b]pyridin-3-yl )-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (3.10 mg, 8.15 µmol) and Hunig's base (5.93 µl, 0.034 mmol). The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 1.5 mg of the title compound (yield: 41%).

¹ H NMR (400 MHz, MeOD) δ 8.92 (s, 1H), 8.81 (d, J=5.4 Hz, 1H), 7.85 (m, 3H), 7.68 (m, 3H), 7.58 (m, 3H), 7.42 (d, J=8.6 Hz, 2H), 4.50 (t, J=5.5 Hz, 2H), 3.87 (t, J=5.5 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m , 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =535.

Example 186: N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1 ,1'-diphenyl]-4-carboxamide

Step 1: 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-biphenyl]-4-carboxylic acid

A solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-fluoro-4-iodophenyl)urea (100 mg, 0.215 mmol) prepared in Example 137, cesium carbonate (175 mg, 0.537 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (53 mg, 0.215 mmol) and PdCl ₂ (dppf) (17.55 mg, 0.021 mmol) in a mixed solvent of dimethylformamide and water (5:1) (1 ml) was reacted at 120° C. for 30 minutes using a microwave oven. After completion of the reaction, water and ethyl acetate were added to the mixture, and the organic layer was extracted. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 39.6 mg of the title compound (white solid, yield: 40%).

Step 2: N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1 ,1'-diphenyl]-4-carboxamide

4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-carboxylic acid (30 mg, 0.065 mmol) obtained in step 1, dissolved in dimethylformamide (1 ml). 2-(1H-imidazol-1-yl)ethanamine (7.26 mg, 0.065 µmol), 2-(3H-[1.2.3]triazolo[4,5-b]pyridin-3-yl )-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (29.8 mg, 0.078 µmol) and Hunig's base (57.0 µl, 0.326 mmol). The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 7 mg of the title compound (yield: 19.4%).

¹ H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 8.81 (d, J=5.4 Hz, 1H), 7.83 (m, 3H), 7.58 (m, 4H), 7.41 (m, 2H), 7.09 (dd, J=2.1 Hz, J=8.4 Hz, 1H), 4.50 (t, J=5.6 Hz, 2H), 4.50 (t, J=5.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =553.

Example 187: N-(2-(2H-1,2,3-triazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2 '-fluoro-[1,1'-diphenyl]-4-carboxamide

4'-(3-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-carboxylic acid (30 mg, 0.065 mmol) obtained in step 1 of example 186, was dissolved in dimethylformamide (1 ml). 2-(1H-1,2,3-triazol-1-yl)ethanamine (7.32 mg, 0.065 mmol), 2-(3H-[1,2,3]triazolo[4,5-b ]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (29.8 mg, 0.078 mmol) and Hunig's base (57.0 μl, 0.326 mmol). The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 6 mg of the title compound (yield: 17%).

¹ H NMR (400 MHz, MeOD): 8.81 (d, J=5.4 Hz, 1H), 8.03 (s, 1H), 7.83 (m, 3H), 7.76 (s, 1H), 7.41 (m, 2H), 7.09 (dd, J=2.1Hz, J=8.4Hz 1H), 4.72 (t, J=5.6Hz, 2H), 3.89 (t, J=5.6Hz, 2H), 2.12-2.08 (m, 2H), 1.93 -1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =554.

Example 188: N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2 '-fluoro-[1,1'-diphenyl]-4-carboxamide

4'-(3-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-carboxylic acid (30 mg, 0.065 mmol) obtained in step 1 of example 186, was dissolved in dimethylformamide (1 ml). 2-(2H-1,2,3-triazol-2-yl)ethan-1-amine (7.32 mg, 0.065 mmol), 2-(3H-[1,2,3]triazolo[4 ,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (29.8 mg, 0.078 mmol) and Hunig's base (57.0 μl, 0.326 mmol). The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 3.5 mg of the title compound (yield: 10%).

¹ H NMR (400 MHz, MeOD): 8.70 (d, J=5.4 Hz, 1H), 7.71 (m, 3H), 7.67 (s, 2H), 7.48 (m, 2H), 7.28 (m, 2H), 6.97 (dd, J=2.1Hz, J=8.4Hz 1H), 4.61 (t, J=5.6Hz, 2H), 3.78 (t, J=5.6Hz, 2H), 2.12-2.08 (m, 2H), 1.93 -1.85 (m, 2H), 1.64-1.52 (m, 4H), 1.35-1.25 (m, 2H), [M+1] ⁺ =554.

Example 189: N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)- [1,1'-diphenyl]-4-carboxamide

4'-(3-(1-(2-Cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-carboxylic acid (10 mg, 0.02 mmol) obtained in example 163 was dissolved in dimethylformamide (0.2 ml). 2-(1H-imidazol-4-yl)ethanamine dihydrochloride (3.61 mg, 0.02 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridine- 3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (8.96 mg, 0.024 µmol) and diisopropylethylamine (17 µl, 0.098 mmol) followed by overnight stirring. The reaction mixture was purified by preparative HPLC to give 5.6 mg of the title compound (brown solid, 47% yield).

¹ H NMR (400 MHz, MeOD) δ 8.72-8.70 (m, 2H), 7.74 (d, J=5.44 Hz, 2H), 7.7 (d, J=8.28 Hz, 2H), 7.43 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 7.28 (d, J=1.96 Hz, 2H), 7.26 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 3.62 (t, J=6.66 Hz, 2H), 2.95 (t, J=6.64 Hz, 2H), 2.14-2.10 (m, 2H), 1.93-1.84 (m, 2H), 1.66-1.56 (m, 4H), 1.35-1.27 (m, 2H)

Purity by HPLC=93%

MSNR (ESI): m/z=603 [M+H]+

Example 190 1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

Step 1: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea

A solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea (100 mg, 0.224 mmol) prepared in Example 132, cesium carbonate (182 mg, 0.560 mmol), ( 4-hydroxyphenyl)boronic acid (30.8 mg, 0.224 mmol) and PdCl ₂ (dppf) (18 mg, 0.022 mmol) in a mixed solvent of dimethylformamide and water (5:1) (1 ml) were reacted at 120°C in for 30 minutes using the microwave. After completion of the reaction, water and ethyl acetate were added to the mixture, and the organic layer was extracted. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and then distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 52 mg of the title compound (white solid, yield: 56%).

Step 2: 1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea

tert-butyl (2-hydroxyethyl)carbamate (17.54 mg, 0.109 mmol) and triphenylphosphine (28.5 mg, 0.109 mmol) were added to methylene chloride (0.363 ml). Diisopropyl azodicarboxylate (21.43 μl, 0.109 mmol) was added to the mixture at 0° C., followed by stirring for 10 minutes. To the mixture was added a solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea obtained in step 1 (15 mg , 0.036 mmol) in methylene chloride (0.363 ml) at 0°C, and then it was stirred for 12 hours. The reaction mixture was distilled under reduced pressure. The resulting residue was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was dissolved in methylene chloride (0.5 ml) and then 2,2,2-trifluoroacetic acid (0.1 ml) was added with stirring. The reaction mixture was distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 1.5 mg of the title compound (yield: 8.95%).

¹ H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.44 Hz, 1H), 7.84 (d, J=5.44 Hz, 1H), 7.55 (d, J=8.80 Hz, 2H), 7.48 (d, J=8.72 Hz, 2H), 7.36 (d, J=8.72 Hz, 2H), 7.08 (d, J=8.80 Hz, 2H), 4.28 (m, 2H), 3.40 (m, 2H), 2.24 (d, J=13.2 Hz, 2H), 2.05 (m, 2H), 1.70 (m, 5H), 1.47 (m, 1H). [M+H] ⁺ =457.10.

Example 191 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(methylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea

tert-butyl (2-hydroxyethyl)(methyl)carbamate (66.1 mg, 0.377 mmol) and triphenylphosphine (99 mg, 0.377 mmol) were added to methylene chloride (1.258 ml). Diisopropyl azodicarboxylate (74.3 μl, 0.377 mmol) was added to the mixture at 0° C., followed by stirring for 10 minutes. To the mixture was added a solution of 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea ( 52 mg, 0.126 mmol) in methylene chloride (1.258 ml) at 0°C, and then it was stirred for 12 hours. The reaction mixture was distilled under reduced pressure. The resulting residue was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure. The resulting residue was dissolved in methylene chloride (4 ml) and then 2,2,2-trifluoroacetic acid (0.4 ml) was added with stirring. The reaction mixture was distilled under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 32 mg of the title compound (yield: 99.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J=5.48 Hz, 1H), 8.80 (s, 1H), 8.64 (s, 2H), 7.88 (d, J=5.44 Hz, 1H) , 7.57 (m, 2H), 7.48 (d, J=8.76 Hz, 2H), 7.38 (d, J=8.76 Hz, 2H), 7.05 (d, J=8.80 Hz, 2H), 6.86 (s, 1H) , 4.26 (m, 2H), 3.37 (m, 2H), 2.66 (t, J=5.44 Hz, 3H), 2.12 (d, J=12.40 Hz, 2H), 1.88 (m, 2H), 1.70 (s, 5H), 1.39 (s, 1H), 1.34 (m, 1H). [M+H] ⁺ =471.0.

Experimental example: analysis of inhibitory activity against cathepsin K, B, L and S

To measure the enzymatic activity of cathepsin K, a buffer solution (pH 5.5) was prepared, consisting of 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 2 mM dithiothreitol (DTT), 2.5 mM ethylenediaminetetraacetic acid (EDTA), 0.01% Triton X-100 and 10% dimethyl sulfoxide (DMSO). Substrate, test material and enzyme were mixed in this buffer solution at a predetermined concentration. The Z-Phe-Arg-AMC substrate was used at a final concentration of 10 μM. The test material was used at final concentrations of 10.0 µM, 3.33 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.00457 µM, 0.00152 µM and 0.000508 µM, respectively. Cathepsin K enzyme was used at a final concentration of 1 nM. The final volume of solution for the enzymatic reaction was 10 μl. After reacting the mixture of substrate, test material and enzyme for 30 minutes, enzymatic activity was measured using a Synergy Neo microplate reader (Biotek) at an absorption wavelength of 355 nm and an emission wavelength of 460 nm. IC ₅₀ values were determined using GraphPad Prism 4-parameter logistic curve fitting software.

To measure the enzymatic activity of cathepsin B, a buffer solution was prepared (pH 6.0) consisting of 50 mM MES, 5 mM DTT, 2.5 mM EDTA, 0.005% polysorbate 20, and 10% DMSO. Substrate, test material and enzyme were mixed in this buffer solution at a predetermined concentration. The Z-Arg-Arg-AMC substrate was used at a final concentration of 40 μM. The test material was used at final concentrations of 10.0 µM, 3.33 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.00457 µM, 0.00152 µM and 0.000508 µM, respectively. Cathepsin B enzyme was used at a final concentration of 1 nM. The final volume of solution for the enzymatic reaction was 10 μl. After reacting the mixture of substrate, test material and enzyme for 90 minutes, enzymatic activity was measured using an EnVision microplate reader (Perkin Elmer) at an absorption wavelength of 340 nm and an emission wavelength of 460 nm. IC ₅₀ values were determined using GraphPad Prism 4-parameter logistic curve fitting software.

To measure the enzymatic activity of cathepsin L, a buffer solution (pH 5.5) was prepared, consisting of 50 mM MES, 2.5 mM DTT, 2.5 mM EDTA, 0.005% polysorbate 20, and 10% DMSO. Substrate, test material and enzyme were mixed in this buffer solution at a predetermined concentration. The Z-Phe-Arg-AMC substrate was used at a final concentration of 2 μM. The test material was used at final concentrations of 10.0 µM, 3.33 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.00457 µM, 0.00152 µM and 0.000508 µM, respectively. The cathepsin L enzyme was used at a final concentration of 3 nM. The final volume of solution for the enzymatic reaction was 10 μl. After reacting the mixture of substrate, test material and enzyme for 30 minutes, enzymatic activity was measured using an EnVision microplate reader (Perkin Elmer) at an absorption wavelength of 340 nm and an emission wavelength of 460 nm. IC ₅₀ values were determined using GraphPad Prism 4-parameter logistic curve fitting software.

To measure the enzymatic activity of cathepsin S, a buffer solution was prepared (pH 6.5) consisting of 50 mM MES, 2.5 mM DTT, 1.0 mM EDTA, 0.001% bovine serum albumin (BSA), and 10% DMSO. Substrate, test material and enzyme were mixed in this buffer solution at a predetermined concentration. The Z-Phe-Arg-AMC substrate was used at a final concentration of 70 μM. The test material was used at final concentrations of 10.0 µM, 3.33 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.00457 µM, 0.00152 µM and 0.000508 µM, respectively. Cathepsin S enzyme was used at a final concentration of 3 nM. The final volume of solution for the enzymatic reaction was 10 µl. After reacting the mixture of substrate, test material and enzyme for 45 minutes, enzymatic activity was measured using an EnVision microplate reader (Perkin Elmer) at an absorption wavelength of 340 nm and an emission wavelength of 460 nm. IC ₅₀ values were determined using GraphPad Prism 4-parameter logistic curve fitting software.

IC ₅₀ values against cathepsin enzymes K, B, L and S, obtained by the measurement described above, are shown in the following tables 1-7.

As can be seen from the results presented in Tables 1-7, the compounds of the present invention exhibit selective inhibitory activity against cathepsin K and therefore can be successfully used for the prevention and treatment of osteoporosis.

Claims (282)

1. The compound according to formula 1 or its pharmaceutically acceptable salt: <Formula 1>

, in which A represents a chemical bond, -CH ₂ - or -C (CH ₃ ) ₂ -, L represents -(CH ₂ ) _m -O-, -(CH ₂ ) _n -NH-, -CH(CH ₃ )-NH- or -N(CH ₃ )-, m is 1 or 2, n is 0, 1 or 2, Ar is an aromatic ring selected from the group consisting of phenyl, phenoxyphenyl, pyridinylphenyl, indazolylphenyl, morpholinylphenyl, piperazinylphenyl, piperidinylphenyl, pyrazolylphenyl, benzylphenyl, phenylaminophenyl, diphenyl, piperazinylbiphenyl, morpholinylbiphenyl, naphthyl, benzodioxolyl, furanyl, indazolyl, quinoxalinyl and indanyl, and aromatic ring is selectively substituted with one to three substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, C₁~C_four alkyl, C₃~C₆ cycloalkyl, C₁~C_four alkoxy, hydroxy-C₁~C_four alkyl, C₁~C_four alkoxy-C₁~C_four alkyl, hydroxycarbonyl-C₁~C_four alkyl, C₁~C_four alkoxycarbonyl-C₁~C_four alkyl, C₁~C_four alkoxy-C₁~C_four alkoxy-C₁~C_four alkyl, C₁~C_four alkylcarbonylamino-C₁~C_four alkyl, amino-C₁~C_four alkoxy, mono- or di-C₁~C_four alkylamino-C₁~C_four alkoxy, aminosulfonyl, C₁~C_four alkylsulfonyl, trifluoromethylsulfonyl, C₃~C₆ cycloalkylaminosulfonyl, mono- or di-C₁~C_four alkylamino, C₁~C_four alkylcarbonylamino, methanesulfonylamino, C₁~C_four alkylcarbonyl, hydroxycarbonyl, mono- or di-C₁~C_four alkylaminocarbonyl, oxolanyl-C₁~C_four alkylaminocarbonyl, di-C₁~C_four alkylamino-C₁~C_four alkylaminocarbonyl, imidazolyl-C₁~C_four alkylaminocarbonyl, C₁~C_four alkoxy-C₁~C_four alkylaminocarbonyl, C₃~C₆ cycloalkylaminocarbonyl, pyrrolidinylcarbonyl, triazolyl-C₁~C_four alkylaminocarbonyl, C₁~C_four alkoxycarbonyl-C₂~C_four alkynyl, hydroxycarbonyl-C₂~C_four alkynyl, hydroxy-C₁~C_four alkylphenyl-C₂~C_four alkynyl and C₁~C_four alkoxy-C₁~C_four alkylphenoxymethyl, or a compound selected from the group consisting of 1-(4-(2-cyanopyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea and 1 -(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea, or a pharmaceutically acceptable salt thereof. 2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic ring is optionally substituted with one to three substituents selected from the group consisting of halo, cyano, hydroxy, trifluoromethyl, C ₁ ~C ₄ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₄ alkoxy, hydroxymethyl, methoxymethyl, hydroxycarbonylmethyl, hydroxycarbonylethyl, methoxycarbonylmethyl, methoxyethoxymethyl, acetylaminomethyl, aminoethoxy, methylaminoethoxy, dimethylaminoethoxy, aminosulfonyl, methanesulfonyl, trifluoromethylsulfonyl, cyclopropylaminosulfonyl, mono- or di-C _{1 ~} alkylamino, acetylamino, methanesulfonylamino, acetyl, hydroxycarbonyl, dimethylaminocarbonyl, oxolanylmethylaminocarbonyl, dimethylaminoethylaminocarbonyl, imidazolylethylaminocarbonyl, methoxyethylaminocarbonyl, cyclopropylaminocarbonyl, pyrrolidinylcarbonyl, triazolylethylaminocarbonyl, methoxycarbonylbutynyl, hydroxyethylphenylmethylbutynyl, and hydroxyethylmethylbutynylbutynyl. 3. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic ring is substituted with one or two substituents selected from the group consisting of halogen, C ₁ ~C ₄ alkyl and acetyl. 4. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A represents -CH ₂ -, L is -(CH ₂ ) _n -NH-, n is 0 Ar is an aromatic ring selected from the group consisting of diphenyl, piperazinyl-biphenyl and morpholinyl-biphenyl, and the aromatic ring is substituted with one or two substituents selected from the group consisting of halogen, C ₁ ~C ₄ alkyl and acetyl. 5. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A represents -CH ₂ -, L is -(CH ₂ ) _n -NH-, n is 0 Ar is a piperazinyl-diphenyl group substituted with one or two substituents selected from the group consisting of halo and C ₁ ~C ₄ alkyl. 6. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: benzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; phenethyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-methoxybenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-cyanobenzyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; benzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 3-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 3-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 3-(trifluoromethyl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 3-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 3-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-bromobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-(trifluoromethyl)benzyl-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-methoxybenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-methylbenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-(trifluoromethyl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-methoxybenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; naphthalene-1-ylmethyl(1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 4-fluorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; 2-chlorobenzyl (1-(2-cyanopyrimidin-4-yl)cyclohexyl)carbamate; (4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)methyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; (4'-(methylsulfonyl)-[1,1'-diphenyl]-3-yl)methyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; (4'-morpholino-[1,1'-diphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; (4'-morpholino-[1,1'-diphenyl]-3-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 4-(6-fluoropyridin-3-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 4-(1-methyl-1H-indazol-6-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-(6-fluoropyridin-3-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 3-(1-methyl-1H-indazol-6-yl)benzyl(1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(ortho-tolyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(meta-tolyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(para-tolyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-fluorobenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-phenylureas; 1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea; 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-phenoxyphenyl)urea; 4-(2-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)ethyl)benzenesulfonamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methylbenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methylbenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methylbenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethoxybenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-dimethylphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-phenylethyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(piperazin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(furan-3-ylmethyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-fluorobenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-1-ylmethyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)benzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)benzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)benzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,4-dimethylphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3,5-dimethylphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dimethylphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,5-difluorophenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(5-fluoro-2-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxybenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxybenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxybenzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-hydroxyphenyl)urea; 4-(3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)ureido)benzenesulfonamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-hydroxyphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-1-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(naphthalen-2-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(1-methyl-1H-indazol-5-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(quinoxalin-6-yl)urea; 1-(benzo[d][1,3]dioxol-5-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-methoxyphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(3-methoxyphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(4-methoxyphenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2,3-dihydro-1H-inden-5-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclopentyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)-4,4-dimethylcyclohexyl)-3-(2,5-dimethylphenyl)urea; 1-(4-(2-cyanopyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-phenylureas; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,5-dimethylphenyl)urea; 1-benzyl-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)benzyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-methylphenyl)urea; 1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea; 2-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-4-(trifluoromethyl)benzoic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea; 1-(4-benzylphenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(phenylamino)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-hydroxyphenyl)urea; 1-(2,5-bis(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-methyl-1-phenylurea; 3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methylurea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2,4-difluoro-5-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(methoxymethyl)-5-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(hydroxymethyl)-5-(trifluoromethyl)phenyl)urea; 1-(3-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(4-bromophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-([1,1'-diphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)urea; 1-([1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-morpholino-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-indazol-6-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-4-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-fluoro-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-fluoro-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-fluoropyridin-3-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(6-methoxypyridin-3-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(pyridin-3-yl)phenyl)urea; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1'-diphenyl]-4-carboxamide; 3-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)propanoic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodophenyl)urea; 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(4-bromo-2-fluorophenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)benzoic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-iodo-3-(trifluoromethyl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3-fluoro-4-iodophenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-morpholinophenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(piperazin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea; 1-(4-(4-(tert-butyl)piperazin-1-yl)phenyl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-isopropylpiperidin-1-yl)phenyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1'-diphenyl]-4-carboxamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-biphenyl]-4-sulfonamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-carboxamide; 1-(3'-chloro-4'-(pyrrolidin-1-carbonyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea ; N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methyl)acetamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; 1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; methyl 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetate; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((2-methoxyethoxy)methyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1'-diphenyl]-4-carboxamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1'-diphenyl]-4-carboxamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylic acid; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)acetamide; N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)methyl)acetamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-sulfonamide; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methanesulfonamide; methyl 5-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)pent-4-inoate; 1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)-4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea ; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2,3'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl) urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-sulfonamide; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)methanesulfonamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)methyl)urea ; 5-(4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)phenyl)pent-4-ic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)urea; N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide; N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide; N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1' -diphenyl]-4-carboxamide; N-(2-(2H-1,2,3-triazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-biphenyl]-4-carboxamide; N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-biphenyl]-4-carboxamide; N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1, 1'-diphenyl]-4-carboxamide; 1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; and 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(methylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea. 7. A compound or pharmaceutically acceptable salt according to claim 1, wherein said compound is selected from the group consisting of: 1-([1,1'-diphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)urea; 1-([1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-hydroxy-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-morpholino-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-fluoro-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-ethynyl-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-fluoro-[1,1'-diphenyl]-4-yl)urea; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1'-diphenyl]-4-carboxamide; 3-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)propanoic acid; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1'-diphenyl]-4-carboxamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-biphenyl]-4-sulfonamide 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-cyclopropyl-[1,1'-diphenyl]-4-carboxamide; 1-(3'-chloro-4'-(pyrrolidin-1-carbonyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea ; N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methyl)acetamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; 1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; methyl 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetate; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((2-methoxyethoxy)methyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1'-diphenyl]-4-carboxamide; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1'-diphenyl]-4-carboxamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; 2-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)acetic acid; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylic acid; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)acetamide; N-((4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1'-diphenyl]-4-yl)methyl)acetamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1'-diphenyl]-4-yl) urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3'-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-sulfonamide; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)methanesulfonamide; methyl 5-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4-yl)pent-4-inoate; 1-(2,2'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-(trifluoromethyl)-4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-4-yl)urea ; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(methylsulfonyl)-2,3'-bis(trifluoromethyl)-[1,1'-diphenyl]-4-yl) urea; 4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-sulfonamide; N-(4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1,1'-diphenyl]-4-yl)methanesulfonamide; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)methyl)urea ; N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide; N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1'-diphenyl]-4 -carboxamide; N-(2-(1H-imidazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro-[1,1' -diphenyl]-4-carboxamide; N-(2-(2H-1,2,3-triazol-1-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-biphenyl]-4-carboxamide; N-(2-(2H-1,2,3-triazol-2-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-fluoro -[1,1'-biphenyl]-4-carboxamide; N-(2-(1H-imidazol-4-yl)ethyl)-4'-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2'-(trifluoromethyl)-[1, 1'-diphenyl]-4-carboxamide; 1-(4'-(2-aminoethoxy)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; and 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(2-(methylamino)ethoxy)-[1,1'-diphenyl]-4-yl)urea. 8. A compound or pharmaceutically acceptable salt according to claim 1, wherein said compound is selected from the group consisting of: 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; 1-(4'-(4-acetylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea; 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-ethylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl)urea; and 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1-yl)-[1,1'-diphenyl]-4-yl) urea. 9. A compound or pharmaceutically acceptable salt according to claim 1, wherein said compound is 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4'-(4-isopropylpiperazin-1-yl)- [1,1'-diphenyl]-4-yl)urea. 10. A compound or pharmaceutically acceptable salt according to claim 1, wherein said compound is 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4'-(4-isopropylpiperazin-1 -yl)-[1,1'-biphenyl]-4-yl)urea. 11. Pharmaceutical composition for the prevention or treatment of osteoporosis by selective inhibition of cathepsin K, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-10 and a pharmaceutically acceptable carrier. 12. Reagent for the inhibition of cathepsin K, containing a compound or salt according to any one of paragraphs. 1-10.