1-(amino)indanes and (1,2-dihydro-3-amino)-benzofurans, benzothiophenes and indoles as Edg receptor agonists

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

m is 0;

p is 1;

G is —C(R 4 ) 2 ,

A is selected from the group consisting of: —CO 2 H, —PO 3 H 2 , —PO 2 H, —SO 3 H, —PO(C 1-3 alkyl)OH and 1H-tetrazol-5-yl;

each R 1 is independently selected from the group consisting of: hydrogen, halo, hydroxy, C 1-6 alkyl and C 1-5 alkoxy, each C 1-6 alkyl and C 1-5 alkoxy optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy;

R 2 and R 3 are joined together to form a 4 or 5-membered monocyclic ring defined as follows:

each R 4 is independently selected from the group consisting of: hydrogen and C 1-4 alkyl, said C 1-4 alkyl optionally substituted from one up to the maximum number of substitutable positions with halo,

each R 5 is independently selected from the group consisting of: halo, C 1-4 alkyl and C 1-3 alkoxy, said C 1-4 alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,

Z is selected from the group consisting of:

(1) C 1-8 alkyl, C 1-8 alkoxy, —(C═O)—C 1-6 alkyl or —CHOH—C 1-6 alkyl, said C 1-8 alkyl, C 1-8 alkoxy, —(C═O)—C 1-6 alkyl and —CHOH—C 1-6 alkyl optionally substituted with phenyl and C 3-6 cycloalkyl, and

(2) phenyl or HET 1 , each optionally substituted with 1–3 substituents independently selected from the group consisting of:

(a) halo,

(b) phenyl, optionally substituted with 1 to 5 groups independently selected from the group consisting of: halo and C 1-4 alkyl, said C 1-4 alkyl optionally substituted with 1–3 halo groups, and

(c) C 1-4 alkyl or C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy,

or Z is not present;

when Z is not present then X is selected from the group consisting of: phenyl, C 5-16 alkyl, C 5-16 C 5-16 alkynyl, —CHOH—C 4-15 alkyl, —CHOH—C 4-15 alkenyl, —CHOH—C 4-15 alkynyl, C 4-15 alkoxy, —O—C 4-15 alkenyl, —O—C 4-15 alkynyl, C 4-15 alkylthio, —S—C 4-15 alkenyl, —S—C 4-15 alkynyl, —CH 2 —C 3-14 alkoxy, —CH 2 —O—C 3-14 alkenyl, —CH 2 —O—C 3-14 alkynyl, —(C═O)—C 4-15 alkyl, —(C═O)—C 4-15 alkenyl, —(C═O)—C 4-15 alkynyl, —(C═O)—O—C 3-14 alkyl, —(C═O)—O—C 3-14 alkenyl, —(C═O)—O—C 3-14 alkynyl, —(C═O)—N(R 6 )(R 7 )—C 3-14 alkyl, —(C═O)—N(R 6 )(R 7 )—C 3-14 alkenyl, —(C═O)—N(R 6 )(R 7 )—C 3-14 alkynyl, —N(R 6 )(R 7 )—(C═O)—C 3-14 alkyl, —N(R 6 )(R 7 )—(C═O)—C 3-14 alkenyl and —N(R 6 )(R 7 )—(C═O)—C 3-14 alkynyl,

when Z is phenyl or HET 1 , optionally substituted as defined above, then X is selected from the group consisting of: —C 1-6 alkyl-, —O—C 1-5 alkyl-, —(C═O)—C 1-5 alkyl-, —(C═O)—O—C 1-4 alkyl-, —(C═O)—N(R 6 )(R 7 )—C 1-4 alkyl-,

phenyl and HET 2 , said phenyl and HET 2 each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-4 alkyl and C 1-4 alkoxy, and wherein when X is —C 1-6 alkyl-, —O—C 1-5 alkyl-, —(C═O)—C 1-5 alkyl-, —(C═O)—O—C 1-4 alkyl-, —(C═O)—N(R 6 )(R 7 )—C 1-4 alkyl-, or

the point of attachment of the group Z is on the alkyl, and

when Z is C 1-8 alkyl, C 1-8 alkoxy, —(C═O)—C 1-6 alkyl or —CHOH—C 1-6 alkyl, optionally substituted as defined above, then X is phenyl, said phenyl optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-4 alkyl and C 1-4 alkoxy;

R 6 and R 7 are independently selected from the group consisting of: hydrogen, C 1-9 alkyl and —(CH 2 ) p -phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1–3 substituents independently selected from the group consisting of: C 1-3 alkyl and C 1-3 alkoxy, each optionally substituted with 1–3 halo groups; and

HET 1 and HET 2 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.

2. The compound according to claim 1 wherein:

Z is phenyl or HET 1 , each optionally substituted with 1–3 substituents independently selected from the group consisting of:

(a) halo,

(b) phenyl, optionally substituted with 1 to 5 groups independently selected from the group consisting of: halo and C 1-4 alkyl, said C 1-4 alkyl optionally substituted with 1–3 halo groups, and

(c) C 1-4 alkyl or C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy,

or Z is not present;

when Z is not present then X is selected from the group consisting of: C 7-12 alkyl, C 7-12 alkenyl, C 7-12 alkynyl, C 6-11 alkoxy, —O—C 6-11 alkenyl, —O—C 6-11 alkynyl, —(C═O)—C 6-11 alkyl, —(C═O)—C 6-11 alkenyl, —(C═O)—C 6-11 alkynyl, —(C═O)—O—C 5-10 alkyl, —(C═O)—O—C 5-19 alkenyl, and —(C═O)—O—C 5-10 alkynyl;

and

when Z is phenyl or HET 1 , optionally substituted as defined above, then X is selected from the group consisting of —C 1-5 alkyl-, —C 1-4 alkoxy-, —(C═O)—C 1-4 alkyl-, —(C═O)—O—C 1-3 alkyl-, phenyl and HET 2 , and wherein when X is —C 1-4 alkoxy-, —(C═O)—C 1-5 alkyl- or —(C═O)—O—C 1-4 alkyl-, the point of attachment of the group Z is on the alkyl.

3. The compound according to claim 1 wherein HET 1 and HET 2 are independently selected from the group consisting of:

wherein R 8 is selected from hydrogen, hydroxy and halo.

4. The compound according to claim 1 wherein X is selected from the group consisting of: C 7-12 alkyl, C 7-12 alkenyl, C 7-12 alkynyl, C 6-11 alkoxy, —O—C 6-11 alkenyl, —O—C 6-11 alkynyl, —(C═O)—C 6-11 alkyl, —(C═O)—C 6-11 alkenyl, —(C═O)—C 6-11 alkynyl, —(C═O)—O—C 5-10 alkyl, —(C═O)—O—C 5-19 alkenyl, and —(C═O)—O—C 5-10 alkynyl and Z is not present.

5. The compound according to claim 1 wherein:

X is methoxy and Z is HET 1 substituted with phenyl and C 1-4 alkyl, said C 1-4 alkyl optionally substituted with 1–3 halo groups, and said phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: halo and C 1-4 alkyl, optionally substituted with 1–3 halo groups.

6. The compound according to claim 1 wherein:

X is HET 2 , optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-4 alkyl and C 1-4 alkoxy, and

Z is phenyl or HET 1 , each optionally substituted with 1–3 substituents independently selected from the group consisting of:

(a) halo, (b) phenyl, optionally substituted with 1 to 5 groups independently selected

from the group consisting of: halo and C 1-4 alkyl, said C 1-4 alkyl optionally substituted with 1–3 halo groups, and

(c) C 1-4 alkyl or C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy.

7. The compound according to claim 1 wherein:

Z is C 1-8 alkyl, C 1-8 alkoxy, —(C═O)—C 1-6 alkyl or —CHOH—C 1-6 alkyl, said C 1-8 alkyl, C 1-8 alkoxy, —(C═O)—C 1-6 alkyl and —CHOH—C 1-6 alkyl optionally substituted with phenyl and C 3-6 cycloalkyl, and

X is phenyl, said phenyl optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-4 alkyl and C 1-4 alkoxy.

8. The compound according to claim 1 wherein G is —CH 2 —.

9. The compound according to claim 1 wherein R 2 and R 3 are joined together to form a 4-membered monocyclic ring defined as follows:

10. The compound according to claim 1 wherein R 2 and R 3 are joined together to form a 5-membered monocyclic ring defined as follows:

11. A compound according to claim 1 of Formula II:

or a pharmaceutically acceptable salt or hydrate thereof, wherein n is 0 or 1.

12. The compound according to claim 11 wherein n is 0 and —X-Z is selected from the following group:

13. The compound according to claim 11 of Formula III

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0 or 1,

Y is oxygen or a bond,

R 10 is C 1-4 alkyl,

each R 9 is independently halo, C 1-4 alkyl or C 1-4 alkoxy.

14. The compound according to claim 13 wherein n is 0, each R 4 is hydrogen and R 5 and R 9 are both not present.

15. A compound or a pharmaceutically acceptable salt thereof selected from the following table:

16. A compound selected from the following:

(1) (RS)-1-(5-(5-(4-(2-Methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof,

(2) (R)-1-(5-(5-(4-(2-Methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and

(3) (S)-1-(5-(5-(4-(2-Methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.