2-[4-(pyrazol-4-ylalkyl)piperazin-1-yl]-3-phenyl pyrazines as 5-HT7 receptor antagonists

1. A compound of the formula:

where:

A and B are each —N═;

n is 1, 2, or 3;

m is 0, 1, 2, or 3;

R 1 is selected from the group consisting of

i) hydrogen, ii) (C 1 -C 6 )alkyl-optionally substituted with hydroxy, cyano, or 1 to 5 fluoro substituents, or alternatively, optionally substituted with hydroxy and 1 to 3 fluoro substituents, iii) (C 3 -C 7 )cycloalkyl-(C 0 -C 2 )alkyl-optionally substituted with hydroxy, iv) (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl-, v) Ph 1 -(C 0 -C 2 )alkyl-, vi) Ar 1 —(C 0 -C 2 )alkyl-, vii) (C 1 -C 2 )alkyl-S(O) 2 —(C 0 -C 3 )alkyl-, viii) Ph 1 -S(O) 2 —, ix) Ar 1 —S(O) 2 —, x) (C 1 -C 2 )alkyl-NH—(C 1 -C 2 )alkyl-, xi) ((C 1 -C 2 )alkyl) 2 -N—(C 1 -C 2 )alkyl-, xii) (C 1 -C 2 )alkyl-NH—C(O)—(C 0 -C 2 )alkyl-, xiii) ((C 1 -C 2 )alkyl) 2 -N—C(O)—(C 0 -C 2 )alkyl-, xiv) pyrrolidin-1-yl-C(O)—(C 0 -C 2 )alkyl-, xv) (C 1 -C 2 )alkyl-C(O)—NH—(C 1 -C 2 )alkyl-, xvi) (C 1 -C 2 )alkyl)-C(O)—N(C 1 -C 2 alkyl)-(C 1 -C 2 )alkyl-, xvii) (C 1 -C 2 )alkyl-S(O) 2 —NH—(C 1 -C 2 )alkyl-, and xviii) 2-oxo-oxazolidin-5-yl-;

R 2 is selected from the group consisting of i) hydrogen, ii) halo, iii) hydroxy, iv) (C 1 -C 4 )alkyl-optionally substituted with hydroxy, cyano, or 1 to 5 fluoro substituents, and v) (C 1 -C 2 )alkyl-O—(C 0 -C 2 )alkyl-;

R 3 is selected from the group consisting of hydrogen, halo, and (C 1 -C 4 )alkyl-;

Each R 4 is independently selected from the group consisting of i) halogen, ii) (C 1 -C 2 )alkyl optionally further substituted with 1 to 5 fluoro substituents, iii) (C 1 -C 2 )alkoxy optionally further substituted with 1 to 5 fluoro substituents, iv) cyclopropyl-(C 0 -C 1 )alkyl-O—, v) cyano, vi) (C 1 -C 2 )alkyl-S(O) 2 —, and vii) (C 1 -C 4 )alkyl-C(O)—,

or alternatively, m is 1 or 2, one R 4 substituent is selected from the group consisting of viii) (C 1 -C 4 )alkyl further substituted with a substituent selected from the group consisting of (hydroxy, (C 1 -C 4 )alkoxy, cyano, and amino), ix) (C 1 -C 2 )alkyl-O—C(O)—, x) (C 1 -C 2 )alkyl-S(O) 2 —(C 1 -C 2 )alkyl-, xi) (C 1 -C 4 )alkyl-C(O)—N(R 6 )—, xii) (C 1 -C 4 )alkyl-C(O)—N(R 6 )-methyl-, xiii) cyclopropyl-C(O)—NH-methyl-, xiv) (C 1 -C 2 )alkyl-S(O) 2 —N(R 6 )—(C 1 -C 2 )alkyl-, xv) (C 1 -C 2 )alkyl-O—(C 0 -C 2 )alkyl-C(O)—N(R 6 )— optionally further substituted with a fluoro group, xvi) (C 1 -C 2 )alkyl-O—(C 0 -C 2 )alkyl-C(O)—N(R 6 )-methyl- optionally further substituted with a fluoro group, xvii) (R 6 )(R 7 )N—C(O)—(C 1 -C 2 )alkyl-, xviii) (C 1 -C 2 )alkyl-C(O)—NH-methyl-C(O)—, xix) (R 6 )(R 7 )N—C(O)—N(H)-methyl-, xx) (R 6 )(R 7 )N—C(S)—N(H)-methyl-, xxi) (R 6 )(R 7 )N—C(O)—O-methyl-, xxii) (R 6 )(R 7 )N—C(O)methoxy-, and xxiii) (R 6 )(R 7 )N—C(O)methoxymethyl-, and if present, the second R 4 substituent is fluoro or chloro;

R 6 is hydrogen or methyl;

R 7 is hydrogen or (C 1 -C 3 )alkyl;

Ph 1 is phenyl optionally substituted with a substituent selected from the group consisting of halo, (C 1 -C 2 )alkyl optionally further substituted with 1 to 3 fluoro substituents, and (C 1 -C 2 )alkoxy optionally further substituted with 1 to 3 fluoro substituents;

Ar 1 is a heteroaryl moiety selected from pyridyl, pyrimidyl, imidazolyl, pyrrolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, any of which may be optionally further substituted with 1 or 2 substituents independently selected from methyl and ethyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 where each R 4 is independently selected from the group consisting of i) halogen, ii) (C 1 -C 2 )alkyl optionally further substituted with 1 to 5 fluoro substituents, iii) (C 1 -C 2 )alkoxy optionally further substituted with 1 to 5 fluoro substituents, iv) cyclopropyl-(C 0 -C 1 )alkyl-O—, v) cyano, vi) (C 1 -C 2 )alkyl-S(O) 2 —, and vii) (C 1 -C 4 )alkyl-C(O)—;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein n is 1.

4. A compound according to claim 1 wherein m is 1 or 2.

5. A compound according to claim 1 of the formula

wherein

R 1 is selected from i) hydrogen, ii) (C 1 -C 3 )alkyl-optionally mono-substituted with hydroxy, iii) phenyl, iv) benzyl, and v) pyridyl;

R 2 is selected from hydrogen and (C 1 -C 3 )alkyl-;

R 3 is selected from hydrogen and (C 1 -C 3 )alkyl-;

R 4 is selected from the group consisting of i) (C 1 -C 4 )alkyl further substituted with a substituent selected from the group consisting of (hydroxy, (C 1 -C 4 )alkoxy, cyano, and amino), ii) (C 1 -C 2 )alkyl-O—C(O)—, iii) (C 1 -C 2 )alkyl-S(O) 2 —(C 1 -C 2 )alkyl-, iv) (C 1 -C 4 )alkyl-C(O)—N(R 6 )—, v) (C 1 -C 4 )alkyl-C(O)—N(R 6 )-methyl-, vi) cyclopropyl-C(O)—NH-methyl-, vii) (C 1 -C 2 )alkyl-S(O) 2 —N(R 6 )—(C 1 -C 2 )alkyl-, viii) (C 1 -C 2 )alkyl-O—(C 0 -C 2 )alkyl-C(O)—N(R 6 )— optionally further substituted with a fluoro group, ix) (C 1 -C 2 )alkyl-O—(C 0 -C 2 )alkyl-C(O)—N(R 6 )-methyl-optionally further substituted with a fluoro group, x) (R 6 )(R 7 )N—C(O)—(C 1 -C 2 )alkyl-, xi) (C 1 -C 2 )alkyl-C(O)—NH-methyl-C(O)—, xii) (R 6 )(R 7 )N—C(O)—N(H)-methyl-, xiii) (R 6 )(R 7 )N—C(S)—N(H)-methyl-, xiv) (R 6 )(R 7 )N—C(O)—O-methyl-, xv) (R 6 )(R 7 )N—C(O)methoxy-, and xvi) (R 6 )(R 7 )N—C(O)methoxymethyl-;

R 5 is fluoro or chloro;

R 6 is hydrogen or methyl;

R 7 is hydrogen or (C 1 -C 3 )alkyl;

p is 0 or 1; and or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 wherein R 1 is methyl, ethyl, or phenyl; R 2 is hydrogen or methyl; R 3 is hydrogen or methyl; p is 0; and R 4 is selected from the group consisting of hydroxymethyl, hydroxyethyl, methoxymethyl, cyanomethyl, methyl-C(O)—N(H)-methyl-, and methyl-S(O) 2 —N(H)-methyl-.

7. A compound according to claim 1 which is 2-[4-(3′-Phenyl-2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-ylmethyl)-pyrazol-1-yl]-ethanol or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 which is N-{4-[4-(1,5-Dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-acetamide or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient in association with a pharmaceutically acceptable carrier, diluent or excipient.