Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same Number:7,071,333 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides for triazolopurine-based tricyclic compounds having the formula (I), ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.<H pharmaceutical, Triazolopurine, Triazolopurine, , 7071333.html, Patent, pto, 7071333

Title: Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same

Abstract: The present invention provides for triazolopurine-based tricyclic compounds having the formula (I), ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.

Patent Number: 7,071,333 Issued on 07/04/2006 to Combs, et al.

Inventors: Combs; Donald (Neptune City, NJ); Langevine; Charles M. (Brooklyn, NY); Qiu; Yuping (Glastonbury, CT); Zusi; Fred Christopher (Hamden, CT)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)

Appl. No.: 901677

Filed: July 29, 2004

Current U.S. Class: 544/251

Current International Class: C07D 487/14 (20060101); A61P 11/06 (20060101); A61P 19/02 (20060101); A61K 31/519 (20060101)

Field of Search: 514/267 544/251

References Cited [Referenced By]

U.S. Patent Documents


6492377	December 2002	Blech et al.

Foreign Patent Documents


WO 98/03511	Jan., 1998	WO
WO 99/65912	Dec., 1999	WO
WO 00012511	Mar., 2000	WO
WO 00/35428	Jun., 2000	WO
WO 02/069945	Sep., 2002	WO
WO 03/105902	Dec., 2003	WO
WO 2004/004704	Jan., 2004	WO

Other References

West, Anthony R., Solid State Chemistry and its Applications, Wiley, New York, 1988, pp. 358 &365. cited by examiner .
Draetta, G. and Pagano, M. in "Annual Reports in Medicinal Chemistry, vol. 31", 1996, Academic Press, San Diego, p. 241-246. cited by examiner .
Chantry, D., Emerging Drugs, 1999, Chapter 1, pp. 5-13. cited by examiner .
Gabor G Illei, and Peter E Lipsky, Current Opinion in Immunology vol. 12, Issue 6, Dec. 1, 2000, pp. 712-718. cited by examiner .
Black, Roy A. et al, Ann. Rep. Med. Chem., 32, 1997, 241-250. cited by exa- miner .
Tenor et al., "1,2,4-Triazoles. VII. Synthesis and Reactivity of 7-amino-s-triazolo[1,5-a]-5-pyrimidones", Univ. Greifswald, Germany, Ber., vol. 97(5), pp. 1373-1382, 1964. (Eng. Abstract). cited by other.

Primary Examiner: McKenzie; Thomas C.
Attorney, Agent or Firm: VanAtten; Mary

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. Provisional Application No. 60/491,170, filed Jul. 30, 2003, which is expressly incorporated fully herein by reference.

Claims

We claim:

1. A compound of Formula (I), ##STR00035## enantiomers, diastereomers, and salts, thereof wherein R.sup.1 is (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1, Z.sup.2 and Z.sup.3; (c) --OR.sup.9.sup.a; R.sup.2 is (a) hydrogen, halo, cyano, (b) alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, heterocyclooxy, aryloxy, heteroaryloxy, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.a, Z.sup.2.sup.a and Z.sup.3.sup.a; or (c) --OR.sup.9.sup.a, --SR.sup.9.sup.a or --SO.sub.2R.sup.9.sup.a R.sup.3 and R.sup.4 are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; (c) --OR.sup.10, --NR.sup.11R.sup.12, --N(R.sup.11)C(O)R.sup.10, --N(R.sup.11)C(O)OR.sup.10, --N(R.sup.11)SO.sub.2R.sup.13, or --C(O)NR.sup.11R.sup.12, --SO.sub.2NR.sup.11R.sup.12, --N(R.sup.11)C(O)NR.sup.11aR.sup.12, or --N(R.sup.11)SO.sub.2NR.sup.11.sup.aR.sup.12; or (d) R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; R.sup.5 is (a) hydrogen, hydroxy, halo, or cyano, (b) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a, --NR.sup.7.sup.aR.sup.8.sup.a, --N(R.sup.7.sup.a)SO.sub.2R.sup.9, --N(R.sup.7.sup.a)SO.sub.2NR.sup.7.sup.bR.sup.8.sup.b, --N(R.sup.7.sup.a)C(O)R.sup.6.sup.a, --N(R.sup.7.sup.a)C(O)NR.sup.7.sup.bR.sup.8.sup.b, --N(R.sup.7.sup.a)C(O)OR.sup.6.sup.a, --C(O)R.sup.6.sup.a, --C(O)OR.sup.6.sup.a, --OC(O)R.sup.6.sup.a, --C(O)NR.sup.7.sup.aR.sup.8.sup.a, or --OC(O)NR.sup.7.sup.aR.sup.8.sup.a; R.sup.6.sup.a and R.sup.6.sup.b are independently (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.c, Z.sup.2.sup.c and Z.sup.3.sup.c; R.sup.7.sup.a, R.sup.7.sup.b, R.sup.8.sup.a and R.sup.8.sup.b are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --OR.sup.6.sup.b, --NR.sup.7.sup.cR.sup.8.sup.c, --N(R.sup.7.sup.c)SO.sub.2R.sup.9.sup.b, --N(R.sup.7.sup.c)C(O)R.sup.6.sup.b, --N(R.sup.7.sup.c)C(O)OR.sup.6.sup.b, --SO.sub.2NR.sup.7.sup.cR.sup.8.sup.c, --SO.sub.2R.sup.9.sup.b, --C(O)R.sup.6.sup.b, --C(O)OR.sup.6.sup.b, or --C(O)NR.sup.7.sup.cR.sup.8.sup.c; (d) R.sup.7.sup.a and R.sup.8.sup.a together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.7.sup.c and R.sup.8.sup.c are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; (c) R.sup.7.sup.c and R.sup.8.sup.c together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.9, R.sup.9.sup.a and R.sup.9.sup.b are independently alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.10, R.sup.11, R.sup.11.sup.a and R.sup.12 are independently (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.e, Z.sup.2.sup.e and Z.sup.3.sup.e; (c) R.sup.11 and R.sup.12 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.13 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.e, Z.sup.2.sup.e and Z.sup.3.sup.e; Z.sup.1-1.sup.e, Z.sup.2-2.sup.e, and Z.sup.3-3.sup.e are optional substituents at each occurrence independently selected from W.sup.1-5 optionally substituted as valance allows with V.sup.1-5; where W.sup.1-5 are independently (1) a bond (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl )alkyl, cycloalkenyl, (cycloalkenyl )alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or where V.sup.1-5 are independently (1) H (2) alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (3) --U.sup.1--O--Y.sup.5, (4) --U.sup.1--S--Y.sup.5, (5) --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.t--Y.sup.5 where t is 1 or 2, (6) --U.sup.1--SO.sub.3--H, or --U.sup.1--S(O).sub.tY.sup.5, (7) --U.sup.1-halo, (8) --U.sup.1-cyano, (9) --U.sup.1-nitro, (10) --U.sup.1--NY.sup.2Y.sup.3, (11) --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, (12) --U.sup.1--N(Y.sup.4)--C(S)--Y.sup.1, (13) --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, (14) --U.sup.1--N(Y.sup.4)--C(S)--NY.sup.2Y.sup.3, (15) --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, (16) --U.sup.1--N(Y.sup.4)--S(O).sub.2--Y.sup.1, (17) --U.sup.1--N(Y.sup.4)--S(O).sub.2--NY.sup.2Y.sup.3, (18) --U.sup.1--C(O)--NY.sup.2Y.sup.3, (19) --U.sup.1--OC(O)--NY.sup.2Y.sup.3, (20) --U.sup.1--S(O).sub.2--N(Y.sup.4)--Y.sup.1, (21) --U.sup.1--N(Y.sup.4)--C(.dbd.NV.sup.1.sup.a)--NY.sup.2Y.sup.3, (22) --U.sup.1--N(Y.sup.4)--C(.dbd.NV.sup.1.sup.a)--Y.sup.1, (23) --U.sup.1--C(.dbd.NV.sup.1.sup.a)--NY.sup.2Y.sup.3, (24) oxo; (25) --Y.sup.5; (26) --U.sup.1--C(O)--NY.sup.2--OY.sup.5, V.sup.1a is independently hydrogen, alkyl, --CN, --C(O)Y.sup.1, --S(O).sub.2Y.sup.5, S(O).sub.2NY.sup.2Y.sup.3; Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 (1) are each independently hydrogen, alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; or (2) Y.sup.2 and Y.sup.3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, or (3) Y.sup.2 or Y.sup.3, together with Y.sup.1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, or (4) Y.sup.2 and Y.sup.3 together with the nitrogen atom to which they are attached may combine to form a group --N.dbd.CY.sup.6Y.sup.7 where Y.sup.6 and Y.sup.7 are each independently H or alkyl; and U.sup.1 is independently (1) a single bond, (2) alkylene, (3) alkenylene, (4) alkynylene, (5) --U.sup.2--O--U.sup.3--, (6) --U.sup.2--NY.sup.4--U.sup.3--, (7) --U.sup.2--S--U.sup.3--, or (8) --U.sup.2--S(O).sub.2--U.sup.3--, U.sup.2 is independently selected from (1) a single bond, (2) alkylene, (3) alkenylene, (4) alkynylene; and U.sup.3 is independently selected from (1) alkylene, (2) alkenylene, (3) alkynylene.

2. The compound of claim 1, wherein R.sup.3 and R.sup.4 are independently (a) hydrogen, (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; or (c) R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b.

3. The compound of claim 2, wherein R.sup.5 is (a) alkyl, alkenyl, alkynyl, aryl or heterocyclo any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO2NR.sup.7.sup.aR.sup.8.sup.a.

4. The compound of claim 3, wherein Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from alkyl, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3; Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5; Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from; (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y.sup.3; (b) alkyl optionally substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3.

5. The compound of claim 4, wherein R.sup.3 is hydrogen; R.sup.4 is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; R.sup.5 is (a) alkynyl optionally substituted with Z.sup.1.sup.d where Z.sup.1.sup.d is aryl which may be further optionally independently substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--N(Y.sup.4)--U.sup.3--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--U.sup.3--Y.sup.5, or --N(Y.sup.4)--U.sup.3--H; (b) aryl optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO2NR.sup.7.sup.aR.sup.8.sup.a; Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --C(O).sub.tH, --C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, N(Y.sup.4)--C(O)O--Y.sup.5, --C(O)--NY.sup.2Y.sup.3, --OC(O)--NY.sup.2Y.sup.3; Z.sup.1.sup.c is (a) --OY.sup.5 where Y.sup.5 is aryl, or (b) aryl-V.sup.3, wherein V.sup.3 is --OH or --OY.sup.5 where Y.sup.5 is alkyl; Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, or (b) alkyl optionally substituted with one or more cyano, halo, --OH, --OY.sup.5, NY.sup.2Y.sup.3, --C(O)--NY.sup.2Y.sup.3, --C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, --N(Y.sup.4)--C(O)O--Y.sup.5, --N(Y.sup.4)--S(O).sub.2--Y.sup.1, --C(O).sub.tH, --C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, --N(Y.sup.4)--U.sup.2--Y, or --N(Y.sup.4)--U.sup.2--H, where U.sup.1 is a bond, alkylenyl or --O--U.sup.3--.

6. The compound of claim 5, wherein R.sup.1 is alkyl; and R.sup.2 is hydrogen.

7. The compound of claim 6, wherein R.sup.5 is (a) phenyl, pyridyl, pyrimidinyl, or acetyleneyl, any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO2NR.sup.7.sup.aR.sup.8.sup.a; R.sup.6.sup.a is alkyl substituted with which may be optionally independently substituted as valence allows with Z.sup.1.sup.c, Z.sup.2.sup.c and Z.sup.3.sup.c; Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5; Y.sup.5 is alkyl.

8. The compound of claim 7, wherein Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from; cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y.sup.3; wherein U.sup.1 is a bond, alkylenyl or --O--U.sup.3-- and Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are independently selected from H or alkyl or haloalkyl.

9. A pharmaceutical composition comprising (a) at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically-acceptable carrier or diluent.

10. A method of treating an inflammatory or immune disease in which the inflammatory or immune disease is selected from rheumatoid arthritis, asthma, inflammatory bowel disease, chronic obstructive pulmonary disease, and psoriasis.

Description

FIELD OF THE INVENTION

The present invention relates to triazolopurine-based tricyclic compounds, to methods of using the compounds in treating inflammatory and immune diseases, and to pharmaceutical compositions comprising same.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF-.alpha.) is a potent cytokine having pro-inflammatory properties that is released by many cell types when stimulated. Studies have shown a relationship between elevated levels of TNF-.alpha. and a variety of diseases such as septic shock, hematopoiesis, tumors, and inflammatory disorders of the central nervous system, including HIV encephalitis, cerebral malaria, and meningitis. More recently agents which inhibit the action of TNF-.alpha. have demonstrated clinical utility in a variety of diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Additionally Certain neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease also are reportedly associated with enhanced TNF-.alpha. levels. See, e.g., Arvin et al., "The Role of Inflammation and Cytokines in Brain Injury," Neuroscience and Biobehavioral Reviews, Vol. 20, No. 3 (1996), at pp. 445 452.

Accordingly, various classes of drugs have been researched and developed to inhibit TNF-.alpha. production at both transcriptional and translational levels, e.g., corticosteroids, rolipram (a phosphodiesterase IV inhibitor suppressing TNF-.alpha. mRNA synthesis), calphostin, and imidazole-type cytokine suppressing anti-inflammatory drugs (CSAIDs). These drugs are useful in treating a variety of diseases. See Dinarello, "Role of Pro- and Anti-Inflammatory Cytokines During Inflammation: Experimental and Clinical Findings, Review, Vol. 0393-974X (1997), at pp. 91 103.

Recently, attention has focussed on the role of Nuclear factor .kappa.B (NF-.kappa.B) in the activation pathway that leads to production of TNF-.alpha. and other inflammatory cytokines and gene products. Besides TNF-.alpha., NF-.kappa.B is involved in the regulation of a variety of genes involved in immune function and inflammation. These include the cytokines IL-1, IL-2, IL-6, IL-2R.alpha., and GM-GSF, the chemokines IL-8, MCP-1 (CCR2), and RANTES, the adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin, the proteases matrix metalloproteinase-1 (MMP-1), MMP-9 and MMP-13, and the pro-inflammatory enzymes cyclooxygenase-2 (COX-2), iNOS, and cPLA.sub.2. Thus, inhibition of NF-.kappa.B and/or its activation pathway provides a means for treating various diseases including autoimmune diseases, inflammatory diseases, Alzheimer's disease, atherosclerosis, oncogenesis, and so forth by a variety of modes of action (i.e. cytokine reduction, chemokine reduction, reduction of adhesion molecule, decreased expression of certain proteases implicated in inflammatory and immune disease processes, and decreased production of enzymes which produce pro-inflammatory mediators) which have been implicated in a variety of disease progression. See, e.g., Baldwin, "The NF-.kappa.B and I.kappa.B Proteins: New Discoveries and Insights," Annual Rev. Immunol., Vol. 14 (1996), at pp. 649 81; see also Christman et al., "Impact of Basic Research on Tomorrow's Medicine, The Role of Nuclear Factor-.kappa.B in Pulmonary Diseases," Chest, Vol. 117 (2000), at pp. 1482 87, and Roshak, et al., "Small-molecule Inhibitors of NF-.kappa.B for the Treatment of Inflammatory Joint Disease." Current Opinion in Pharmacol. Vol. 2 (2002) pp. 316 321.

I.kappa.B is a cytoplasmic protein that controls NF-.kappa.B activity by retaining NF-.kappa.B in the cytoplasm. I.kappa.B is phosphorylated by the I.kappa.B kinase (IKK), which has two isoforms, IKK-.alpha. ("IKK-1") and IKK-.beta. ("IKK-2"). When IKK phosphorylates I.kappa.B, NF-.kappa.B is rapidly released from the cytoplasm into the cell. Upon release into the cell, NF-.kappa.B translocates to the nucleus where it binds to the promoters of many genes and up-regulates the transcription of pro-inflammatory genes. Thus inhibitors of IKK-1 and/or IKK-2 would prevent translocation of NF-.kappa.B to the nucleus and prevent transcription of the pro-inflammatory gene products described above. For example see Burke, et al. "BMS-345541 is a Highly Selective Inhibitor of I.kappa.B Kinase that Binds at an Allosteric Site of the Enzyme and Blocks NF-.kappa.B dependent Transcription in Mice." J. Biol. Chem. Vol. 278, (2003) pp. 1450 1456.

The therapeutic effects of glucocorticoids are mediated in part by their ability to inhibit NF-.kappa.B activity by two mechanisms, i.e., up-regulating I.kappa.B protein levels and inhibiting NF-.kappa.B subunits. The deleterious side effects of glucocorticoids (such as osteoporosis, hyperglycemia, fat redistribution, etc.) have been postulated to result from the interaction of glucocorticoids with the glucocorticoid receptor (GR) or the glucocorticoid response element (GRE). For example see Schacke, et al. "Mechanisms Involved in the Side Effects of Glucocorticoids" Pharmacol. and Therapeutics Vol 96 (2002) pp. 23 43. Thus inhibitors of IKK-1 and/or IKK-2 inhibitors should provide much of the therapeutic benefit of glucocorticoids with a greatly improved side effect profile.

As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness, bioavailability, and solubility, having fewer side effects, and/or providing the physician and consumer with a choice of options. Particularly in the area of immune response, many individuals respond differently depending upon the type of treatment and chemical agent used. Mechanisms of action continue to be studied to aid in understanding the immune response and in developing compounds effective for treating inflammatory and immune-related disorders.

The present invention provides triazolopurine-based tricyclic compounds useful as inhibitors of IKK.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I), useful in treating inflammatory or immune conditions:

##STR00002## enantiomers, diastereomers, salts, and solvates thereof.

The invention also relates to pharmaceutical compositions containing at least one compound of formula (I) and a pharmaceutically-acceptable carrier or diluent, for use in treating inflammatory and immune diseases. Also included within the invention are methods of treating such diseases comprising administering to a mammal in need of such treatment an effective amount of at least one compound of formula (I).

The invention also relates to novel compounds for use in therapy.

The present invention also relates to the use of novel cyclic derivatives for the manufacture of a medicament for the treatment of inflammatory diseases.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[1] In one embodiment, the present invention is directed to a compound of formula (I),

##STR00003##

enantiomers, diastereomers, salts, and solvates thereof wherein R.sup.1 is (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1, Z.sup.2 and Z.sup.3; (c) --OR.sup.9.sup.a; R.sup.2 is (a) hydrogen, halo, cyano, (b) alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, heterocyclooxy, aryloxy, heteroaryloxy, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.a, Z.sup.2.sup.a and Z.sup.3.sup.a; or (c) --OR.sup.9.sup.a, --SR.sup.9.sup.a or --SO.sub.2R.sup.9.sup.a R.sup.3 and R.sup.4 are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; (c) --OR.sup.10, --NR.sup.11R.sup.12, --N(R.sup.11)C(O)R.sup.10, --N(R.sup.11)C(O)OR.sup.10, --N(R.sup.11)SO.sub.2R.sup.13, or --C(O)NR.sup.11R.sup.12, --SO.sub.2NR.sup.11R.sup.12, --N(R.sup.11)C(O)NR.sup.11.sup.aR.sup.12, or --N(R.sup.1l)SO.sub.2NR.sup.11.sup.aR.sup.12; or (d) R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; R.sup.5 is (a) hydrogen, hydroxy, halo, or cyano, (b) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --R.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a, NR.sup.7.sup.aR.sup.8.sup.a, N(R.sup.7.sup.a)SO.sub.2R.sup.9, --N(R.sup.7.sup.a)SO.sub.2NR.sup.7.sup.bR.sup.8.sup.b, --N(R.sup.7.sup.a)C(O)R.sup.6.sup.a, N(R.sup.7.sup.a)C(O)NR.sup.7.sup.bR.sup.8.sup.b, --N(R.sup.7.sup.a)C(O)OR.sup.6.sup.a, --C(O)R.sup.6.sup.a, --C(O)OR.sup.6.sup.a, --OC(O)R.sup.6.sup.a, --C(O)NR.sup.7.sup.aR.sup.8.sup.a, or --OC(O)NR.sup.7.sup.aR.sup.8.sup.a; R.sup.6.sup.a and R.sup.6.sup.b are independently (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.c, Z.sup.2.sup.c and Z.sup.3.sup.c; R.sup.7.sup.a, R.sup.7.sup.b, R.sup.8.sup.a and R.sup.8.sup.b are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --OR.sup.6.sup.b, --NR.sup.7CR.sup.8.sup.c, --N(R.sup.7.sup.c)SO.sub.2R.sup.9.sup.b, --N(R.sup.7.sup.c)C(O)R.sup.6.sup.b, --N(R.sup.7.sup.c)C(O)OR.sup.6.sup.b, --SO.sub.2NR.sup.7CR.sup.8.sup.c, --S.sub.2R.sup.9.sup.b, --C(O)R.sup.6.sup.b, --C(O)OR.sup.6.sup.b, or C(O)NR.sup.7CR.sup.8.sup.c; (d) R.sup.7.sup.a and R.sup.8.sup.a together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.7.sup.c and R.sup.8.sup.c are independently (a) hydrogen, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; (c) R.sup.7.sup.c and R.sup.8.sup.c together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.9, R.sup.9.sup.a and R.sup.9.sup.b are independently alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.10, R.sup.11, R.sup.11.sup.a and R.sup.12 are independently (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.e, Z.sup.2.sup.e and Z.sup.3.sup.e; (c) R.sup.11 and R.sup.12 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; R.sup.13 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.e, Z.sup.2.sup.e and Z.sup.3.sup.e; Z.sup.1-1.sup.e, Z.sup.2-2.sup.e, and Z.sup.3-3.sup.e are optional substituents at each occurrence independently selected from W.sup.1-5 optionally substituted as valance allows with V.sup.1-5; where W.sup.1-5 are independently (1) a bond (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or where V.sup.1-5 are independently (1) H (2) alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (3) --U.sup.1--O--Y.sup.5, (4) --U.sup.1--S--Y.sup.5, (5) --U.sup.1--(O).sub.r--H, --U.sup.1--C(O).sub.t--Y.sup.5 where t is 1 or 2, (6) --U.sup.1--SO.sub.3--H, or --U.sup.1--S(O).sub.tY.sup.5, (7) --U.sup.1-halo, (8) --U.sup.1-cyano, (9) --U.sup.1-nitro, (10) --U.sup.1--NY.sup.2Y.sup.3, (11) --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, (12) --U.sup.1--N(Y.sup.4)--C(S)--Y.sup.1, (13) --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, (14) --U.sup.1--N(Y.sup.4)--C(S)--NY.sup.2Y.sup.3, (15) --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, (16) --U.sup.1--N(Y.sup.4).sub.n--S(O).sub.2--Y.sup.1, (17) --U.sup.1--N(Y.sup.4)--S(O).sub.2--NY.sup.2Y.sup.3, (18) --U.sup.1--C(O)--NY.sup.2Y.sup.3, (19) --U.sup.1--OC(O)--NY.sup.2Y.sup.3, (20) --U.sup.1--S(O).sub.2--N(Y.sup.4)--Y.sup.1, (21) --U.sup.1--N(Y.sup.4)--C(.dbd.NV.sup.1.sup.a)--NY.sup.2Y.sup.3, (22) --U.sup.1--N(Y.sup.4)--C(.dbd.NV.sup.1.sup.a)--Y.sup.1, (23) --U.sup.1--C(.dbd.NV.sup.1.sup.a)--NY.sup.2Y.sup.3, (24) oxo; (25) Y.sup.5; (26) --U.sup.1--C(O)--NY.sup.2--OY.sup.5, V.sup.1.sup.a is independently hydrogen, alkyl, --CN, --C(O)Y.sup.1, --S(O).sub.2Y.sup.5, S(O).sub.2NY.sup.2Y.sup.3; Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 (1) are each independently hydrogen, alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; or (2) Y.sup.2 and Y.sup.3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, or (3) Y.sup.2 or Y.sup.3, together with Y.sup.1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, or (4) Y.sup.2 and Y.sup.3 together with the nitrogen atom to which they are attached may combine to form a group --N.dbd.CY.sup.6Y.sup.7 where Y.sup.6 and Y.sup.7 are each independently H or alkyl; and U.sup.1 is independently (1) a single bond, (2) alkylene, (3) alkenylene, (4) alkynylene, (5) --U.sup.2--O--U.sup.3--, (6) --U.sup.2--NY.sup.4--U.sup.3--, (7) --U.sup.2--S--U.sup.3--, or (8) --U.sup.2--S(O).sub.2--U.sup.3--, U.sup.2 is independently selected from (1) a single bond, (2) alkylene, (3) alkenylene, (4) alkynylene; and U.sup.3 is independently selected from (1) alkylene, (2) alkenylene, (3) alkynylene. [2] In another embodiment, the present invention is directed to a compound of Formula (I) wherein R.sup.3 and R.sup.4 are independently (a) hydrogen, (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; or (c) R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b. [3] In another embodiment, the present invention is directed to a compound of Formula (I) wherein R.sup.5 is (a) alkyl, alkenyl, alkynyl, aryl or heterocyclo any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a. [4] In another embodiment, the present invention is directed to a compound of Formula (I) wherein Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from alkyl, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3; Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5; Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from; (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1 --N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U .sup.1--N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y.sup.3. (b) alkyl optionally substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3. [5] In another embodiment, the present invention is directed to a compound of Formula (I) wherein R.sup.3 is hydrogen; R.sup.4 is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; R.sup.5 is (a) alkynyl optionally substituted with Z.sup.1.sup.d where Z.sup.1.sup.d is aryl which may be further optionally independently substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY, --U.sup.1--N(Y.sup.4)--U.sup.3--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--U.sup.3--Y.sup.5, or --N(Y.sup.4)--U.sup.3--H; (b) aryl optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) --OR.sup.6.sup.a, SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a; Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --C(O).sub.tH, --C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, N(Y.sup.4)--C(O)O--Y.sup.5, --C(O)--NY.sup.2Y.sup.3, --OC(O)--NY.sup.2Y.sup.3; Z.sup.1.sup.c is (a) --OY.sup.5 where Y.sup.5 is aryl, or (b) aryl-V.sup.3, wherein V.sup.3 is --OH or --OY.sup.5 where Y.sup.5 is alkyl; Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, or (b) alkyl optionally substituted with one or more cyano, halo, --OH, --OY.sup.5, NY.sup.2Y.sup.3, --C(O)--NY.sup.2Y.sup.3, --C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, --N(Y.sup.4)--C(O)O--Y.sup.5, --N(Y.sup.4)--S(O).sub.2--Y.sup.1, --C(O).sub.tH, --C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, --N(Y.sup.4)--U.sup.2--Y, or --N(Y.sup.4)--U.sup.2--H., where U.sup.1 is a bond, alkylenyl or --O--U.sup.3--. [6] In another embodiment, the present invention is directed to a compound of Formula (I) wherein R.sup.1 is alkyl; and R.sup.2 is hydrogen. [7] In another embodiment, the present invention is directed to a compound of Formula (I) wherein R.sup.5 is (a) phenyl, pyridyl, pyrimidinyl, or acetyleneyl, any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a; R.sup.6.sup.a is alkyl substituted with which may be optionally independently substituted as valence allows with Z.sup.1.sup.c, Z.sup.2.sup.c and Z.sup.3.sup.c; Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5; Y.sup.5 is alkyl. [8] In another embodiment, the present invention is directed to a compound of Formula (I) wherein Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from; cyano, halo, --U.sup.1--OH, --U.sup.1--Y.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1 --N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y.sup.3; wherein U.sup.1 is a bond, alkylenyl or --O--U.sup.3-- and Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are independently selected from H or alkyl or haloalkyl. [9] In another embodiment, the present invention is directed to a compound of Formula (I) wherein, wherein the compound is selected from the examples.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising (a) at least one compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and (b) a pharmaceutically-acceptable carrier or diluent.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder comprising administering to a mammal in need thereof a therapeutically-effective amount of at least one compound of Formula (I).

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from rheumatoid arthritis, asthma, inflammatory bowel disease, chronic obstructive pulmonary disease, and psoriasis.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from rheumatoid arthritis.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from asthma.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from inflammatory bowel disease.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from chronic obstructive pulmonary disease.

In another embodiment, the present invention is directed to a method of treating an inflammatory or immune disease or disorder in which the inflammatory or immune disease is selected from psoriasis.

In another embodiment, the present invention is directed to compounds of Formula (I) for use in therapy.

In another embodiment, the present invention is directed to the use of compounds of Formula (I) in the preparation of a medicament for treating inflammatory or immune disease.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.1 is hydrogen or alkyl.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.1 is alkyl.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.2 is hydrogen or alkyl.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.2 is hydrogen.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.3 and R.sup.4 are independently (a) hydrogen, (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b; or (c) R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.3 is hydrogen; R.sup.4 is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.5 is (a) alkyl, alkenyl, alkynyl, aryl or heterocyclo any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.5 is (a) alkynyl optionally substituted with Z.sup.1.sub.d where Z.sup.1.sup.d is aryl which may be further optionally independently substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--N(Y.sup.4)--U.sup.3--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--U.sup.3--Y.sup.5, or --N(Y.sup.4)--U.sup.3--H; (b) aryl optionally independently substituted as valence allows with one or more Z.sup.1.sub.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (c) OR.sup.6.sup.a, SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein R.sup.5 is (a) phenyl, pyridyl, pyrimidinyl, or acetyleneyl, any of which may be optionally independently substituted as valence allows with one or more Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d; or (b) --OR.sup.6.sup.a, --SR.sup.9.sup.a, SO.sub.2R.sup.9.sup.a, SO.sub.2NR.sup.7.sup.aR.sup.8.sup.a.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5; Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from; (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y.sup.3. (b) alkyl optionally substituted with one or more cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.c is (a)--OY.sup.5 where Y.sup.5 is aryl, or (b) aryl-V.sup.3, wherein V.sup.3 is --OH or --OY.sup.5 where Y.sup.5 is alkyl;

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.c is (a) --OH, --OY.sup.5 or (b) aryl-V.sup.3, wherein V.sup.3 is H, --OH or --OY.sup.5.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from alkyl, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U --N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1--OC(O)--NY.sup.2Y.sup.3.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.b, Z.sup.2.sup.b and Z.sup.3.sup.b are optional substituents independently selected from --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --C(O).sub.tH, --C(O).sub.tY.sup.5, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, N(Y.sup.4)--C(O)O--Y.sup.5, --C(O)--NY.sup.2Y.sup.3, --OC(O)--NY.sup.2Y.sup.3.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from (a) cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, or (b) alkyl optionally substituted with one or more cyano, halo, --OH, --OY.sup.5, NY.sup.2Y.sup.3, --C(O)--NY.sup.2Y.sup.3, --C(O)--NY.sup.2--OY.sup.5, --N(Y.sup.4)--C(O)--Y.sup.1, --N(Y.sup.4)--C(O)O--Y.sup.5, --N(Y.sup.4)--S(O).sub.2--Y.sup.1, --C(O).sub.tH, --C(O).sub.tY.sup.5, --S(O).sub.tY.sup.1, --N(Y.sup.4)--U.sup.2--Y, or --N(Y.sup.4)--U.sup.2--H, where U.sup.1 is a bond, alkylenyl or --O--U.sup.3--.

In another embodiment, the present invention is directed to compounds of Formula (I) wherein Z.sup.1.sup.d, Z.sup.2.sup.d and Z.sup.3.sup.d are optional substituents independently selected from cyano, halo, --U.sup.1--OH, --U.sup.1--OY.sup.5, --U.sup.1--NY.sup.2Y.sup.3, --U.sup.1--C(O).sub.tH, --U.sup.1--C(O).sub.tY.sup.5, --U.sup.1--S(O).sub.tY.sup.1, --U.sup.1--C(O)--NY.sup.2--OY.sup.5, or --U.sup.1--N(Y.sup.4)--C(O)--NY.sup.2Y.sup.3, --U.sup.1--N(Y.sup.4)--C(O)--Y.sup.1, --U.sup.1--N(Y.sup.4)--C(O)O--Y.sup.5, --U.sup.1--C(O)--NY.sup.2Y.sup.3, --U.sup.1 --N(Y.sup.4)--S(O).sub.2--Y.sup.1, --U.sup.1--OC(O)--NY.sup.2Y

The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

DEFINITIONS

The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C.dbd.N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom or ring is replaced with a selection from the indicated group, provided that the designated atom's or ring atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R.sup.a) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 2 R.sup.a, then said group may optionally be substituted with up to two R.sup.a groups and R.sup.a at each occurrence is selected independently from the definition of R.sup.a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "alkyl" as used herein by itself or as part of another group refers to straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are often most preferred.

The term "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like.

The term "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.

When the term "alkyl" is used together with another group, such as in "(aryl)alkyl", this conjunction is meant to refer to a substituted alkyl group wherein at least one of the substituents is the specifically named group in the conjunction. For example, "(aryl)alkyl" refers to a substituted alkyl group as defined above wherein at least one of the substituents is an aryl, such as benzyl.

Where alkyl groups as defined above have single bonds for attachment to two other groups, they are termed "alkylene" groups. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment to two other groups, they are termed "alkenylene groups" and "alkynylene groups" respectively. Examples of alkylene, alkenylene and alkynylene groups include:

##STR00004## and the like. Alkylene groups may be optionally independently to substituted as valence allows with one or more groups provided in the definition of Z.sup.1.

The term "cycloalkyl" as used herein by itself or as part of another group refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons, forming the ring. The rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro union to 1 or 2 aromatic, cycloalkyl or heterocyclo rings. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl,

##STR00005## and the like.

The term "cycloalkylene" as employed herein refers to a "cycloalkyl" group which includes free bonds and thus is a linking group such as

##STR00006## and the like.

One skilled in the field will understand that, when the designation "CO.sub.2" is used herein, this is intended to refer to the group

##STR00007##

The term "alkoxy" refers to an alkyl or substituted alkyl group as defined above bonded through an oxygen atom (--O--), i.e., the groups --OR.sub.d, wherein R.sub.d is alkyl or substituted alkyl.

The term "alkylthio" refers to an alkyl or substituted alkyl group as defined above bonded through a sulfur atom (--S--), i.e., the groups --SR.sub.d, wherein R.sub.d is alkyl or substituted alkyl.

The term "acyl" refers to a carbonyl group linked to an organic radical, more particularly, the group C(.dbd.O)R.sub.g, wherein R.sub.g can be selected from alkyl, alkenyl, substituted alkyl, or substituted alkenyl, as defined herein.

The term "alkoxycarbonyl" refers to a carboxy group

##STR00008## linked to an organic radical (CO.sub.2R.sub.g), wherein R.sub.g is as defined above for acyl.

The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.

The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl.

The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF.sub.3.

The terms "ar" or "aryl" as used herein by itself or as part of another group refer to aromatic homocyclic (i.e., hydrocarbon) monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbons in the ring portion (such as phenyl, biphenyl, naphthyl (including 1-naphthyl and 2-naphthyl) and antracenyl) and may optionally include one to three additional rings (either cycloalkyl, heterocyclo or heteroaryl) fused thereto. Examples include:

##STR00009## and the like.

The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic rings containing from 5 to 10 atoms, which includes 1 to 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocyclo ring, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl

##STR00010## and the like.

In compounds of formula (I), preferred heteroaryl groups include

##STR00011## and the like, which optionally may be substituted at any available carbon or nitrogen atom.

The terms "heterocyclic" or "heterocyclo" as used herein by itself or as part of another group refer to optionally substituted, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, preferably containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valance allows. The rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions. Exemplary heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl,

##STR00012## and the like.

Preferred heterocyclo groups in compounds of formula (I) include

##STR00013## which optionally may be substituted.

The term "ring" encompasses homocyclic (i.e., as used herein, all the ring atoms are carbon) or "heterocyclic" (i.e., as used herein, the ring atoms include carbon and one to four heteroatoms selected from N, O and/or S, also referred to as heterocyclo), where, as used herein, each of which (homocyclic or heterocyclic) may be saturated or partially or completely unsaturated (such as heteroaryl).

Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl),