# US 11,299,478 B2 · 2-cyanopyrimidin-4-yl carbamate or urea derivative or salt thereof, and pharmaceutical composition including same

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- Number: US 11,299,478 B2
- Document ID: US11299478B2
- Status: Granted
- Kind: B2
- Application number: 17/041,883
- Filed: 2019-03-20
- Published: 2021-02-18
- Granted: 2022-04-12
- Earliest claimed: 2018-03-28
- Assignees: Hanlim Pharmaceutical Co., Ltd.
- Applicants: Hanlim Pharmaceutical Co., Ltd.
- Inventors: Kyung-Hee Kim; Jung-Wook Chin; Ji-Hoon Lee; Shin-Ae Kim; Kyung-Jin Jung; Jun-Woo Kim; Sang-Hyun Min; Ji-Hoon Yu; Ju-Suk Lee; Won-Seok Lee; Jae-Young Song; Eung-Seok Lee; Tae-Cheon Jeong; Jung-Ae Kim
- Web page: https://patentgrep.com/patent/US11299478B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 19/10: for osteoporosis
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided is a 2-cyanopyrimidin-4-yl carbamate or urea derivative or pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The 2-cyanopyrimidin-4-yl carbamate or urea derivative or pharmaceutically acceptable salt thereof selectively inhibits cathepsin K and therefore can be usefully applied for preventing or treating osteoporosis.

## Claims

### Claim 1

A compound of Formula 1 or pharmaceutically acceptable salt thereof:
wherein,
A is a bond, —CH2—, —O—, 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 the group consisting of phenyl, phenoxy-phenyl, pyridinyl-phenyl, indazolyl-phenyl, morpholinyl-phenyl, piperazinyl-phenyl, piperidinyl-phenyl, pyrazolyl-phenyl, benzyl-phenyl, phenylaminophenyl, biphenyl, piperazinyl-biphenyl, morpholinyl-biphenyl, naphthyl, benzodioxolyl, furanyl, indazolyl, quinoxalinyl, and indanyl, and
the aromatic ring is optionally substituted with one to three substituents selected from the 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-C1˜C4 alkyl, C1˜C4 alkylcarbonylamino-C1˜C4 alkyl, amino-C1˜C4 alkoxy, mono- or di-C1˜C4 alkylamino-C1˜C4 alkoxy, aminosulfonyl, C1˜C4 alkyl-sulfonyl, trifluoromethylsulfonyl, C3˜C6 cycloalkylaminosulfonyl, mono- or di-C1˜C4 alkylamino, C1˜C4 alkylcarbonylamino, methanesulfonylamino, C1˜C4 alkylcarbonyl, 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 cycloalkylaminocarbonyl, pyrrolidinylcarbonyl, triazolyl-C1˜C4 alkylaminocarbonyl, C1˜C4 alkoxycarbonyl-C2˜C4 alkynyl, hydroxycarbonyl-C2˜C4 alkynyl, hydroxy-C1˜C4 alkylphenyl-C2˜C4 alkynyl, and C1˜C4 alkoxy-C1˜C4 alkyl-phenoxymethyl.

### Claim 2 (depends on 1)

The 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 halogen, cyano, hydroxy, trifluoromethyl, C1˜C4 alkyl, C3˜C6 cycloalkyl, C1˜C4 alkoxy, hydroxymethyl, methoxymethyl, hydroxycarbonylmethyl, hydroxycarbonylethyl, methoxycarbonylmethyl, methoxyethoxymethyl, acetylaminomethyl, aminoethoxy, methylaminoethoxy, dimethylaminoethoxy, aminosulfonyl, methanesulfonyl, trifluoromethylsulfonyl, cyclopropylaminosulfonyl, mono- or di-C1˜C4 alkylamino, acetylamino, methanesulfonylamino, acetyl, hydroxycarbonyl, dimethylaminocarbonyl, oxolanylmethylaminocarbonyl, dimethylaminoethylaminocarbonyl, imidazolylethylaminocarbonyl, methoxyethylaminocarbonyl, cyclopropylaminocarbonyl, pyrrolidinylcarbonyl, triazolylethylam inocarbonyl, methoxycarbonylbutynyl, hydroxycarbonylbutynyl, hydroxymethylphenylethynyl, and methoxyethylphenoxymethyl.

### Claim 3 (depends on 1)

The 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, C1˜C4 alkyl, and acetyl.

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein
A is —CH2—,
L is —(CH2)n—NH—,
n is 0,
Ar is an aromatic ring selected from the group consisting of biphenyl, piperazinyl-biphenyl, and morpholinyl-biphenyl, and
the aromatic ring is substituted with one or two substituents selected from the group consisting of halogen, C1˜C4 alkyl, and acetyl.

### Claim 5 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein
A is —CH2—,
L is —(CH2)n—NH—,
n is 0,
Ar is a piperazinyl-biphenyl group substituted with one or two substituents selected from the group consisting of halogen and C1˜C4 alkyl.

### Claim 6 (depends on 1)

The compound or 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;
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′-biphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;
(4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;
(4′-morpholino-[1,1′-biphenyl]-4-yl)methyl (1-(2-cyanopyrimidin-4-yl)cyclopentyl)carbamate;
(4′-morpholino-[1,1′-biphenyl]-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-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′-biphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)urea;
1-([1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-hydroxy-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-morpholino-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-ethynyl-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3′-fluoro-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2′-fluoro-[1,1′-biphenyl]-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′-biphenyl]-4-yl)acetamide;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide;
3-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-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′-biphenyl]-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′-biphenyl]-4-carboxamide;
1-(3′-chloro-4′-(pyrrolidin-1-carbonyl)-[1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
N-((4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)methyl)acetamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
1-(4′-(4-acetylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
methyl 2-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)acetate;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((2-methoxyethoxy)methyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-4-carboxamide;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-carboxamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-ethylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
2-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)acetic acid;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)acetamide;
N-((4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-fluoro-[1,1′-biphenyl]-4-yl)methyl)acetamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((trifluoromethyl)sulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3′-fluoro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-sulfonamide;
N-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)methanesulfonamide;
methyl 5-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)pent-4-ynoate;
1-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-2,3′-bis(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-sulfonamide;
N-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methanesulfonamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)urea;
5-(4-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)phenyl)pent-4-ynoic 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′-biphenyl]-4-carboxamide;
N-(2-(1H-imidazol-1-yl)ethyl)-4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-carboxamide;
N-(2-(1H-imidazol-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-(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′-biphenyl]-4-carboxamide;
1-(4′-(2-aminoethoxy)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea.

### Claim 7 (depends on 1)

The compound or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from the group consisting of:
1-([1,1′-biphenyl]-3-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)urea;
1-([1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-hydroxy-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-morpholino-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-fluoro-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-ethynyl-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3′-fluoro-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2′-fluoro-[1,1′-biphenyl]-4-yl)urea;
N-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)acetamide;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide;
3-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)propanoic acid;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-methoxyethyl)-[1,1′-biphenyl]-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′-biphenyl]-4-carboxamide;
1-(3′-chloro-4′-(pyrrolidin-1-carbonyl)-[1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
N-((4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)methyl)acetamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((4-(2-methoxyethyl)phenoxy)methyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
1-(4′-(4-acetylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)-3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)urea;
methyl 2-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)acetate;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((2-methoxyethoxy)methyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-((tetrahydrofuran-2-yl)methyl)-[1,1′-biphenyl]-4-carboxamide;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-N-(2-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-carboxamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-ethylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
2-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)acetic acid;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-2-(trifluoromethyl)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)acetamide;
N-((4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-fluoro-[1,1′-biphenyl]-4-yl)methyl)acetamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(1-cyclopropylpiperidin-4-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-((trifluoromethyl)sulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(3′-fluoro-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-sulfonamide;
N-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)methanesulfonamide;
methyl 5-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-yl)pent-4-ynoate;
1-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(methylsulfonyl)-2,3′-bis(trifluoromethyl)-[1,1′-biphenyl]-4-yl)urea;
4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-sulfonamide;
N-(4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methanesulfonamide;
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-((4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)urea;
N-(2-(1H-imidazol-4-yl)ethyl)-4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-carboxamide;
N-(2-(1H-imidazol-1-yl)ethyl)-4′-(3-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)ureido)-[1,1′-biphenyl]-4-carboxamide;
N-(2-(1H-imidazol-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-(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′-biphenyl]-4-carboxamide;
1-(4′-(2-aminoethoxy)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea.

### Claim 8 (depends on 1)

The compound or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from the group consisting of:
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea;
1-(4′-(4-acetylpiperazin-1-yl)-[1,1′-biphenyl]-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′-biphenyl]-4-yl)urea; and
1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea.

### Claim 9 (depends on 1)

The compound or pharmaceutically acceptable salt according to claim 1, wherein the compound is 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea.

### Claim 10 (depends on 1)

The compound or pharmaceutically acceptable salt according to claim 1, wherein the compound is 1-(1-(2-cyanopyrimidin-4-yl)cyclohexyl)-3-(2-fluoro-4′-(4-isopropylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)urea.

### Claim 11 (depends on 1)

A method for preventing or treating osteoporosis comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1; and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A reagent composition for inhibiting cathepsin K comprising the compound or salt thereof according to claim 1.