Alkyne-aryl phosphodiesterase-4 inhibitors Number:6,743,802 from the United States Patent and Trademark Office (PTO) owispatent Compounds represented by Formula (I): ##STR1##or a pharmaceutically acceptable salt thereof, are phosphodiesterase 4 inhibitors useful in the treatment of asthma and inflammation.<H phosphodiesterase, inhibitors, Alkyne, aryl, pho, 6743802.html, Patent, pto, 6743802

Title: Alkyne-aryl phosphodiesterase-4 inhibitors

Abstract: Compounds represented by Formula (I): ##STR1##or a pharmaceutically acceptable salt thereof, are phosphodiesterase 4 inhibitors useful in the treatment of asthma and inflammation.

Patent Number: 6,743,802 Issued on 06/01/2004 to Guay, et al.

Inventors: Guay; Daniel (Ile-Perrot, CA), Girard; Mario (Saint-Lazare, CA), Hamel; Pierre (Vimont-Laval, CA), Laliberte; Sebastien (Ile Perrot, CA), Friesen; Richard (Kirkland, CA)
Assignee: Merck Frosst Canada & Co. (Kirkland, CA)

Appl. No.: 10/226,980

Filed: August 23, 2002

Current U.S. Class: 514/300 ; 546/123

Current International Class: A61K 45/06 (20060101); C07D 471/04 (20060101); A61K 45/00 (20060101); A61K 31/435 (20060101); C07D 471/00 (20060101)

Field of Search: 546/123 514/300

Foreign Patent Documents


0 978 516	Feb., 2000	EP
WO 99/07704	Feb., 1899	WO
99/07704	Feb., 1999	WO
WO 99/09504	Feb., 2000	WO

Other References

Matsuura, et al., Biological & Pharmaceutical Bulletin, vol. 17, No. 4, pp. 498-503, 1994..

Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Panzer; Curtis C. Rose; David L.

Parent Case Text

BACKGROUND OF THE INVENTION

This application claims benefit of priority of provisional application, serial No. 60/316,093, filed Aug. 29, 2001.

Claims

What is claimed is:

1. A compound represented by Formula (I): ##STR61##

or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --C.sub.0-6 alkyly)--SO.sub.n --(aryl), phenyl, wherein aryl is selected from phenyl or naphthyl and wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyly)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is pyridyl or pyridonyl, or pyridyl N-oxide.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.8 is pyridyl, or pyridyl N-oxide.

3. The compound according to claim 1, consisting of N-Isopropyl-1-[3-(2-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4 -one-3-carboxamide; N-Isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4 -one-3-carboxamide; N-Isopropyl-1-[3-(1-oxido-4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphth yridin-4-one-3-carboxamide; N-Isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4 -one-3-carboxamide; N-Isopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphth yridin-4-one-3-carboxamide; N-Cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin -4-one-3-carboxamide; N-Cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naph thyridin-4-one-3-carboxamide; N-Isopropyl-1-[3-(6-amino-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphth yridin4-one-3-carboxamide; N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]ph enyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1- {3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8 ]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]ph enyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1, 4-dihydro[1 ,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1, 4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1, 4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl] phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; 1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide; or 1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

5. The compound according to claim 1, which is N-Cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin -4-one-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 5 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

7. The compound according to claim 1, which is N-Cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naph thyridin-4-one-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 7 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

9. A compound according to claim 1 wherein R is Hydrogen.

10. A compound according to claim 1 wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each hydrogen.

11. A compound according to claim 1 wherein R.sup.1 is -C.sub.3--6 cycloalkyl.

12. A compound according to claim 1 wherein R is Hydrogen; and R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each hydrogen.

13. A compound according to claim 12 wherein R.sup.8 is pyridyl or pyridyl N-oxide.

14. A compound according to claim 12 wherein R.sup.1 is .sub.3-- cycloalkyl.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 2 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 12 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

Description

FIELD OF THE INVENTION

The present invention is directed to compounds that are alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention is directed to phenyl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors wherein the phenyl group is at the 1-position and contains a 2-alkyne substituent group further optionally substituted.

RELATED BACKGROUND

Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3',5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases ("PDE") are a family of enzymes that metabolize 3',5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 ("PDE4", also known as "PDE-IV"), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., ("Burnouf"), Ann. Rep. In Med. Chem., 33:91-109(1998). B. Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al., J.Med. Chem., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M. D. Houslay et al., Adv. In Pharmacol., 44:225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.

International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors. International Patent Publication WO9907704 describes 1-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.

A.H. Cook, et al., J.Chem. Soc., 413-417(1943) describes gamma-pyridylquinolines. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc., 114(17):6940-6941(1992).

Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.

U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.

However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones represented by Formula (I): ##STR2##

or pharmaceutically acceptable salts thereof, which are phosphodiesterase-4 inhibitors.

This invention also provides a pharmaceutical composition which includes an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia--maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cAMP levels--by the administration of an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones or a precursor compound which forms in vivo the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

A compound of this invention is represented by Formula (I): ##STR3##

or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(CO6alkyl)(CO6alkyl), --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.NO--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or oxides thereof when R.sup.8 is a heteroaryl; or H, --C.sub.1-6 alkyl, or --C.sub.3-6 cycloalkyl, and any alkyl is optionally substituted with 1-6 independent halogen, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.3-7 cycloalkyl), N-heterocycloC.sub.4-7 alkyl, --SO.sub.n --(C.sub.1-6 alkyl), --SO.sub.n --(aryl), or --OH substituents.

In one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent; n is 0, 1, or 2; R.sup.3 is absent; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is H.

In a second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)-SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl.sub.--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3.sub.7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)C.sub.0-6 alkyl, --C(O)O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.0-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or oxides thereof when R.sup.8 is a heteroaryl.

In an embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C 16alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)--SO.sub.n C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is phenyl.

In another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n C.sub.1-6 alkyl), --NHC(O)C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)SO.sub.n C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is pyridyl, or oxides thereof.

In yet another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R .sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is quinolinyl, or oxides thereof.

In still another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R.sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)SO.sub.n C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or H substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is thienyl, or oxides thereof.

In another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R .sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)-O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or H substituents; and R.sup.8 is thiazolyl, or oxides thereof.

In a third aspect, a compound of this invention is represented by Formula (1) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R .sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)SO.sub.n --(C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or H substituents; and R.sup.8 is --C.sub.3-6 cycloalkyl, optionally substituted with 1-6 independent halogen, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.3-7 cycloalkyl), N-heterocycloC.sub.4-7 alkyl, --SO.sub.n --(C.sub.1-6 alkyl), --SO.sub.n --(aryl), or H substituents.

In a fourth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H, --C.sub.1-6 alkyl or --C.sub.3-6 cycloalkyl; R .sup.1 is H, or a --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl, --C.sub.3-6 alkynyl, --C(O)--C.sub.1-6 alkyl, --C(O)-aryl, --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), --(C.sub.0-6 alkyl)SO.sub.n --(aryl), phenyl, heteroaryl, or heterocycloC.sub.3-7 alkyl group, wherein any of the groups is optionally substituted with 1-3 independent --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --(C.sub.0-6 alkyl)--SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, or halogen substituents; R.sup.2 is absent, H, halogen, --C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, --C.sub.1-6 alkyl(C.sub.3-6 cycloalkyl)(C.sub.3-6 cycloalkyl), --C.sub.1-6 alkoxy, phenyl, heteroaryl, heterocycloC.sub.3-7 alkyl, nitro, CN, .dbd.N--O--C.sub.1-6 alkyl, --O--N.dbd.C.sub.1-6 alkyl, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --NHSO.sub.n --(C.sub.1-6 alkyl), --NHC(O)--C.sub.1-6 alkyl, --NHC(O)-aryl, --C(O)--C.sub.1-6 alkyl, --C(O)--O--C.sub.1-6 alkyl, --C.sub.1-6 alkyl(.dbd.N--OH), --C(N.dbd.NOH)C.sub.1-6 alkyl, --C.sub.0-6 alkyl(oxy)C.sub.1-6 alkyl-phenyl, --SO.sub.n NH(C.sub.0-6 alkyl), or --(C.sub.0-6 alkyl)SO.sub.n C.sub.1-6 alkyl), wherein the phenyl, heteroaryl or heterocycloC.sub.3-7 alkyl is optionally substituted with halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, hydroxy, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), or --C(O)--O--C.sub.1-6 alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; n is 0, 1, or 2; R.sup.3 is absent, H, OH, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), halogen or C.sub.1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl) substituents; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each independently is H, halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --SO.sub.n --(C.sub.1-6 alkyl), nitro, CN, or --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or --OH substituents; and R.sup.8 is --C.sub.1-6 alkyl, optionally substituted with 1-6 independent halogen, --N(C.sub.0-6 alkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.0-6 alkyl), --N(C.sub.3-7 cycloalkyl)(C.sub.3-7 cycloalkyl), N-heterocycloC.sub.4-7 alkyl, --SO.sub.n --(C.sub.1-6 alkyl), --SO.sub.n --(aryl), or --OH substituents.

As used herein, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.

The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

The term "cycloalkyloxy" unless specifically stated otherwise includes a cycloalkyl group connected to the oxy connecting atom.

The term "alkoxy" unless specifically stated otherwise includes an alkyl group connected to the oxy connecting atom.

The term "aryl" unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.

The term "aryloxy" unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl, connected through the oxy connecting atom to the connecting site.

The term "C.sub.0-6 alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminus moiety. An alkyl with no carbon atoms is a direct bond when the alkyl is a bridging moiety.

The term "hetero" unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The heteroatoms replace ring carbon atoms. Thus, for example, a heterocycloC.sub.5 alkyl is a five membered ring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The term "heteroaryloxy" unless specifically stated otherwise describes a heteroaryl group connected through an oxy connecting atom to the connecting site.

Examples of heteroaryl(C.sub.1-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC.sub.3-7 alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term "N-heterocycloC.sub.4-7 alkyl" describes nonaryl heterocyclic compounds having 3-6 carbon atoms and one nitrogen atom forming the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl.

Examples of aryl(C.sub.1-6)alkyl include, for example, phenyl(C.sub.1-6)alkyl, and naphthyl(C.sub.1-6)alkyl.

Examples of heterocycloC.sub.3-7 alkylcarbonyl(C.sub.1-6)alkyl include, for example, azetidinyl carbonyl(C.sub.1-6)alkyl, pyrrolidinyl carbonyl(C.sub.1-6)alkyl, piperidinyl carbonyl(C.sub.1-6)alkyl, piperazinyl carbonyl(C.sub.1-6)alkyl, morpholinyl carbonyl(C.sub.1-6)alkyl, and thiomorpholinyl carbonyl(C.sub.1-6)alkyl.

The term "amine" unless specifically stated otherwise includes primary, secondary and tertiary amines.

Unless otherwise stated, the term "carbamoyl" is used to include --NHC(O)OC.sub.1-4 alkyl, and --OC(O)NHC.sub.1-4 alkyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, the substitution can be made at any of the groups. For example, substituted aryl(C.sub.1-6)alkyl includes substitution on the aryl group as well as substitution on the alkyl group.

The term "oxide" of heteroaryl groups is used in the ordinary well-known chemical sense and include, for example, N-oxides of nitrogen heteroatoms.

Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.

Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixtures of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAID"), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.

Dosage levels from about 0.001mg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia--which are responsive to PDE4 inhibition, or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 2.5 g per patient per day. Further, it is understood that the PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01 mg to about 1000 mg of the active ingredient, typically 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

The compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals of, for example, i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia--maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cAMP levels--by the administration of an effective amount of the compounds of this invention. The term "mammals" includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited exampl