Heterocyclic compounds Number:6,803,362 from the United States Patent and Trademark Office (PTO) owispatent Heterocyclic compounds and methods of making them and using them.<H Heterocyclic, compounds, Heterocyclic, co, 6803362.html, Patent, pto, 6803362

Title: Heterocyclic compounds

Abstract: Heterocyclic compounds and methods of making them and using them.

Patent Number: 6,803,362 Issued on 10/12/2004 to Carruthers, et al.

Inventors: Carruthers; Nicholas I. (Poway, CA); Chai; Wenying (San Diego, CA); Dvorak; Curt A. (San Diego, CA); Edwards; James P. (San Diego, CA); Grice; Cheryl A. (Carlsbad, CA); Jablonowski; Jill A. (San Diego, CA); Karlsson; Lars (La Jolla, CA); Khatuya; Haripada (San Diego, CA); Kreisberg; Jennifer D. (Del Mar, CA); Kwok; Annette K. (San Diego, CA); Lovenberg; Timothy W. (San Diego, CA); Ly; Kiev S. (San Diego, CA); Pio; Barbara (San Diego, CA); Shah; Chandravadan R. (San Diego, CA); Sun; Siguan (San Diego, CA); Thurmond; Robin L. (San Diego, CA); Wei; Jianmei (San Diego, CA); Xiao; Wei (San Diego, CA)
Assignee: Ortho-McNeil Pharmaceutical inc. (Raritan, NJ)

Appl. No.: 10/094,357

Filed: March 8, 2002

Current U.S. Class: 514/183 ; 514/254.09; 544/358; 544/372; 548/452; 548/465; 548/469; 548/517; 548/518

Field of Search: 514/183,254,9 544/358,372 548/452,469,465,517,518

References Cited [Referenced By]

U.S. Patent Documents


4115569	September 1978	Weber et al.
4374990	February 1983	Weber et al.
5563142	October 1996	Palmer et al.
5614523	March 1997	Audia et al.
5795894	August 1998	Shue et al.
5814644	September 1998	Kulagowski et al.
5891902	April 1999	Machii et al.

Foreign Patent Documents


2157424	May., 1973	DE
4307883	Sep., 1993	DE
0318235	May., 1989	EP
0324431	Jul., 1989	EP
0548798	Jun., 1993	EP
0624575	Nov., 1994	EP
0655440	May., 1995	EP
0978512	Feb., 2000	EP
01132579	May., 1989	JP
5025131	Feb., 1993	JP
05025131	Feb., 1993	JP
9124631	May., 1997	JP
10740940	Apr., 1992	SU
WO 91/09849	Jul., 1991	WO
WO 94/09781	May., 1994	WO
WO 97/03965	Feb., 1997	WO
WO 98/01443	Jan., 1998	WO
WO 99/05121	Feb., 1999	WO
WO 99/09025	Feb., 1999	WO
9909025	Feb., 1999	WO
WO 01/64676	Sep., 2001	WO
WO 01/74774	Oct., 2001	WO

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Primary Examiner: Raymond; Richard L.
Assistant Examiner: Patel; Sudhaker B.

Parent Case Text

This application claims the benefit of provisional U.S. Application Sr. No. 60274900 filed on Mar. 9, 2001, and provisional U.S. Sr. No. 60343259, filed Dec. 21, 2001.

Claims

What is claimed is:

1. A compound of formula (I) wherein: ##STR91## Wherein R.sub.1 is R.sub.a, R.sub.a R.sub.b --, R.sub.a --O--R.sub.b --, or (R.sub.c)(R.sub.d)N--R.sub.b --, where R.sub.a is H, cyano, --(C.dbd.O)N(R.sub.c)(R.sub.d), --C(.dbd.NH)(NH.sub.2), C.sub.1-10 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.b is C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.3-8 cycloalkylene, bivalent C.sub.3-8 heterocyclic radical, or phenylene; and R.sub.c and R.sub.d are each independently H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, or phenyl; R.sub.2 ' is H, methyl, ethyl, NR.sub.p R.sub.q, --(CO)NR.sub.p R.sub.q, --(CO)OR.sub.r, --CH.sub.2 NR.sub.p R.sub.q, or CH.sub.2 OR.sub.r ; where R.sub.p, R.sub.q, and R.sub.r are independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl; (C.sub.3-6 cycloalkyl)(C.sub.1-2 alkylene), benzyl or phenethyl; or R.sub.p and R.sub.q taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R.sub.3 ' is H, methyl, ethyl, NR.sub.s R.sub.t, --(CO)NR.sub.s R.sub.t, --(CO)OR.sub.u, --CH.sub.2 NR.sub.s R.sub.t, or CH.sub.2 OR.sub.u ; where R.sub.s, R.sub.t, and R.sub.u are independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl; (C.sub.3-6 cycloalkyl)(C.sub.1-2 uualkylene), benzyl or phenethyl; or R.sub.s and R.sub.1 taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R.sub.5 ' is methyl, ethyl, or H; R.sub.6 ' is methyl, ethyl, or H; R.sub.7 ' is methyl, ethyl, or H; R.sub.3 is F, Cl, Br, CHO, R.sub.f, R.sub.f R.sub.g --, R.sub.f --O--R.sub.g --, or (R.sub.h)(R.sub.i)N--R.sub.g --, where R.sub.f is H, C .sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.g is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.3-6 cycloalkylene, bivalent C.sub.3-6 heterocyclic radical, or phenylene; and R.sub.h and R.sub.i are each independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, or phenyl; R.sub.e is H or C.sub.1-6 alkyl; each of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.5 is H, F, Cl, Br, I, (C.dbd.O)R.sub.j, OH, nitro, NR.sub.j R.sub.k, cyano, phenyl, --OCH.sub.2 --Ph, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, I, (C.dbd.O)R.sub.m, OH, nitro, NR.sub.l R.sub.m, cyano, phenyl, --OCH.sub.2 --Ph C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; wherein each of R.sub.j, R.sub.k, R.sub.l, and R.sub.m is independently selected from H, C.sub.1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C.sub.1-6 alkoxy; each of the above hydrocarbyl (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, and so on) or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C.sub.1-3 alkyl, halo, hydroxy, amino, and C.sub.1-3 alkoxy; wherein n is 0, 1, or 2; where n is 2, the moiety --(CHR.sub.5 ').sub.n=2 -- is --(CHR.sub.5 '--CHR.sub.7 ')-- where CHR.sub.5 ' is between CHR.sub.6 ' and CHR.sub.7 '; provided at least one of R.sub.1, R.sub.2 ', R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H; and provided, where n=1, and each of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' is H, then (a) where R.sub.e is H, then R.sub.1 is not methyl, pyridyl, phenyl, or benzyl; and provided, where R.sub.e is H, n=1, R.sub.1 is methyl, and each of R.sub.4, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' is H, then R.sub.5 is not methoxy; or a pharmaceutically acceptable salt, ester, or amide thereof.

2. A compound of claim 1 of the following formula wherein: ##STR92## Wherein R.sub.1 is R.sub.a, R.sub.a R.sub.b --, R.sub.a --O--R.sub.b --, or (R.sub.c)(R.sub.d)N--R.sub.b --, where R.sub.a is H, C.sub.1-10 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.b is C.sub.1-8 alkylene, C.sub.3-8 alkenylene, C.sub.3-8 cycloalkylene, bivalent C.sub.3-8 heterocyclic radical, or phenylene; and R.sub.c and R.sub.d are each independently H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, or phenyl; R.sub.2 is ortho or meta, and is methyl or H; R.sub.3 is F, Cl, Br, R.sub.f, R.sub.f R.sub.g --, R.sub.f --O--R.sub.g --, or (R.sub.h)(R.sub.i)N--R.sub.g --, where R.sub.f is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.g is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.3-6 cycloalkylene, bivalent C.sub.3-6 heterocyclic radical, or phenylene; and R.sub.h and R.sub.j are each independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, or phenyl; R.sub.e is H or C.sub.1-6 alkyl; each of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C.sub.1.varies. alkoxy, or C.sub.1-4 alkyl; R.sub.5 is H, F, Cl, Br, I, (C.dbd.O)R.sub.j, OH, nitro, NR.sub.j R.sub.k, cyano, --OCH.sub.2 --Ph, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, I, (C.dbd.O)R.sub.m, OH, nitro, NR.sub.l R.sub.m, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; wherein each of R.sub.j, R.sub.k, R.sub.l, and R.sub.m is independently selected from H, C.sub.1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C.sub.1-6 alkoxy; each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C.sub.1-3 alkyl, halo, hydroxy, amino, and C.sub.1-3 alkoxy; provided at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H; or a pharmaceutically acceptable salt, ester, or amide thereof.

3. A compound of claim 1, wherein R.sub.1 is R.sub.a, R.sub.a R.sub.b --, R.sub.a --O--R.sub.b --, or (R.sub.c)(R.sub.d)N--R.sub.b --, where R.sub.a is H, C.sub.1-10 alkyl, C.sub.2-5 alkenyl, C.sub.3-8 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.b is C.sub.1-6 alkylene, or C.sub.2-8 alkenylene; and R.sub.c and R.sub.d are each independently H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, or phenyl; R.sub.2 ' is methyl or H; R.sub.3 ' is methyl or H; R.sub.5 ' is methyl or H; R.sub.6 ' is methyl or H; R.sub.7 ' is methyl or H; R.sub.3 is F, Cl, Br, methyl, ethyl, or propyl; R.sub.e is H or C.sub.1-6 alkyl; each of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C.sub.1-3 alkoxy, or C.sub.1-3 alkyl; R.sub.5 is H, F, Cl, Br, I, (C.dbd.O)R.sub.j, OH, nitro, NR.sub.j R.sub.k, cyano, --OCH.sub.2 --Ph, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, I, (C.dbd.O)R.sub.m, OH, nitro, NR.sub.l R.sub.m, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; wherein each of R.sub.j, R.sub.k, R.sub.l, and R.sub.m is independently selected from H, C.sub.1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C.sub.1-6 alkoxy; each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C.sub.1-3 alkyl, halo, hydroxy, amino, and C.sub.1-3 alkoxy; n is 1; provided at least one of R.sub.1, R.sub.2 ', R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H; or a pharmaceutically acceptable salt, ester, or amide thereof.

4. A compound of claim 1, wherein R.sub.1 is H, methyl, or ethyl; One of R.sub.2 ' and R.sub.3 ' is methyl, and the other is H, where R.sub.1 is H; R.sub.2 is otherwise H; R.sub.e is H or C.sub.1-3 alkyl; each of R.sub.4 and R.sub.6 is independently H, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, or amino; R.sub.5 is H, F, Cl, Br, COOH, OH, amino, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; and R.sub.7 is H, F, Cl, Br, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, or amino; provided at least one of R.sub.5 and R.sub.7 is not H.

5. A compound of claim 1, wherein R.sub.1 is H, methyl, or ethyl; R.sub.2 ' and R.sub.3 ' are independently methyl or H; R.sub.3 is H, F, or Cl; R.sub.e is H or C.sub.1-6 alkyl; each of R.sub.4 and R.sub.6 is H; R.sub.5 is H, F, Cl, Br, methyl, ethyl, or propyl; and R.sub.7 is H, F, Cl, Br, or C.sub.1-4 alkyl; provided at least one of R.sub.5 and R.sub.7 is not H.

6. A compound of claim 1, wherein R.sub.1 is H, methyl or ethyl.

7. A compound of claim 6, wherein R.sub.1 is methyl.

8. A compound of claim 1, wherein R.sub.2 ' is H.

9. A compound of claim 1, wherein R.sub.2 ' is methyl.

10. A compound of claim 1, wherein R.sub.3 is H or Cl.

11. A compound of claim 10, wherein R.sub.3 is Cl.

12. A compound of claim 1, wherein R.sub.5 is F, Cl, Br, or methyl and R.sub.7 is F, Cl, or Br.

13. A compound of claim 1, wherein each of R.sub.5 and R.sub.7 is independently selected from H, F, Cl, Br, and methyl, provided at least one of R.sub.5 and R.sub.7 is not H.

14. A compound of claim 1, wherein each of R.sub.4 and R.sub.6 is independently H, methyl, or Cl.

15. A compound of claim 1, wherein R.sub.3 is H or Cl; R.sub.5 is F, Cl, Br, or methyl; and R.sub.7 is H, F, Cl, or Br.

16. A compound of claim 15, wherein each of R.sub.4 and R.sub.6 is independently H, methyl, or Cl.

17. A compound of claim 1 selected from: (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl )-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-I indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl )-(4-methyl-piperazin-1-yl)-methanone; (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl )-methanone.

18. A compound of claim 1 selected from: (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazinyl-1-yl)-methanone; (1H-Indol-2-yl)-(3-methyl-piperazin-1-yl )-methanone; and (7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

19. A compound of claim 17 selected from: (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl )-(4-methyl-piperazin-1-yl )-methanone; (5-Methyl-1H-indol-2-yl )-(4-methyl-piperazin-1-yl )-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

20. A compound of claim 1, selected from: (4-Methyl-piperazin-1-yl )-(5-trifluoromethyl-1H-indol-2-yl )-methanone; (7-Amino-5-methyl-1H-indol-2-yl )-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Amino-5-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Fluoro-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-5-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-6-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (4-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (4-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-I-yl)-methanone.

21. A compound of claim 1, selected from: (5,7-Dichloro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5,7-Difluoro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5, 7-Difluoro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; (5,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (4,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

22. A compound of claim 1, selected from: 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid amide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid amide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methylamine; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methylamide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid dimethylamide; 1-(5-Chloro-1H-1-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid dimethylamide; (5-Chloro-1H-indol-2-yl)-(3-hydroxymethyl-4-methyl-piperazin-1-yl)-methano ne; (5-Chloro-1H-indol-2-yl)-(3-methoxymethyl-4-methyl-piperazin-1-yl )-methanone; (5-Chloro-1H-indol-2-yl)-(2-methoxymethyl-4-methyl-piperazin-1-yl)-methano ne; (5-Chloro-1H-indol-2-yl)-(4-methyl-3-methylaminomethyl-piperazin-1-yl)-met hanone; (5-Chloro-1H-indol-2-yl)-(4-methyl-2-methylaminomethyl-piperazin-1-yl)-met hanone; (5-Chloro-1H-indol-2-yl)-(3-dimethylaminomethyl-4-methyl-piperazin-1-yl)-m ethanone; and (5-Chloro-1H-indol-2-yl)-(2-dimethylaminomethyl-4-methyl-piperazin-1-yl)-m ethanone.

23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition of claim 20, comprising a compound selected from (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7- Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; and (7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

27. A packaged drug comprising (a) a pharmaceutical composition comprising a compound of claim 1, 2, or 3 and a pharmaceutically acceptable carrier, and (b) instructions for the administration of said composition for the treatment or prevention of an H.sub.4 -mediated disease or condition.

28. A method for treating an H.sub.4 -mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1.

29. A method for treating an H.sub.4 -mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective H.sub.4 -inhibiting amount of a composition comprising a compound of claim 1.

30. A method of claim 29 wherein said compound is a compound of claim 2.

31. A method of claim 29, wherein said compound is a compound of claim 3.

32. A method of claim 29, wherein said compound is selected from: (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; and (7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

33. A method of claim 29, wherein said H.sub.4 -mediated condition is selected from: inflammatory disorders, asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders.

34. A method of claim 33, wherein said H.sub.4 -mediated condition is an inflammatory disorder or an allergic disorder.

35. A method of claim 34, wherein said inflammatory disorder is an inflammation-mediated condition selected from: acute inflammation, allergic inflammation, and chronic inflammation.

36. A method for treating asthma in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1, 18, or 19.

37. A method for treating an allergic disorder in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1, 18, or 19.

Description

FIELD OF THE INVENTION

The invention relates to novel, pharmaceutically-active fused heterocyclic compounds and methods of using them to treat or prevent disorders and conditions mediated by the histamine H.sub.4 receptor.

BACKGROUND

Histamine was first identified as a hormone (Barger et al., J. Physiology 41:19-59, 1910) and has since been demonstrated to play a major role in a variety of physiological processes, including the inflammatory "triple response" via H.sub.1 receptors (Ash et al., Br. J. Pharmacology 27:427-439, 1966), gastric acid secretion via H.sub.2 receptors (Black et al., Nature 236:385-390, 1972), and neurotransmitter release in the central nervous system via H.sub.3 receptors (Arrang et al., Nature 302: 832-837, 1983) (for review see Hill et al., Pharmacol. Rev. 49: 253-278, 1997). All three histamine receptor subtypes have been demonstrated to be members of the superfamily of G-protein coupled receptors (Gantz et al., Proc. Natl. Acad. Sci. U.S.A. 88:429-433, 1991; Lovenberg et al., Mol. Pharmacol. 55:1101-1107, 1999; Yamashita et al., Proc. Natl. Acad. Sci. U.S.A. 88:11515-11519, 1991). There are, however, additional functions of histamine that have been reported, for which no receptor has been identified. For example, in 1994, Raible et al. demonstrated that histamine and R-.alpha.-methylhistamine could activate calcium mobilization in human eosinophils (Raible et al., Am. J. Respir. Crit. Care Med. 149:1506-1511, 1994). These responses were blocked by the H.sub.3 -receptor antagonist thioperamide. However, R-.alpha.-methylhistamine was significantly less potent than histamine which was not consistent with the involvement of known H.sub.3 receptor subtypes. Therefore, Raible et al. hypothesized the existence of a novel histamine receptor on eosinophils that was non-H.sub.1, -H.sub.2, or -H.sub.3. Most recently several groups (Oda et al., J. Biol. Chem. 275(47):36781-36786, 2000; Liu et al., Mol. Pharmacol. 59:420-426, 2001; Nguyen et al., Mol. Pharmacol. 59:427-433, 2001; Zhu et al., Mol. Pharmacol. 59(3):434-441, 2001; Morse et al., J. Pharmacol. Exp. Ther. 296(3):1058-1066, 2001) have identified and characterized a fourth histamine receptor subtype, the H.sub.4 receptor. This receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40% homology to the histamine H.sub.3 receptor. In contrast to the H.sub.3 receptor, which is primarily located in the brain, the H.sub.4 receptor is expressed at greater levels in neutrophils and mast cells, among other cells, as reported by Morse et al. (see above).

Events that elicit the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function, or a combination of these. Many conditions, such as allergies, asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis, and autoimmune diseases, including rheumatoid arthritis and lupus, are characterized by excessive or prolonged inflammation. Inhibition of leukocyte recruitment can provide significant therapeutic value. Inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.

Mast cell de-granulation (exocytosis) leads to an inflammatory response that may be initially characterized by a histamine-modulated wheal and flare reaction. A wide variety of immunological (e.g., allergens or antibodies) and non-immunological (e.g., chemical) stimuli may cause the activation, recruitment, and de-granulation of mast cells. Mast cell activation initiates allergic (H.sub.1) inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response. The histamine H2 receptors modulate gastric acid secretion, and the histamine H3 receptors affect neurotransmitter release in the central nervous system.

Examples of textbooks on the subject of inflammation include J. I. Gallin and R. Snyderman, Inflammation: Basic Principles and Clinical Correlates, 3.sup.rd Edition, (Lippincott Williams & Wilkins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin, "Inflammation and Fever", Pathophysiology Principles of Diseases (Textbook for Medical Students, Academic Press, 1995); Cecil et al., Textbook Of Medicine, 18.sup.th Edition (W. B. Saunders Company, 1988); and Steadmans Medical Dictionary.

A summary of the present invention follows.

SUMMARY OF THE INVENTION

The invention features a compound of formula (I) wherein: ##STR1##

Wherein R.sub.1 is R.sub.a, R.sub.a R.sub.b --, R.sub.a --O--R.sub.b --, or (R.sub.c)(R.sub.d)N--R.sub.b --, where R.sub.a is H, cyano, --(C.dbd.O)N(R.sub.c)(R.sub.d), --C(.dbd.NH)(NH.sub.2), C.sub.1-10 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.b is C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.3-8 cycloalkylene, bivalent C.sub.3-8 heterocyclic radical, or phenylene; and R.sub.c and R.sub.d are each independently H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, or phenyl; R.sub.2 ' is H, methyl, ethyl, NR.sub.p R.sub.q, --(CO)NR.sub.p R.sub.q, --(CO)OR.sub.r, --CH.sub.2 NR.sub.p R.sub.q, or CH.sub.2 OR.sub.r ; where R.sub.p, R.sub.q, and R.sub.r are independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl; (C.sub.3-6 cycloalkyl)(C.sub.1-2 alkylene), benzyl or phenethyl; or R.sub.p and R.sub.q taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R.sub.3 ' is H, methyl, ethyl, NR.sub.s R.sub.t, --(CO)NR.sub.s R.sub.t, --(CO)OR.sub.u, --CH.sub.2 NR.sub.s R.sub.t, or CH.sub.2 OR.sub.u ; where R.sub.s, R.sub.t, and R.sub.u are independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl; (C.sub.3-6 cycloalkyl)(C.sub.1-2 alkylene), benzyl or phenethyl; or R.sub.s and R.sub.t taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N; R.sub.5 ' is methyl, ethyl, or H; R.sub.6 ' is methyl, ethyl, or H; R.sub.7 ' is methyl, ethyl, or H; X.sub.4 is NR.sub.1 or S; X.sub.1 is CR.sub.3 ; R.sub.3 is F, Cl, Br, CHO, R.sub.f, R.sub.f R.sub.g --, R.sub.f --O--R.sub.g --, or (R.sub.h)(R.sub.i)N--R.sub.g --, where R.sub.f is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.g is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.3-6 cycloalkylene, bivalent C.sub.3-6 heterocyclic radical, or phenylene; and R.sub.h and R.sub.i are each independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, or phenyl; X.sub.2 is NR.sub.e or O, provided that X.sub.2 is NR.sub.e where X.sub.1 is N; R.sub.e is H or C.sub.1-6 alkyl; X.sub.3 is N; Z is .dbd.O or .dbd.S; each of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.5 is H, F, Cl, Br, I, (C.dbd.O)R.sub.j, OH, nitro, NR.sub.j R.sub.k, cyano, phenyl, --OCH.sub.2 --Ph, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, I, (C.dbd.O)R.sub.m, OH, nitro, NR.sub.l R.sub.m, cyano, phenyl, --OCH.sub.2 --Ph C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; wherein each of R.sub.j, R.sub.k, R.sub.l, and R.sub.m is independently selected from H, C.sub.1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C.sub.1-6 alkoxy; each of the above hydrocarbyl (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, and so on) or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C.sub.1-3 alkyl, halo, hydroxy, amino, and C.sub.1-3 alkoxy; wherein n is 0, 1, or 2; where n is 2, the moiety --(CHR.sub.5 ').sub.n=2 -- is --(CHR.sub.5 '--CHR.sub.7 ')-- where CHR.sub.5 ' is between CHR.sub.6 ' and CHR.sub.7 '; provided at least one of R.sub.1, R.sub.2 ', R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H when Z is O; and provided, where Z is O, n=1, and each of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' is H, (or at least 7, 8, or 9 of these 10 limitations apply) then (a) where X.sub.2 is NH, then R.sub.1 is (i) not methyl, pyridyl, phenyl, or benzyl, or (ii) is selected from the disclosed possibilities, but not C.sub.1-2 alkyl and not a six-membered aryl or six-membered nitrogen-containing heteroaryl, or phenyl(C.sub.1-2 alkylene) (alternatively, provided, where Z is O, n=1, and X.sub.2 is NH, then at least two (or three) of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' is other than H); and (b) where X.sub.2 is O, then R.sub.1 is not methyl; and provided, where Z is O, X.sub.2 is NH, n=1, R.sub.1 is methyl, each of R.sub.4, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' is H (or at least 7, 8, 9, or 10 of these 11 limitations apply), then R.sub.5 is (i) not methoxy, (ii) not methoxy, or ethoxy, (iii) not C.sub.1-4 alkoxy, or (iv) not methoxy or hydroxy; or a pharmaceutically acceptable salt, ester, or amide thereof.

According to one aspect of the invention, the invention features compounds of the following formula (Ib): ##STR2##

Wherein R.sub.1 is R.sub.a, R.sub.a R.sub.b --, R.sub.a --O--R.sub.b --, or (R.sub.c)(R.sub.d)N--R.sub.b --, where R.sub.a is H, C.sub.1-10 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.b is C.sub.1-8 alkylene, C.sub.3-8 alkenylene, C.sub.3-8 cycloalkylene, bivalent C.sub.3-8 heterocyclic radical, or phenylene; and R.sub.c and R.sub.d are each independently H, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl, or phenyl; R.sub.2 is ortho (like R.sub.2 ' in formula (I)) or meta (like R.sub.3 ' in formula (I)), and is methyl or H; X.sub.1 is CR.sub.3 ; R.sub.3 is F, Cl, Br, R.sub.f, R.sub.f R.sub.g --, R.sub.f --O--R.sub.g --, or (R.sub.h)(R.sub.i)N--R.sub.g --, where R.sub.f is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-5 heterocyclic radical, or phenyl; where R.sub.g is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.3-6 cycloalkylene, bivalent C.sub.3-6 heterocyclic radical, or phenylene; and R.sub.h and R.sub.i are each independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, or phenyl; X.sub.2 is NR.sub.e or O, provided that X.sub.2 is NR.sub.e when X.sub.1 is N; R.sub.e is H or C.sub.1-6 alkyl; X.sub.3 is N; Z is .dbd.O or .dbd.S; each of R.sub.4 and R.sub.6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.5 is H, F, Cl, Br, I, (C.dbd.O)R.sub.j, OH, nitro, NR.sub.j R.sub.k, cyano, --OCH.sub.2 --Ph, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, I, (C.dbd.O)R.sub.m, OH, nitro, NR.sub.l R.sub.m, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; wherein each of R.sub.j, R.sub.k, R.sub.l, and R.sub.m is independently selected from H, C.sub.1-6 alkyl, hydroxy, and C.sub.1-6 alkoxy; and each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C.sub.1-3 alkyl, halo, hydroxy, amino, and C.sub.1-3 alkoxy; provided at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H when Z is .dbd.O; or a pharmaceutically acceptable salt, ester, or amide thereof.

The invention also features methods of making and using such compounds in pharmaceutical composition, packaged drugs, and in the treatment or prevention of H.sub.4 -mediated diseases and conditions, particularly those wherein it is desirable to antagonize the H.sub.4 receptor. For example, the expression of the H.sub.4 receptor in immune cells, including some leukocytes and mast cells, establishes it as an important target for therapeutic intervention in a range of immunological and inflammatory disorders (such as allergic, chronic, or acute inflammation). Specifically H.sub.4 receptor ligands are expected to be useful for the treatment or prevention of various mammalian disease states. Examples include: inflammatory disorders (such as those mediated by leukocytes or mast cells), asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, atherosclerosis, and immunodeficiency disorders.

In addition, H.sub.4 receptor ligands may be useful as adjuvants to chemotherapy. In the above methods of treatment, the invention also includes using compounds described in formula (I) and (Ib) without the provisos such as "provided at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is other than H when Z is O" above in pharmaceutical compositions for treating H.sub.4 -mediated conditions, and in methods of treatment of H.sub.4 -mediated diseases. Such a compound is, for example, Example 4.

Important synthetic intermediates of the above compounds include those wherein one or more of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is Br, I, cyano, nitro, alkoxy, or --OCH.sub.2 Ph, which can be further modified to provide a wide range of substituents.

Other features and advantages of the invention will be apparent in the following detailed description, examples, and the appended claims.

DETAILED DESCRIPTION

The invention features compounds of formulae (I) and (Ib), methods of making them, and methods of using them in the preparation of pharmaceutical compositions for the treatment or prevention of H.sub.4 -mediated diseases and conditions.

A. Terms

The following terms are defined below, and by their usage throughout the disclosure.

"Alkyl" includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl does not include cycloalkyl.

"Alkenyl" includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp.sup.2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl does not include cycloalkenyl.

"Alkynyl" include straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.

"Alkoxy" includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO.sub.2.

"Aryl" includes phenyl, naphthyl, biphenylyl, and so on.

"Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.

"Cycloalkenyl" includes cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclohexatrienyl (phenyl), cycloheptenyl, and so on. "Cycloalkynyl" includes the analogous rings with one or more triple bonds.

"Heterocyclic radicals" include aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO.sub.2, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Examples of heterocyclic radicals include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclic radicals for R.sub.8 include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino,and more preferably, piperidyl.

"Halo" includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro.

"Patient" or "subject" includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human.

"Composition" includes a product comprising the specified ingredients in the specified amounts as well as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts.

Concerning the various radicals in this disclosure and in the claims, two general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals (hydrocarbyl), whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. Hydrocarbyl includes alkoxy, in that the alkyl portion of an alkoxy group may be substituted. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical linking two parts of the molecule is R.sub.b in formula (I), which can link N(R.sub.c)(R.sub.d) with the ring nitrogen atom of the rest of the molecule. Another example of a bivalent moiety is an alkylene or alkenylene.

Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Using "alkyl" as an example, "alkyl" should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl), hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, and so on. Preferred substitutions for R.sub.a include methyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoromethoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoroethoxy, fluoro, chloro, and bromo, and particularly methyl, fluoromethyl, perfluoro, trifluoromethoxy, difluoromethoxy, methoxy, and fluoro.

B. Compounds

The invention features compounds of formula (I) and (Ib). Preferred compounds include those wherein: (a) X.sub.1 is CR.sub.3 ; (b) X.sub.3 is N; (c) X.sub.2 is N; (d) R.sub.1 is H, methyl, or ethyl; (e) X.sub.2 is N and X.sub.1 is CR.sub.3 ; (f) X.sub.2 is O and X.sub.1 is CR.sub.3 ; (g) X.sub.2 is N and Z is O; (h) R.sub.7 is H or Cl; (i) R.sub.1 is methyl or ethyl; R.sub.3 ' or R.sub.2 ' is, or both are, H; (k) R.sub.3 is H or Cl; (l) each of R.sub.5 and R.sub.7 is independently selected from H, F, Cl, and Br; (m) R.sub.3 is Cl; (n) at least one of R.sub.5 and R.sub.7 is F, Cl, Br, or methyl; (o) R.sub.5, or R.sub.7, or both is (are independently selected from) H, F, Cl, or Br; (p) R.sub.3 ' or R.sub.2 ' is methyl where R.sub.1 is H; R.sub.3 ' or R.sub.2 ' is otherwise H; or (q) at least one of R.sub.5 and R.sub.7 is not H; or (r) combinations thereof.

Additional examples of preferred compounds or combinations of the above include those wherein: (s) X.sub.3 is N; R.sub.3 is H or Cl; R.sub.5 is F, Cl, Br, or methyl; and R.sub.7 is H, F, Cl, or Br; (t) R.sub.3 is H or Cl; R.sub.5 is F, Cl, Br, or methyl; and R.sub.7 is H, F, Cl, Br, or methyl; (u) R.sub.2 is methyl where R.sub.1 is H; R.sub.2 is otherwise H; X.sub.1 is CR.sub.3 ; R.sub.3 is H, F, or Cl; X.sub.2 is NR.sub.e or O, provided that X.sub.2 is NR.sub.e where X.sub.1 is N; R.sub.e is H or C.sub.1-3 alkyl; Z is .dbd.O or .dbd.S; each of R.sub.4 and R.sub.6 is independently H, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, or amino; R.sub.5 is H, F, Cl, Br, (C.dbd.O)R.sub.j, OH, amino, cyano, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; R.sub.7 is H, F, Cl, Br, (C.dbd.O)R.sub.m, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, or amino; and (v) R.sub.3 ' and R.sub.2 ' is methyl or H; X.sub.1 is CR.sub.3 ; R.sub.3 is H, F, or Cl; X.sub.2 is NR.sub.e or O, provided that X.sub.2 is NR.sub.e where X.sub.1 is N; R.sub.e is H or C.sub.1-6 alkyl; Z is .dbd.O or .dbd.S; each of R.sub.4 and R.sub.6 is H; R.sub.5 is H, F, Cl, Br, methyl, ethyl, or propyl; and R.sub.7 is H, F, Cl, Br, or C.sub.1-4 alkyl.

Examples of compounds include: (4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-1H-indol-2-yl)-methanone; (7-Amino-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Amino-5-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Fluoro-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-5-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-6-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (4-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (4-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

Additional examples of compounds include: (5,7-Dichloro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5,7-Difluoro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5,7-Difluoro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; (5,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (4,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

Further examples of compounds include: 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid amide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid amide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methylamide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methylamide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid dimethylamide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid dimethylamide; (5-Chloro-1H-indol-2-yl)-(3-hydroxymethyl-4-methyl-piperazin-1-yl)-methano ne; (5-Chloro-1H-indol-2-yl)-(3-methoxymethyl-4-methyl-piperazin-1-yl)-methano ne; (5-Chloro-1H-indol-2-yl)-(2-methoxymethyl-4-methyl-piperazin-1-yl)-methano ne; (5-Chloro-1H-indol-2-yl)-(4-methyl-3-methylaminomethyl-piperazin-1-yl)-met hanone; (5-Chloro-1H-indol-2-yl)-(4-methyl-2-methylaminomethyl-piperazin-1-yl)-met hanone; (5-Chloro-1H-indol-2-yl)-(3-dimethylaminomethyl-4-methyl-piperazin-1-yl)-m ethanone; and (5-Chloro-1H-indol-2-yl)-(2-dimethylaminomethyl-4-methyl-piperazin-1-yl)-m ethanone.

Examples of preferred compounds include: (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone. More preferred compounds in this group include (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Amino-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

Further examples of preferred compounds include (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; (7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione.

The most preferred compound is (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

The disclosed compounds can be prepared according to the next section.

C. Synthesis

The disclosed compounds may be made by combinatorial or traditional organic synthetic methods, as outlined below in Schemes 1-12 and Chemical Examples 1-86, or by analogous reactions. ##STR3##

Compounds of formula III may be prepared from the compounds of formula II using conventional methods of amide bond formation. For example the carboxyl group of compound II may be activated as an active ester, acid chloride, anhydride, mixed anhydride, carbonic mixed anhydride or the like and treated with an amine containing group to give a compound of formula III. For example the compound of formula II may be converted to the corresponding active ester upon treatment with 1-hydroxybenzotriazole in the presence of a carbodiimide for example dicyclohexylcarbodiimide or 1-ethyl-3-(3'-dimethyl-aminopropyl)-carbodiimide hydrochloride in the presence of a base such as triethylamine or N,N-diisopropylethylamine to give a compound of formula III. In a preferred embodiment the compound of formula II is treated with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoro-phosphat e, (HATU) and 1-hydroxy-7-azabenzotriazole, (HOAT) and N,N-diisopropylethyl-amine in a solvent, for example DMF, THF or the like, together with an amine component IV to give a compound of formula III. In an additional preferred embodiment a compound of formula II may be treated with carbonyldiimidazole (CDI) in a solvent, for example THF, DMF, dichloromethane or the like, followed by an amine component IV to give a compound of formula III. ##STR4##

Compounds of formula III may be prepared according to the Fischer-Indole synthesis, which involves the condensation of a phenylhydrazine with an aldehyde or ketone to give an intermediate hydrazone. Thus a compound of formula V may be condensed with ethylpyruvate, usually in the presence of an acid catalyst, for example sulfuric acid to afford a hydrazone of formula VI. Compounds of formula VI may be converted into indoles of formula VII upon treatment with a protic or Lewis acid, if required at elevated temperature, to effect cyclisation. Examples of acids include; polyphosphoric acid, para-toluenesulfonic acid, pyridine hydrochloride, zinc chloride, phosphorus trichloride, polyphosphoric acid trimethylsilyl ester and acetic acid. Compound VI may also be converted to compound VII under thermal conditions by heating a compound of formula VI in a solvent, for example ethylene glycol, tetralin, or the like at elevated temperature, for example at about 150 to 250.degree. C. It will be recognized by one skilled in the art that cyclization of compounds of formula VI to compounds of formula VII can give rise to isomers when compounds of formula V contain substituents. It will be further recognized that the conditions to effect cyclization may be different for different compounds of formula VI.

In a further embodiment, compounds of formula VII may be prepared by condensing an appropriately substituted 2-nitrotoluene with an oxalate di-ester in the presence of a base followed by reduction of the intermediate to afford a compound of formula VII. In a preferred embodiment, a 2-nitrotoluene is condensed with ethylpyruvate in the presence of a base such as sodium methoxide