Inhibitors of protease-activated receptor-2

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is F;

X is CH;

Y is C or N; and

Z is C or N, wherein Y and Z are not both N, and

(1) when both Z and Y are C, the bond “ ” is a double bond, and

R 1 is selected from C 2-6 alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl, wherein R 1 is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR a R b ′, —N(R a )C(O) alkyl; —N(R a )CO 2 alkyl; —N(R a )SO 2 alkyl; —C(O)alkyl; —CO 2 H; —CO 2 alkyl; —CONR a R b ; —SO 2 alkyl; and —SO 2 NR a R b ; wherein R a and R b are independently for each occurrence H or alkyl;

R 2 is H or halogen; or

R 1 and R 2 may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms or heteroatom groups independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is substituted with 0-3 R, and wherein said ring is optionally fused to a C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR a R b; , —N(R a )C(O) alkyl; —N(R a )CO 2 alkyl; —N(R a )SO 2 alkyl; —C(O)alkyl; —CO 2 H; —CO 2 alkyl; —CONR a R b ; —SO 2 alkyl; and —SO 2 NR a R b ; wherein R a and R b are independently for each occurrence H or alkyl; or

(2) when one of Z and Y is N, the other is C, the bond “ ” is a single bond, and R 1 and R 2 are taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring having 1-3 heteroatoms or heteroatom groups independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is substituted with 0-3 R, and wherein said ring is optionally fused to a C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said C 6-10 aryl, 5-to 10-membered heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR a R b; , —N(R a )C(O) alkyl; —N(R a )CO 2 alkyl; —N(R a )SO 2 alkyl; —C(O)alkyl; —CO 2 H; —CO 2 alkyl; —CONR a R b ; —SO 2 alkyl; and —SO 2 NR a R b ; wherein R a and R b are independently for each occurrence H or alkyl.

2. The compound of claim 1 , wherein both Z and Y are C and R 1 is C 2-6 alkyl optionally substituted with 0-3 R.

3. The compound of claim 2 , wherein R 2 is —H.

4. The compound of claim 1 , wherein the structure

is selected from:

wherein R 5 is —H or —C 1-3 alkyl, n is selected from 0-3.

5. The compound of claim 1 , wherein the structure

is selected from:

6. The compound of claim 1 , wherein the structure

is selected from:

7. The compound of claim 1 which is selected from the group consisting of:

(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(R)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(2-Cyclopentenyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(2-Cyclopentyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(2-Cyclobutyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(E)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol;

(Z)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol;

(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(R)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(S)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(R)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(S)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(R)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(S)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(2-(Azetidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(3-fluoro-3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-((S)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-((R)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(2-(3,3-Difluoropyrrolidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-((R)-3-methylpyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;

(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(2-(Bicyclo[3.1.0]hexan-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(oxazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(thiazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol;

(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(R)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(S)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(8-Fluoro-3-methylindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(8-Fluoro-3-isopropylindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(3-Cyclopropyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(R)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(S)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(R)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(S)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;

(R)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;

(S)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;

(7-Fluoro-3-methylbenzofuran-4-yl)(1H-imidazol-2-yl)methanol;

(4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;

(R)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;

(S)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;

(1-Ethyl-4-fluoro-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-8-methylnaphthalen-1-yl)(1H-imidazol-2-yl)methanol;

(1-Ethyl-5-fluoro-indolizin-8-yl)-(1H-imidazol-2-yl)methanol;

(3-Chloro-8-fluoro-indolizin-5-yl)-(1H-imidazol-2-yl)methanol;

(4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-2-(thiazol-2-yl)phenyl)(1H-imidazol-2-yl)methanol;

[7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1H-imidazol-2-yl)methanol;

and pharmaceutically acceptable salts thereof.

8. The compound of claim 1 , wherein the compound is selected from:

(R)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(2-(3,3-Difluoropyrrolidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;

(S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

(4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol;

(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;

(S)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(R)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;

(4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol;

(R)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;

(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;

and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising (a) a compound of claim 1 and (b) a pharmaceutically acceptable excipient.

10. A method of treating a disease or disorder mediated by PAR2 activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of claim 1 .

11. The method of claim 10 , wherein the disease or disorder is pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, or colitis.

12. A method of modulating the activity of PAR2, comprising contacting a cell comprising the PAR2 with an effective amount of at least one compound of claim 1 .

13. A method of treating a disease or disorder in a patient in need thereof, comprising administering a compound of claim 1 , wherein the disease or disorder is pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, or colitis.