USE OF AGONISTS OF FORMYL PEPTIDE RECEPTOR 2 FOR TREATING DERMATOLOGICAL DISEASES

Abstract

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

Claims

1. A method of treating dermal inflammation or a dermal disease in a subject in need of such treatment, the method comprising administering to the subject, by local or systemic delivery, a pharmaceutical composition comprising a therapeutically effective amount of at least one formyl peptide receptor 2 (FPR2) agonist, wherein the dermal inflammation or dermal disease is selected from the group consisting of dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, disorders of pigmentation, alopecia, scarring and non-scarring forms.

2. The method of claim 1, wherein the FPR2 agonist is a compound of Formula II: ##STR00203## wherein: a is 1 and b is 0; a is 0 and b is 1; a is 1 and b is 1; R.sup.1 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, —NR.sup.11R.sup.12 or —OR.sup.13; R.sup.2 is optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.3 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.4 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.5 is halogen, —CF.sub.3 or —S(O).sub.nR.sup.14; n is 0, 1 or 2; R.sup.6 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.7 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl; R.sup.8 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.9 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.10 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.9a is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.10a is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl; R.sup.11 is hydrogen or optionally substituted C.sub.1-8 alkyl; R.sup.12 is hydrogen or optionally substituted C.sub.1-8 alkyl; R.sup.13 is hydrogen or optionally substituted C.sub.1-8 alkyl; R.sup.14 is hydrogen, CF.sub.3 or optionally substituted C.sub.1-8 alkyl; and R.sup.15 is hydrogen or optionally substituted C.sub.1-8 alkyl; or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the FPR2 agonist is a compound selected from the group consisting of: ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## and pharmaceutically acceptable salts thereof.

4. The method of claim 1, wherein the treating is by local delivery.

5. The method of claim 4, wherein the local delivery is topical dermal delivery.

6. The method of claim 1, wherein the compound is administered in a form selected from a cream, a lotion, a gel, a solution, a spray and a foam.

7. The method of claim 1, wherein the treating is by systemic delivery.

8. The method of claim 1, wherein the compound is administered intravenously, intramuscularly, intrathecally, subcutaneously, orally or intraperitoneally.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 FPR2 agonists show potent wound healing in a mouse model of punch dermal wound.

[0011] FIG. 2 FPR2 agonists block inflammation induced by LL-37 in mouse ears p<0.05 vs. vehicle, at all-time points.

[0012] FIG. 3. Absorption of FPR2 agonists in an in vitro human skin penetration model.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention relates to a method for treating dermatological inflammation and dermatological diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

[0014] In another aspect, the invention provides the use of at least one agonist of FPR2 for the manufacture of a medicament for the treatment of a dermatological inflammation disease or condition mediated by FPR2 in a mammal

[0015] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/668,835, provided that the compounds have binding activity at the FPR2 receptor.

[0016] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/668,835 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0017] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/668,835 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0018] The compounds disclosed in U.S. patent application Ser. No. 13/668,835 are represented by Formula I:

##STR00001##

wherein:
R.sup.1 is sec-butyl, C.sub.6-10 aryl, —CH.sub.2—(C.sub.6-10)aryl, —CH.sub.2-heterocycle, C.sub.4-8 cycloalkyl or C.sub.3-8 cycloalkenyl or heterocycle;
R.sup.2 is halogen or methyl;
R.sup.3 is halogen;
R.sup.4 is H, methyl or halogen;
R.sup.5 is OR.sup.6 or NH.sub.2; and
R.sup.6 is H or C.sub.2-4 alkyl.

[0019] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/523,579, provided that the compounds have binding activity at the FPR2 receptor.

[0020] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/523,579 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0021] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/523,579 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0022] The compounds disclosed in U.S. patent application Ser. No. 13/523,579 are represented by Formula II:

##STR00002##

wherein:
a is 1 and b is 0;
a is 0 and b is 1;
a is 1 and b is 1;
R.sup.1 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.3-8 cycloalkenyl, —NR.sup.11R.sup.12 or —OR.sup.13;
R.sup.2 is optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.3 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12, NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;
R.sup.4 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12, NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;
R.sup.5 is halogen, —CF.sub.3 or —S(O).sub.nR.sup.14;
n is 0, 1 or 2;
R.sup.6 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12, NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;
R.sup.7 is hydrogen, optionally substituted C.sub.1-8 alkyl, halogen, —COOR.sup.15, —OR.sup.13, —NR.sup.11R.sup.12, NO.sub.2, optionally substituted heterocycle, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.3-8 cycloalkenyl;
R.sup.8 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.9 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.10 is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.9a is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.10a is hydrogen, optionally substituted C.sub.1-8 alkyl or optionally substituted C.sub.6-10 aryl;
R.sup.11 is hydrogen or optionally substituted C.sub.1-8 alkyl;
R.sup.12 is hydrogen or optionally substituted C.sub.1-8 alkyl;
R.sup.13 is hydrogen or optionally substituted C.sub.1-8 alkyl;
R.sup.14 is hydrogen, CF.sub.3 or optionally substituted C.sub.1-8 alkyl; and
R.sup.15 is hydrogen or optionally substituted C.sub.1-8 alkyl.

[0023] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/673,800, provided that the compounds have binding activity at the FPR2 receptor.

[0024] In another aspect, the invention provides the use of at least a compound as disclosed in U.S. patent application Ser. No. 13/673,800 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0025] In another aspect, the invention provides the use of at least a compound as disclosed in U.S. patent application Ser. No. 13/673,800 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0026] The compounds disclosed in U.S. patent application Ser. No. 13/673,800 are represented by Formula III:

##STR00003##

wherein:
R.sup.1 is halogen, hydrogen, optionally substituted C.sub.1-8 alkyl, OR.sup.9, C(O)R.sup.10, NO.sub.2, NR.sup.13R.sup.14, CN, SR.sup.15 or SO.sub.2R.sup.16;
R.sup.2 is halogen, optionally substituted C.sub.1-8 alkyl, CF.sub.3, OR.sup.9, C(O)R.sup.10, NO.sub.2, NR.sup.13R.sup.14, CN, SR.sup.15 or SO.sub.2R.sup.16;
R.sup.3 is hydrogen, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.3-8 cycloalkenyl, optionally substituted C.sub.6-10 aryl, optionally substituted heterocycle, or together with R.sup.5 forms a 10- or 11-membered polycyclic ring which is optionally substituted;
R.sup.4 is hydrogen, optionally substituted C.sub.1-8 alkyl,

##STR00004## ##STR00005##

optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.3-8 cycloalkenyl, optionally substituted C.sub.6-10 aryl, optionally substituted heterocycle, or together with R.sup.5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;
R.sup.5 is hydrogen, optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.3-6 cycloalkenyl, optionally substituted C.sub.6-10 aryl, optionally substituted heterocycle, or together with R.sup.4 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R.sup.3 forms a 5 or 6 member ring which is optionally substituted;
R.sup.6 is halogen, hydrogen, optionally substituted C.sub.1-8 alkyl, OR.sup.9, C(O)R.sup.10, NO.sub.2, NR.sup.13R.sup.14, CN, SR.sup.15 or SO.sub.2R.sup.16;
R.sup.7 is halogen, hydrogen, optionally substituted C.sub.1-8 alkyl, OR.sup.9, C(O)R.sup.10, NO.sub.2, NR.sup.13R.sup.14, CN, SR.sup.15 or SO.sub.2R.sup.16;
R.sup.8 is halogen, hydrogen, optionally substituted C.sub.1-8 alkyl, OR.sup.9, C(O)R.sup.10, NO.sub.2, NR.sup.13R.sup.14, CN, SR.sup.15 or SO.sub.2R.sup.16;
R.sup.9 is hydrogen, C(O)(C.sub.1-8 alkyl) or optionally substituted C.sub.1-8 alkyl;
R.sup.10 is hydrogen, optionally substituted C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NR.sup.11R.sup.12 or OH;
R.sup.11 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.12 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.13 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.14 is hydrogen, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.1-8 alkyl, C(O)(C.sub.1-8 alkyl) or SO.sub.2(C.sub.1-8 alkyl);
R.sup.15 is hydrogen, optionally substituted C.sub.1-8 alkyl or O(C.sub.1-8 alkyl);
R.sup.16 is OH, O(C.sub.1-8 alkyl), (C.sub.1-8 alkyl) or NR.sup.11R.sup.12;
R.sup.17 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.18 is hydrogen, C(O)(C.sub.1-8 alkyl), optionally substituted C.sub.6-10 aryl, or optionally substituted C.sub.1-8 alkyl;
R.sup.19 is hydrogen, C(O)(C.sub.1-8 alkyl), optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.20 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
R.sup.21 is hydrogen, optionally substituted C.sub.6-10 aryl or optionally substituted C.sub.1-8 alkyl;
n is 1, 2, 3, 4, or 5; and
m is 1, 2, 3, 4, or 5.
In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/765,527, provided that the compounds have binding activity at the FPR2 receptor.

[0027] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/765,527 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0028] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/765,527 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0029] The compounds disclosed in U.S. patent application Ser. No. 13/765,527 are represented by Formula IV:

##STR00006##

wherein:
R.sup.1 is hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C.sub.6-10 aryl, or together with R.sup.2 can form an optionally substituted cyclobutyl;
R.sup.2 is isopropyl or together with R.sup.3 can form a substituted or unsubstituted 3 to 6 member ring heterocycle or together with R.sup.1 can form an optionally substituted cyclobutyl, cyclopropyl; and
R.sup.3 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C.sub.6-10 aryl or together with R.sup.2 can form a substituted or unsubstituted 3 to 6 member ring heterocycle.

[0030] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a therapeutically effective amount of a pharmaceutical composition, comprising at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/409,228, provided that the compounds have binding activity at the FPR2 receptor.

[0031] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/409,228 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0032] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/409,228 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

##STR00007##

wherein:
is a single bond or a double bond;
is a single bond or a double bond;
R.sup.1 is H, halogen, —S(O)R.sup.10, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl or hydroxyl;
R.sup.2 is H, halogen, —S(O)R.sup.10, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl or hydroxyl;
R.sup.3 is H, halogen, —S(O)R.sup.10, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, C.sub.6-10 aryl or hydroxyl;
R.sup.4 is H or C(O)R.sup.12;
R.sup.5 is H, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl or—C.sub.2-6 alkynyl;
R.sup.6 is H, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl or—C.sub.2-6 alkynyl;

Y is O or S;

X is O, NR, or CH.SUB.2.;

[0033] R.sup.a is C.sub.6-10 aryl,

##STR00008##

heteroaryl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl or H;
R.sup.b is halogen;
c is 0, 1 or 2;

##STR00009##

R.sup.7 is H, halogen, —S(O)R.sup.10, —S(O).sub.2R.sup.11, nitro, hydroxyl, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkenyl or C.sub.3-8 cycloalkyl;
R.sup.8 is H, halogen, —S(O)R.sup.10, —S(O).sub.2R.sup.11, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkenyl or C.sub.3-8 cycloalkyl;
R.sup.9 is H, —S(O).sub.2R.sup.11, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, C.sub.3-8 cycloalkenyl or C.sub.3-8 cycloalkyl;
R.sup.10 is —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or C.sub.3-8 cycloalkenyl;
R.sup.11 is H, hydroxyl, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl;
R.sup.12 is H, hydroxyl, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, NR.sup.13R.sup.14 or —OC.sub.1-6 alkyl;
R.sup.13 is H, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, SO.sub.2R.sup.11 or C(O)R.sup.15;
R.sup.14 is H, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkenyl, aryl, heterocycle or C.sub.3-8 cycloalkyl;
R.sup.15 is H, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkenyl or C.sub.3-8 cycloalkyl; and
R is H, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkenyl or C.sub.3-8 cycloalkyl; with the proviso:
when is a double bond then R.sup.5 and R.sup.6 are void.

[0034] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/370,472, provided that the compounds have binding activity at the FPR2 receptor.

[0035] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/370,472 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0036] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/370,472 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0037] The compounds as disclosed in U.S. patent application Ser. No. 13/370,472 are represented by Formula VI:

##STR00010##

wherein:
A is C.sub.6-10 aryl, heterocyle, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl;
R.sup.17 is C.sub.1-6 alkyl or

##STR00011##

B is C.sub.6-10 aryl, heterocyle, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl;
R.sup.1 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.2 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.3 is H, C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl;
R.sup.4 is H, C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl;
R.sup.5a is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.5b is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.5c is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.5d is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.6 is H, —S(O).sub.2R.sup.11, —C.sub.1-6 alkyl, —(CH.sub.2).sub.nNR.sup.13R.sup.14, —(CH.sub.2).sub.m heterocycle, C(O)R.sup.12NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, or heterocycle;
R.sup.7 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.8 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.9 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;
R.sup.10 is H, halogen, —S(O)R.sup.15, —S(O).sub.2R.sup.11, nitro, cyano, —OC.sub.1-6 alkyl, —SC.sub.1-6 alkyl, —C.sub.1-6 alkyl, —C.sub.2-6 alkenyl, —C.sub.2-6 alkynyl, C(O)R.sup.12, NR.sup.13R.sup.14, C.sub.3-8 cycloalkyl or hydroxyl;

X is O or S;

Y is O or S;

[0038] R.sup.11 is H, hydroxyl, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl or NR.sup.13R.sup.14;
R.sup.12 is H, hydroxyl, —C.sub.1-6 alkyl, hydroxyl, C.sub.3-8 cycloalkyl, NR.sup.13R.sup.14 or —OC.sub.1-6 alkyl;
R.sup.13 is H, —C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, SO.sub.2R.sup.11 or C(O)R.sup.16;
R.sup.14 is H, —C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl;
R.sup.15 is —C.sub.1-6 alkyl, or C.sub.3-8 cycloalkyl;
R.sup.16 is H, —C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl;
n is 1-4; and
m is 1-4.

[0039] In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/863,934, provided that the compounds have binding activity at the FPR2 receptor.

[0040] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/863,934 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0041] In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/863,934 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

[0042] The compounds as disclosed in U.S. patent application Ser. No. 13/863,934 are represented by Formula VII:

##STR00012##

wherein:
n is 0 or 1;
R.sup.1 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, halogen, —NR.sup.8R.sup.9, —NC(O)R.sup.20, —OR.sup.10, —OC(O)R.sup.21, —SR.sup.11, —C(O)R.sup.12, CN or NO.sub.2;
R.sup.2 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, halogen, —NR.sup.8R.sup.9, —NC(O)R.sup.20, —OR.sup.10, —OC(O)R.sup.21, —SR.sup.11, —C(O)R.sup.12, CN or NO.sub.2;
R.sup.3 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, halogen, —NR.sup.8R.sup.9, —NC(O)R.sup.20—OR.sup.10, —OC(O)R.sup.21, —SR.sup.11, —C(O)R.sup.12, CN, NO.sub.2, CF.sub.3, S(O)R.sup.15 or S(O).sub.2R.sup.16;
R.sup.4 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, halogen, —NR.sup.8R.sup.9, —NC(O)R.sup.20—OR.sup.10, —OC(O)R.sup.21, —SR.sup.11, —C(O)R.sup.12, CN or NO.sub.2;
R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, halogen, —NR.sup.8R.sup.9, —NC(O)R.sup.20—OR.sup.10, —OC(O)R.sup.21, SR.sup.11, —C(O)R.sup.12, CN or NO.sub.2;
R.sup.6 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.6-10 aryl, substituted or unsubstituted C.sub.3-8 cycloalkenyl or —CH.sub.2R.sup.19;
R.sup.7 is substituted or unsubstituted heterocycle, —SR.sup.11, —NR.sup.8R.sup.9, —N(H)C(O)N(H)S(O).sub.2R.sup.19, —BR.sup.13R.sup.14, —S(O)R.sup.15, —C(O)N(H)(CN), —C(O)N(H)S(O).sub.2R.sup.19, —S(O)(N)(PO.sub.3H.sub.2), —S(O).sub.2R.sup.16 or —P(O)R.sup.17R.sup.18;
R.sup.8 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C.sub.6-10 aryl;
R.sup.9 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C.sub.6-10 aryl;
R.sup.10 is hydrogen or substituted or unsubstituted C.sub.1-8 alkyl;
R.sup.11 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl or —CF.sub.3;
R.sup.12 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, hydroxyl, —OR.sup.24 or —NR.sup.8R.sup.9;
R.sup.13 is —OR.sup.22;
R.sup.14 is —OR.sup.23;
R.sup.15 is substituted or unsubstituted C.sub.1-8 alkyl;
R.sup.16 is substituted or unsubstituted C.sub.1-8 alkyl, —NR.sup.8R.sup.9, —NHS(O).sub.2R.sup.19 or hydroxyl;
R.sup.17 is OR.sup.10 or NR.sup.8R.sup.9;
R.sup.18 is OR.sup.10 or NR.sup.8R.sup.9;
R.sup.19 is substituted or unsubstituted heterocycle, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.6-10 aryl or substituted or unsubstituted C.sub.3-8 cycloalkenyl;
R.sup.20 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C.sub.6-10 aryl;
R.sup.21 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C.sub.6-10 aryl;
R.sup.22 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, or together with R.sup.23 can form a cycle;
R.sup.23 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, or together with R.sup.22 can form a cycle; and
R.sup.24 is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C.sub.6-10 aryl.

[0043] The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (—CH.sub.2—) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C.sub.3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups.

[0044] The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C.sub.1-8 alkyl groups, sulfoxide C.sub.1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, —OC.sub.1-8 alkyl groups, —SC.sub.1-8 alkyl groups, —C.sub.1-8 alkyl groups, —C.sub.2-6 alkenyl groups, —C.sub.2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups.

[0045] The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC.sub.1-6 alkyl groups, —SC.sub.1-6 alkyl groups, —C.sub.1-6 alkyl groups, —C.sub.2-6 alkenyl groups, —C.sub.2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups.

[0046] The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.

[0047] The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (—CH.sub.2—) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C.sub.3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C.sub.2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups, as defined above or by halogen atoms.

[0048] The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One methylene (—CH.sub.2—) group, of the alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C.sub.3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.

[0049] The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S and N heteroatoms can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC.sub.1-6 alkyl groups, —SC.sub.1-6 alkyl groups, —C.sub.1-8 alkyl groups, —C.sub.2-6 alkenyl groups, —C.sub.2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups.

[0050] The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom. Aryl can be substituted by halogen atoms, sulfonyl C.sub.1-6 alkyl groups, sulfoxide C.sub.1-6 alkyl groups, sulfonamide groups, carboxylic acid groups, C.sub.1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, —OC.sub.1-6 alkyl groups, —SC.sub.1-6 alkyl groups, —C.sub.1-6 alkyl groups, —C.sub.2-6 alkenyl groups, —C.sub.2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic.

[0051] The term “hydroxyl” as used herein, represents a group of formula “—OH”.

[0052] The term “carbonyl” as used herein, represents a group of formula “—C(O)—”.

[0053] The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —(CO)R.sup.x, wherein R.sup.x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0054] The term “amine” as used herein, represents a group of formula “—NR.sup.xR.sup.y”, wherein R.sup.x and R.sup.y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0055] The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.

[0056] The term “sulfonyl” as used herein, represents a group of formula “—SO.sub.2—”.

[0057] The term “sulfate” as used herein, represents a group of formula “—O—S(O).sub.2—O—”.

[0058] The term “sulfonate” as used herein, represents a group of the formula “—S(O).sub.2—O—”.

[0059] The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.

[0060] The term “nitro” as used herein, represents a group of formula “—NO.sub.2”.

[0061] The term “cyano” as used herein, represents a group of formula “—CN”.

[0062] The term “amide” as used herein, represents a group of formula “—C(O)NR.sup.xR.sup.y” wherein R.sup.x and R.sup.y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0063] The term “sulfonamide” as used herein, represents a group of formula “—S(O).sub.2NR.sup.xR.sup.y” wherein R.sup.x and R.sup.y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0064] The term “sulfoxide” as used herein, represents a group of formula “—S(O)—”.

[0065] The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH).sub.2”.

[0066] The term “phosphoric acid” as used herein, represents a group of formula “—OP(O)(OH).sub.2”.

[0067] The term “sulphonic acid” as used herein, represents a group of formula “—S(O).sub.2OH”.

[0068] The formula “H”, as used herein, represents a hydrogen atom.

[0069] The formula “O”, as used herein, represents an oxygen atom.

[0070] The formula “N”, as used herein, represents a nitrogen atom.

[0071] The formula “S”, as used herein, represents a sulfur atom.

[0072] In another aspect, agonists of FPR2 are compounds selected from Table 1:

TABLE-US-00001 TABLE 1 FPRL-1 Ga16-CHO EC.sub.50 Structure IUPAC name (efficacy) [00013] 2-({[(4- chlorophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid 110 nM (1.0) [00014] (2S)-2-({[(4- methoxyphenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid 1754 nM (0.90) [00015] (2S)-3-phenyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl) amino]propanoic acid 120 nM (0.97) [00016] (2S)-2-({[(3,4- dichlorophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid 10 μM (0.57) [00017] (2S)-2-({[(4- nitrophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid 574 nM (0.82) [00018] 3-phenyl-2-[({[4- (trifluoromethoxy)phenyl]amino} carbonyl)amino]propanoic acid 1572 nM (0.79) [00019] 2-({[(3,4- dimethoxyphenyl)amino]carbonyl} amino)-3-phenylpropanoic acid 2793 nM (0.72) [00020] methyl 2-({[(4- iodophenyl)amino]carbonyl}amino)-3- phenylpropanoate 14.3 nM (1.0) [00021] (2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid 31 nM (1.0) [00022] (2R)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid 1819 nM (0.99) [00023] 3-phenyl-2-{[(pyridin-3- ylamino)carbonyl]amino}propanoic acid [00024] (2S,3S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-methylpentanoic acid 4.1 nM (0.89) [00025] (2S)-({[(4- bromophenyl)amino]carbonyl}amino) (phenyl)acetic acid 25.8 nM (0.94) [00026] 2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-(1H-indol-3-yl)propanoic acid 67.0 nM (0.89) [00027] (2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-methylbutanoic acid 72 nM (0.91) [00028] (2S)-2-({[(4-bromo-2- fluorophenyl)amino]carbonyl}amino)-3- methylbutanoic acid 152 nM (0.91)

[0073] US 2005/0137230 A1 and U.S. Pat. No. 7,820,673 disclose inhibitors of coagulation Factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and/or the treatment of tumors. 2-({[(4-chlorophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, (2S)-2-({[(4-methoxyphenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, (2S)-3-phenyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)amino]propanoic acid, methyl 2-({[(4-iodophenyl)amino]carbonyl}amino)-3-phenylpropanoate, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, (2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, are intermediates in the synthesis of urea derivatives as activated blood coagulation factor X (FXa) inhibitors.

[0074] JP 63232846 discloses the resolution of N-(p-bromophenylcarbamyl) derivatives ((2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, (2S,3S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylpentanoic acid, 2-({[(4-bromophenyl)amino]carbonyl}amino)-3-(1H-indol-3-yl)propanoic acid, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylbutanoic acid) on HPLC column with novel chromatographic chiral stationary phases.

[0075] Journal of Chromatography (1987), 404(1), 117-22 and Chromatographia (1987), 23(10), 727-30 describe the resolution of p-Bromophenylcarbamyl derivatives of enantiomeric protein amino acids ((2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid), on novel chiral stationary phase by elution with an aqueous mobile phase.

[0076] Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1972), 272(4), 667-71 describes compound (2S)-2-({[(4-nitrophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid) in poly(uridylic acid)-dependent binding of para nitrophenyl-carbamyl-phenylalanyl tRNA.

[0077] In another aspect, agonists of FPR2 are compounds selected from Table 2:

TABLE-US-00002 TABLE 2 FPRL-1 Ga16-CHO EC50 Structure IUPAC name (efficacy) [00029] 1-(4-chlorophenyl)-3-(2,4-dioxo- 1,3-diazaspiro[4,5]decan-3-yl) urea 49 nM (0.98) [00030] 1-(4-chlorophenyl)-3-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)urea 157 nM (0.96) [00031] 1-[4-methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1-yl]-3- phenylurea 223 nM (1.0) [00032] 1-(8-methyl-2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)-3-(p- tolyl)urea 363 nM (0.91) [00033] 1-(2-fluorophenyl)-3-[4-methyl- 2,5-dioxo-4-(2- phenylethyl)imidazolidin-1-yl]urea 258 nM (0.94)

[0078] Compounds of Table 2 are available from Chemical Libraries such as Aurora Fine Chemicals.

[0079] In another aspect, agonists of FPR2 are compounds selected from Table 3:

TABLE-US-00003 TABLE 3 FPRL-1 Gal16-CHO EC.sub.50 Structure IUPAC name (efficacy) [00034] N-(4-bromophenyl)-2-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)acetamide 719 nM (0.94) [00035] N-(4-bromophenyl)-2-(4,4-diethyl- 2,5-dioxoimidazolidin-1-yl)acetamide 96 nM (0.98) [00036] N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.5]dec-3-yl)acetamide 738 nM (0.89) [00037] N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.4]non-3-yl)acetamide 322 nM (0.96) [00038] N-(4-bromophenyl)-2-(2,5-dioxo-4,4- dipropylimidazolidin-1-yl)acetamide 645 nM (0.98) [00039] N-(4-bromophenyl)-2-(4-ethyl-2,5- dioxo-4-phenylimidazolidin-1- yl)acetamide 523 nM (0.83) [00040] N-(4-bromophenyl)-2-(4-cyclopropyl- 4-methyl-2,5-dioxoimidazolidin-1- yl)acetamide 166 nM (0.84) [00041] N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.6]undec-3-yl)acetamide 679 nM (0.96) [00042] N-(4-bromophenyl)-2-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)acetamide 485 nM (1.0) [00043] N-(4-chlorophenyl)-2-(4,4-diethyl- 2,5-dioxoimidazolidin-1-yl)acetamide 314 nM (0.79) [00044] 2-(4,4-diethyl-2,5-dioxoimidazolidin- 1-yl)-N-(4-fluorophenyl)acetamide 2771 nM (0.67) [00045] N-(4-bromophenyl)-2[4-methyl-2,5- dioxo-4-(2-phenylethyl)imidazolidin-1-yl]acetamide 860 nM (0.88) [00046] N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7-methano- 2H-isoindole-2-acetamide 575 (0.90) [00047] N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-2H-isoindole-2- acetamide 395 (0.98)

[0080] The compounds of Table 3 are available from Chemical Libraries such as Chemical Block Ltd.

[0081] In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of the N-formyl peptide receptor like-1 receptor.

[0082] Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.

[0083] Therapeutic utilities of the N-formyl peptide receptor like-1 receptor modulators are dermatological inflammation and diseases including, but not limited to, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, other disorders of pigmentation, and alopecia (scarring and non-scarring forms).

[0084] These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by the N-formyl peptide receptor like-1 receptor modulation: dermatological inflammation and diseases including, but not limited to, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, other disorders of pigmentation, and alopecia (scarring and non-scarring forms).

[0085] In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of the FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.

[0086] The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.

[0087] The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

[0088] In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0089] Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.

[0090] Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[0091] In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0092] Pharmaceutical compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.

[0093] The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

[0094] The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

[0095] Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.

[0096] The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of the N-formyl peptide receptor like-1 (FPRL-1) receptor. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of the N-formyl peptide receptor like-1 (FPRL-1) receptor. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.

Materials and Methods

[0097] FPR2 agonists would be expected to have significant effects in many different types of dermatological inflammation, but have been exemplified by demonstrating wound healing in a mouse model of punch dermal wound (FIG. 2). Anti-inflammatory activity in this model has been exemplified with the FPR2 agonists described in Table 4.

[0098] FLIPR: HEK-Gα16 cells stably expressing the human FPR2 receptor was utilized. Cells were plated into 384-well poly-D-lysine coated plates at a density of 18,000 cells per well one day prior to use. The growth media was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1% antibiotic-antimycotic, 50 μg/ml hygromycin, and 400 μg/ml geneticin. On the day of the experiment, the cells were washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/hepes buffer). The cells were then dye loaded with 2 μM Fluo-4 diluted in the HBSS/Hepes buffer and incubated at 37° C. for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates. Data for Ca.sup.+2 responses were obtained in relative fluorescence units.

TABLE-US-00004 TABLE 4 Com- FPR2 pound EC50 number Structure IUPAC name (% eff) 1 [00048] 1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(2- phenylethyl)imidazolidin-1- yl]urea 3.0 (0.96) 2 [00049] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}acetic acid 2 (0.91) 3 [00050] {[(2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3- methylpentanoyl]amino} acetic acid 1.98 (1.0) 4 [00051] 1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(propan-2- yl)imidazolidin-1-yl]urea 6.7 (0.90) 5 [00052] (2S,3S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 3-methylpentanoic acid 31 (0.96) 6 [00053] 2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino}-2- methylpropanoic acid 1.66 (0.91) 7 [00054] {[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methylpentanoyl]amino} acetic acid 3.57 (1.0) 8 [00055] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} acetic acid 0.78 (0.78) 9 [00056] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4-methylpentanoic acid 5.95 (0.77) 10 [00057] 2-{[(4- bromophenyl)carbamoyl] amino}-N-(2-oxoazepan-3-yl)-3- phenylpropanamide 11 nM (0.89) 11 [00058] 3-[(4- iodophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′- cyclopropane]-5-ene-2- carboxylic acid 1.6 nM (1.00) 12 [00059] 3-[(4- bromophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′- cyclopropane]-5-ene-2- carboxylic acid 4 nM (0.97) 13 [00060] 1-(4-acetylphenyl)-3-{3-(4- cyanophenyl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin- 7-yl}urea 11 nM (0.80) 14 [00061] rel-(2R,3S)-3-[(4- bromophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′- cyclopropane]-2-carboxylic acid 4 nM (0.90) 15 [00062] 3-[(4- iodophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′- cyclopropane]-2-carboxylic acid 0.60 nM (0.87) 16 [00063] 1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl]-3- [4- (methylsulfanyl)phenyl]urea 2.5 nM (0.70) 17 [00064] 1-{3-(4-cyanophenyl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfanyl)phenyl]urea 5.5 nM (0.92) 18 [00065] 1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl]-3- [4- (methylsulfonyl)phenyl]urea 10 nM (0.86) 19 [00066] 1-{3-(4-cyanophenyl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfonyl)phenyl]urea 20 nM (1.00) 20 [00067] 3-[(4-iodophenyl)carbamoyl]- 7-(propan-2- ylidene)bicyclo[2.2.1]hept-5- ene-2-carboxylic acid 11 nM (0.94) 21 [00068] 3-[(4- bromophenyl)carbamoyl]-7,7- dimethylbicyclo[2.2.1]heptane- 2-carboxylic acid 10 nM (0.85) 22 [00069] 3-[(4-iodophenyl)carbamoyl]- 7,7- dimethylbicyclo[2.2.1]heptane- 2-carboxylic acid 1.7 nM (0.97) 23 [00070] 1-{3-(furan-2-yl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin- 7-yl}-3-[4- (methylsulfanyl)phenyl]urea 19 nM (0.83) 24 [00071] 1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4-(methylsulfinyl)phenyl]urea 11.8 nM (0.93) 25 [00072] 1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfonyl)phenyl]urea 10.5 nM (1.0) 26 [00073] N-(4- bromophenyl)spiro[bicyclo [2.2.1]heptane-7,1′- cyclopropane]-5-ene-2,3- dicarboxamide 4.8 nM (0.91) 27 [00074] 1-{3-(5-chlorofuran-2-yl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfanyl)phenyl]urea 17 nM (0.81) 28 [00075] 1-{3-(6-chloropyridin-3-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfanyl)phenyl]urea 6.3 nM (0.89) 29 [00076] 3-{[4- (methylsulfanyl)phenyl]carba moyl}spiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-2- carboxylic acid 7 nM (0.96) 30 [00077] N-(4- bromophenyl)spiro[bicyclo[2.2.1] heptane-7,1′- cyclopropane]-2,3- dicarboxamide 2.5 nM (0.96) 31 [00078] 3-{[4- (methylsulfanyl)phenyl]carbamoyl} spiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-5- ene-2-carboxylic acid 14 nM (0.85) 32 [00079] 1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfanyl)phenyl]urea 13.5 nM (0.91) 33 [00080] 1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3- [4- (methylsulfonyl)phenyl]urea 9.5 nM (0.99) 34 [00081] N-(4-bromophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide 15 nM (0.83) 35 [00082] N-(4-iodophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide 2.6 nM (0.81) 36 [00083] (+)1-[(3R)-2-(3-aminopropyl)- 3-(4-cyanophenyl)-1-oxo- 1,2,3,4-tetrahydroisoquinolin- 7-yl]-3-[4- (methylsulfanyl)phenyl]urea 3.3 nM (0.97) 37 [00084] 7,7-dimethyl-N-[4- (methylsulfanyl)phenyl]bicyclo [2.2.1]heptane-2,3- dicarboxamide 17 nM (0.85) 38 [00085] N-(4- iodophenyl)spiro[bicyclo[2.2.1] heptane-7,1′- cyclopropane]-2,3- dicarboxamide 1.9 nM (0.95) 39 [00086] N-(4- iodophenyl)spiro[bicyclo[2.2.1] heptane-7,1′- cyclopropane]-5-ene-2,3- dicarboxamide 1.6 nM (0.90) 40 [00087] (+) tert-butyl {3-[(3R)-3-(4- cyanophenyl)-7-({[4- (methylsulfinyl)phenyl]carba moyl}amino)-1-oxo-3,4- dihydroisoquinolin-2(1H)- yl]propyl}carbamate 103 nM (0.91) 41 [00088] (+) 1-[(3R)-2-(3- aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfinyl)phenyl]urea 10.6 nM (0.94) 42 [00089] 1-[2-(3-aminopropyl)-3- methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl]-3- [4- (methylsulfanyl)phenyl]urea 15 nM (1.00) 43 [00090] 1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl]-3- (4-iodophenyl)urea 13.7 nM (0.94) 44 [00091] (+) (2S,3R)-3-[(4- bromophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′- cyclopropane]-2-carboxylic acid <1 nM (0.98) 45 [00092] (−) N-(4- bromophenyl)spiro[bicyclo [2.2.1]heptane-7,1′- cyclopropane]-2,3- dicarboxamide <1 nM (0.91) 46 [00093] N-(4-bromophenyl)-N′- methylspiro[bicyclo[2.2.1] heptane-7,1′-cyclopropane]-2,3- dicarboxamide 8.5 nM (1.0) 47 [00094] N-(4-bromophenyl)-N′- ethylspiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-2,3- dicarboxamide 9.3 nM (1.0) 48 [00095] N-(4-bromophenyl)-N′- (propan-2- yl)spiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-2,3- dicarboxamide 6.7 nM (1.0) 49 [00096] 1-(4-bromophenyl)-3-(4,4- diethyl-2,5-dioxoimidazolidin- 1-yl)urea 11.5 nM (0.98) 50 [00097] 1-(4-bromo-2-fluorophenyl)- 3-(4,4-diethyl-2,5- dioxoimidazolidin-1-yl)urea 15.7 nM (1.0) 51 [00098] (2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 3-phenylpropanoic acid 14.5 nM (1.0) 52 [00099] 1-(4-bromophenyl)-3-(2,4- dioxo-1,3-diazaspiro[4.5]dec- 3-yl)urea 15.1 nM (1.0) 53 [00100] (2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methylpentanoic acid 12.9 nM (0.9) 54 [00101] 1-(4-bromophenyl)-3-[4- methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1- yl]urea 5.1 nM (0.87) 55 [00102] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-3- phenylpropanoyl]amino} acetic acid 7.7 nM (0.99) 56 [00103] 3-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-3- phenylpropanoyl]amino} propanoic acid 18 nM (0.98) 57 [00104] (+) 1-(4-bromophenyl)-3-[4- methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1- yl]urea 3.2 nM (0.93) 58 [00105] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-(2-hydroxyethyl)-3- phenylpropanamide 7.0 nM (0.86) 59 [00106] {[(2S,3S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 3-methylpentanoyl]amino} acetic acid 5.5 nM (0.95) 60 [00107] (2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methylpentanamide 4.6 nM (0.91) 61 [00108] 1-(4-bromo-2-fluorophenyl)- 3-[4-ethyl-2,5-dioxo-4- (propan-2-yl)imidazolidin-1- yl]urea 9.2 nM (0.97) 62 [00109] (2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 3-methylpentanamide 10.3 nM (1.0) 63 [00110] (2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methyl-N-(2- oxopropyl)pentanamide 10.5 nM (0.97) 64 [00111] 1-(4-bromophenyl)-3-[2,5- dioxo-4,4-di(propan-2- yl)imidazolidin-1-yl]urea 3.8 nM (1.0) 65 [00112] 1-(4-bromophenyl)-3-(4,4- dicyclopropyl-2,5- dioxoimidazolidin-1-yl)urea 14.3 nM (1.0) 66 [00113] (+)1-(4-bromophenyl)-3-[4- ethyl-2,5-dioxo-4-(propan-2- yl)imidazolidin-1-yl]urea 4.3 nM (0.96) 67 [00114] (−)1-(4-bromophenyl)-3[4- ethyl-2,5-dioxo-4-(propan-2- yl)imidazolidin-1-yl]urea 3.3 nM (1.0) 68 [00115] (2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- N-(2-oxopropyl)-3- phenylpropanamide 12.4 nM (0.94) 69 [00116] 1-(4-bromo-2-fluorophenyl)- 3-[4-ethyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1- yl]urea 13.4 nM (0.91) 70 [00117] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoic acid 7.1 nM (1.0) 71 [00118] (2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- N-(2-hydroxyethyl)-3- phenylpropanamide 15.6 nM (0.98) 72 [00119] methyl {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}acetate 16.4 nM (0.86) 73 [00120] propan-2-yl {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}acetate 14.5 nM (1.0) 74 [00121] {[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino} pentanoyl]amino}acetic acid 4.1 nM (0.91) 75 [00122] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-(2-hydroxyethyl)-4- methylpentanamide 13.5 nM (0.76) 76 [00123] 1-(4-bromophenyl)-3-{4-[2- (furan-2-yl)ethyl]-4-methyl- 2,5-dioxoimidazolidin-1- yl}urea 5.2 nM (0.99) 77 [00124] (2S)-N-(2-amino-2-oxoethyl)- 2-{[(4- bromophenyl)carbamoyl] amino}-4-methylpentanamide 1.1 nM (1.0) 78 [00125] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4-methyl-N-(2- oxopropyl)pentanamide 4.7 nM (0.82) 79 [00126] (2S)-N-(2-amino-2-oxoethyl)- 2-{[(4- bromophenyl)carbamoyl]ami no}pentanamide 2.5 nM (0.97) 80 [00127] 1-(4-bromophenyl)-3-{4-[2-(2- fluorophenyl)ethyl]-4-methyl- 2,5-dioxoimidazolidin-1- yl}urea 14.3 nM (99) 81 [00128] (2S)-N-(2-amino-2-oxoethyl)- 2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino} pentanamide 5.2 nM (0.96) 82 [00129] 1-(4-bromophenyl)-3-{4-[2-(4- fluorophenyl)ethyl]-4-methyl- 2,5-dioxoimidazolidin-1- yl}urea 16.3 nM (1.0) 83 [00130] 1-(4-bromophenyl)-3-{4-[2-(3- fluorophenyl)ethyl]-4-methyl- 2,5-dioxoimidazolidin-1- yl}urea 11.1 nM (1.0) 84 [00131] (2S)-N-(2-amino-2-oxoethyl)- 2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methylpentanamide 4.5 nM (0.95) 85 [00132] (2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methyl-N-(2- oxopropyl)pentanamide 20 nM (0.99) 86 [00133] 1-(4-bromophenyl)-3-{4-[2-(4- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 13.3 nM (1.0) 87 [00134] (2S)-2-{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-4- methylpentanoyl]amino}propanoic acid 12.1 nM (0.95) 88 [00135] 1-(4-bromophenyl)-3-{4- methyl-2,5-dioxo-4-[2- (thiophen-2- yl)ethyl]imidazolidin-1- yl}urea 7.9 nM (0.94) 89 [00136] 1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(4- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 8.7 nM (0.85) 90 [00137] (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} propanoic acid 11.6 nM (1.0) 91 [00138] (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino}-3- methylbutanoic acid 1.7 nM (0.97) 92 [00139] (2S)-N-[(2S)-1-amino-3- methyl-1-oxobutan-2-yl]-2- {[(4- bromophenyl)carbamoyl]ami no}-4-methylpentanamide 5.8 nM (1.0) 93 [00140] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-(2-hydroxy-2- methylpropyl)-4- methylpentanamide 2.5 nM (0.93) 94 [00141] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-(1,3-dihydroxypropan- 2-yl)-4-methylpentanamide 7.4 nM (0.96) 95 [00142] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-(2,3-dihydroxypropyl)- 4-methylpentanamide 5.1 nM (0.98) 96 [00143] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-[(2R)-1- hydroxypropan-2-yl]-4- methylpentanamide 3.0 nM (1.0) 97 [00144] 1-(4-bromophenyl)-3-{4- methyl-4-[2-(5-methylfuran-2- yl)ethyl]-2,5- dioxoimidazolidin-1-yl}urea 3.5 nM (0.95) 98 [00145] 1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(3-fluoro-4- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 7.4 nM (0.91) 99 [00146] 1-(4-bromophenyl)-3-{4-[2-(3- fluoro-4- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 8.0 nM (1.0) 100 [00147] tert-butyl (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} pentanoate 13.0 nM (1.0) 101 [00148] (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} pentanoic acid 1.0 nM (0.95) 102 [00149] (2S)-N-[(2S)-1-amino-1- oxopentan-2-yl]-2-{[(4- bromophenyl)carbamoyl] amino}-4-methylpentanamide 7.3 nM (0.99) 103 [00150] (2S)-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} (phenyl)ethanoic acid 9.1 nM (1.0) 104 [00151] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4-methyl-N-(1H-tetrazol- 5-ylmethyl)pentanamide 2.3 nM (0.81) 105 [00152] ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} methyl)phosphonate 0.95 nM (0.88) 106 [00153] 1-(4-bromo-2-fluorophenyl)- 3-[4-[2-[2- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 4.0 nM (0.91) 107 [00154] 1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(3- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 2.2 nM (0.79) 108 [00155] 1-(4-bromophenyl)-3-{4-[2-(3- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 2.1 nM (1.0) 109 [00156] 1-(4-bromophenyl)-3-{4-[2-(2- hydroxyphenyl)ethyl]-4- methyl-2,5-dioxoimidazolidin- 1-yl}urea 0.97 nM (0.93) 110 [00157] 2-{[(4- bromophenyl)carbamoyl] amino}-2,4-dimethylpentanoic acid 19.4 nM (0.98) 111 [00158] [(2-{[(4- bromophenyl)carbamoyl] amino}-2,4- dimethylpentanoyl)amino] acetic acid 19.1 nM (0.99) 112 [00159] diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}4- methylpentanoyl]amino} methyl)phosphonate 0.48 nM (0.95) 113 [00160] (2-{[(4- bromophenyl)carbamoyl] amino}-2- ethylbutanoyl)amino]acetic acid 18.7 nM (1.0) 114 [00161] diethyl ({[(2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3- methylpentanoyl]amino} methyl)phosphonate 2.9 nM (1.0) 115 [00162] ethyl hydrogen ({[(2S,3S)-2- {[(4- bromophenyl)carbamoyl] amino}3- methylpentanoyl]amino} methyl)phosphonate 2.7 nM (0.88) 116 [00163] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-[(3-hydroxy-1,2-oxazol- 5-yl)methyl]-4- methylpentanamide 12.0 nM (1.0) 117 [00164] diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}methy) phosphonate 0.27 nM (1.0) 118 [00165] diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-3- phenylpropanoyl]amino} methyl)phosphonate 16.1 nM (0.93) 119 [00166] diethyl (2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino}ethyl) phosphonate 16.1 nM (0.97) 120 [00167] (2S)-2-{[(4- bromophenyl)carbamoyl] amino}-N-[2-(dimethylamino)-2- oxoethyl]-4- methylpentanamide 1.7 nM (0.99) 121 [00168] (2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 4-methylpentanoic acid 4.0 nM (0.93) 122 [00169] (2R,3R)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methylpentanoic acid 10 μM (0.59) 123 [00170] ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}methyl) phosphonate 1 nM (0.96) 124 [00171] {[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanoyl] amino}acetic acid 1.8 nM (1.0) 125 [00172] dipropan-2-yl ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}methyl) phosphonate 1.2 nM (1.0) 126 [00173] ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}3- phenylpropanoyl]amino} methyl)phosphonate 16.0 nM (1.0) 127 [00174] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}4- methylpentanoyl]amino} methanesulfonic acid 2.0 nM (0.91) 128 [00175] (2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl] carbamoyl}amino)pentanoic acid 16.8 nM (0.92) 129 [00176] propan-2-yl hydrogen {[(2- {[(4-bromophenyl)carbamoyl] amino}pentanoyl)amino] methyl}phosphonate 1.87 nM (0.89) 130 [00177] {[(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl] carbamoyl}amino)pentanoyl] amino}acetic acid 3.0 nM (1.0) 131 [00178] dipropan-2-yl({[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl]amino} methyl)phosphonate 4.0 nM (1.0) 132 [00179] 1-(4-bromophenyl)-3[4- (hydroxymethyl)-2,5-dioxo-4- (propan-2-yl)imidazolidin-1- yl]urea 16.2 nM (0.86) 133 [00180] 2-[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 2.7 nM (1.0) 134 [00181] diethyl ({[(2S)-4-methyl-2- ({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 5.5 nM (0.97) 135 [00182] ethyl hydrogen ({[(2S)-4- methyl-2-({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 1.9 nM (0.91) 136 [00183] (2S)-4-methyl-N-(1H-tetrazol- 5-ylmethyl)-2-({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanamide 3.7 nM (0.96) 237 [00184] {[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanoyl] amino}methanesulfonic acid 1.9 nM (0.99) 138 [00185] diethyl ({[(2S)-4-methyl-2- ({[4- (methylsulfanyl)phenyl] carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 3.5 nM (0.91) 139 [00186] 2-methyl-2-{[(2S)-4-methyl-2- ({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanoyl] amino}propanoic acid 2.5 nM (0.92) 140 [00187] tert-butyl (2S)-2-{[(4- bromophenyl)sulfamoyl] amino}-4-methylpentanoate NA 141 [00188] methyl 2-[2-(1-{[(4- bromophenyl)carbamoyl] amino}-4-ethyl-2,5- dioxoimidazolidin-4- yl)ethyl]benzoate 10.3 nM (0.92) 142 [00189] 2-[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4-yl]-N-(1,3- dihydroxypropan-2- yl)acetamide 13.8 nM (0.92) 143 [00190] 2-[2-(1-{[(4- bromophenyl)carbamoyl] amino}-4-ethyl-2,5- dioxoimidazolidin-4- yl)ethyl]benzoic acid 17.2 nM (1.0) 144 [00191] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- (methylsulfanyl)butanoyl] amino}acetic acid 6.3 nM (0.91) 145 [00192] 3-({[1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)propanoic acid 1.0 nM (1.0) 146 [00193] 2-[2-(1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-ethyl-2,5- dioxoimidazolidin-4- yl)ethyl]benzoic acid 11.1 nM (1.0) 147 [00194] 3-({[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)propanoic acid 3.9 nM (0.99) 148 [00195] 2-[1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2- yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 6.9 nM (0.98) 149 [00196] ethyl 3-[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]propanoate 6.6 nM (0.94) 150 [00197] {[2-{[(4- bromophenyl)carbamoyl] amino}-3-(1H-indol-3- yl)propanoyl]amino}acetic acid 1.4 nM (0.98) 151 [00198] 2-{2-[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]ethyl}benzoic acid 5.8 nM (1.0) 152 [00199] diethyl [2-({[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)ethyl] phosphonate 11 nM (1.0) 153 [00200] ethyl 3-{[(4- bromophenyl)carbamoyl] amino}-2,4-dioxo-1,3- diazaspiro[4.5]decane-8- carboxylate 12 nM (0.99) 154 [00201] tert-butyl {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl](methyl) amino}acetate 12 nM (0.85) 155 [00202] {[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4- methylpentanoyl](methyl) amino}acetic acid 1.0 nM (1.0)

[0099] Immunohistochemistry: Fluorescent immunohistochemistry with antibodies specific to FPR2 was used to determine localization in normal human skin. Anti-FPR2 antibody (Abcam) was used at a dilution of 1:200 to detect FPR2 protein.

[0100] Dermal wound healing model: Groups of 5 ICR male mice weighing 24-28 g were used. During the study, the tested animals were housed in individual cages. Under hexobarbital (90 mg/kg, i.p.) anesthesia, the shoulder and back region of each animal was shaved. A sharp punch (ID 12 mm) was applied to remove the skin including panniculus carnosus and adherent tissues. The wound area, traced onto clear plastic sheets, was measured by use of an Image—ProPlus (Media Cybernetics, Version 4.5.0.29) on days 1, 3, 5, 7, 9 and 11. Test substances and vehicle (Placebo, 20 μL/mouse) were administered topically (TOP) once daily post skin punch for a total of 10 consecutive days. The positive control of CGS-21680 in 0.5% CMC/PBS, pH 7.4 was given topically as the same regimen. The percent closure of the wound (%) was calculated, and wound half-closure time (CT50) was analyzed by linear regression using Graph-Prism (Graph Software USA). One-way ANOVA followed by Dunnett's test was applied for comparison between the treated and vehicle groups at each measurement time point. Differences are considered significant at P<0.05.

[0101] LL37-induced model of rosacea in mice: Prior to dosing, animals are lightly anaesthetized with isofluorane and baseline right and left ear thickness measurements are made with a digital caliper (Mitutoyo 293-340). At t=−1 hrs, animals are lightly anaesthetized with isoflurane to allow topical application (dorsal side) of 10 μL of FPR2 agonist formulated in a vehicle consisting of PBS:ethanol (50:50), or vehicle control to both ears. At t=0 hr, mice are re-anaesthetized. Following ear thickness measurements, 20 uL of LL-37 (100 μM) is injected into the right ear, while PBS is injected into the left ear. Additional ear thickness measurements are taken at t=3 and 6 hours. After the last time point, mice are euthanized by CO.sub.2 inhalation and ears collected for additional analyses.

[0102] In vitro human skin penetration model: Briefly, split-thickness human abdominal skin (˜0.50 mm) sections from two donors were mounted in flow-through diffusion cells (PermeGear). FPR2 agonists are applied at a dose of 10 μL to a surface area of 0.64 cm.sup.2 (n=7 per compound). PBS is pumped beneath the skin at a constant flow rate of ˜42 μL/min. Receptor fluid samples are collected at 1, 3, 6, 12, and 24 hrs and analyzed by LC/MS/MS.