Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes

• US 20020111495A1
• Filed: 01/31/2002
• Published: 08/15/2002
• Est. Priority Date: 04/04/1997
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Marfat, Anthony, Chambers, Robert James, Magee, Thomas Victor
• Application Number:
  US10/062,811
• Publication Number:
  US 20020111495A1
• Time in Patent Office: Days
• US Class Current: 546/291
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/643 2-Phenoxypyridines; Derivatives thereof
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds useful as inhibitors of PDE4 in the treatment of diseases regulated by the activation and degranulation of eosinophils, especially asthma, chronic bronchitis, and chronic obstructuive pulmonary disease, of the formula:

wherein j is 0 or 1, k is 0 or 1, m is 0, 1, or 2; n is 1 or 2; A is selected from the partial Formulas:

where q is 1, 2, or 3, W³ is —O—; —N(R⁹)—; or —OC(═O)—; R⁷ is selected from —H; —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, or —(C₂-C₆) alkynyl substituted by 0 to 3 substituents R¹⁰; —(CH₂)_u—(C₃-C₇) cycloalkyl where u is 0, 1 or 2, substituted by 0 to 3 R¹⁰; and phenyl or benzyl substituted by 0 to 3 R¹⁴; R⁸ is tetrazol-5-yl; 1,2,4-triazol-3-yl; 1,2,4-triazol-3-on-5-yl; 1,2,3-triazol-5-yl; imidazol-2-yl; imidazol-4-yl; imidazolidin-2-on-4-yl; 1,3,4-oxadiazolyl; 1,3,4-oxadiazol-2-on-5-yl; 1,2,4-oxadiazol-3-yl; 1,2,4-oxadiazol-5-on-3-yl; 1,2,4-oxadiazol-5-yl; 1,2,4-oxadiazol-3-on-5-yl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; morpholinyl; parathiazinyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl; pyrazolyl; succinimidyl; glutarimidyl; pyrrolidonyl; 2-piperidonyl; 2-pyridonyl; 4-pyridonyl; pyridazin-3-onyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; indolyl; indolinyl; isoindolinyl; benzo[b]furanyl; 2,3-dihydrobenzofuranyl; 1,3-dihydroisobenzofuranyl; 2H-1-benzopyranyl; 2-H-chromenyl; chromanyl; benzothienyl; 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl; phthalazinyl; 1,8-naphthyridinyl; quinolinyl; isoquinolinyl; quinazolinyl; quinoxalinyl; pyrazolo[3,4-d]pyrimidinyl; pyrimido[4,5-d]pyrimidinyl; imidazo[1,2-a]pyridinyl; pyridopyridinyl; pteridinyl; or 1H-purinyl; or A is selected from phosphorous and sulfur acid groups; W is —O—; —S(═O)_t—, where t is 0, 1, or 2; or —N(R³)—; Y is ═C(R¹_a)—, or —[N(O)_k] where k is 0 or 1; R⁴, R⁵ and R⁶ are (1) —H; provided that R⁵ and R⁶ are not both —H at the same time, —F; —Cl; —(C₂-C₄) alkynyl; —R¹⁶; —OR¹⁶; —S(═O)_pR¹⁶; —C(═O)R¹⁶, —C(═O)OR¹⁶, —C(═O)OR¹⁶; —OC(═O)R¹⁶; —CN; —NO₂; —C(═O)NR¹⁶R¹⁷; —OC(═O)NR¹⁶R¹⁷; —NR¹²_aC(═O)NR¹⁶R¹⁷; —NR¹²_aC(═NR¹²)NR¹⁶R¹⁷; —NR¹²_aC(═NCN)NR¹⁶R¹⁶; —NR¹²_aC(═N—NO₂)NR¹⁵R¹⁶; —C(═NR¹²_a)NR¹⁵R¹⁶; —CH₂C(═NR¹²_a)NR¹⁶R¹⁷; —OC(═NR¹²_a)NR¹⁶R¹⁷; —OC(═N—NO₂)NR¹⁶R¹⁷; —NR¹⁶R¹⁷; —CH₂NR¹⁶R¹⁷; —NR¹²_aC(═O)R¹⁶; —NR¹²_aC(═O)OR¹⁶; ═NOR¹⁶; —NR¹²_aS(═O)_pR¹⁷ —S(═O)_pNR¹⁶R¹⁷; and —CH₂C(═NR¹²_a)NR¹⁶R¹⁷; (2) —(C₁-C₄) alkyl including dimethyl and —(C₁-C₄) alkoxy substituted with 0 to 3 substituents —F or —Cl; or 0 or 1 substituent (C₁-C₂) alkoxycarbonyl-, (C₁-C₂) alkylcarbonyl-, or (C₁-C₂) alkylcarbonyloxy-; or (3) an aryl or heterocyclic moiety; or (4) R⁵ and R⁶ are taken together to form a moiety of partial Formulas (1.3.1) through (1.3.15):

or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of Formula (1.0.0):

2. A compound according to claim 1 wherein A is a moiety of partial Formula (1.1.4) where v is 0 or 1, and R⁸ is a member selected from the group consisting of partial Formulas (1.1.11) through (1.1.38):

3. A compound according to claim 2 wherein R⁸ is a member selected from the group consisting of the following partial Formulas:

4. A compound according to claim 3 wherein R⁸ is a member selected from the group consisting of the following partial Formulas:

5. A compound according to claim 2 wherein R⁸ is a member selected from the group consisting of partial Formulas (4.8.1) through (4.8.80):

6. A compound according to claim 1 wherein the group A is a moiety of partial Formula (1.1.4) and v is 0 or 1, wherein the moiety R⁸ is a bicyclic heterocyclic group selected from the group consisting of indolyl;

indolinyl;

isoindolinyl;

benzo[b]furanyl;

2,3-dihydrobenzofuranyl;

1,3-dihydroisobenzofuranyl;

2H-1-benzopyranyl;

2-H-chromenyl;

chromanyl;

benzothienyl;

1H-indazolyl;

benzimidazolyl;

benzoxazolyl;

benzisoxazolyl;

benzothiazolyl;

benzotriazolyl;

benzotriazinyl;

phthalazinyl;

1,8-naphthyridinyl;

quinolinyl;

isoquinolinyl;

quinazolinyl;

quinoxalinyl;

pyrazolo[3,4-d]pyrimidinyl;

pyrimido[4,5-d]pyrimidinyl;

imidazo[1,2-a]pyridinyl;

pyridopyridinyl;

pteridinyl; and

1H-purinyl.

7. A compound according to claim 6 wherein said R⁸ moiety is a member selected from the group consisting of partial Formulas (5.0.1) through (5.0.28):

8. A compound according to claim 1 wherein the moiety B¹ is phenyl and R⁵ and R⁶ are taken together to form a moiety which is a member selected from the group consisting of partial Formulas (1.3.1), (1.3.11), (1.3.12), and (1.3.15):

9. A compound according to claim 1 wherein B¹ and the substituents R⁴, R⁵, and R⁶ are selected in such a way that the left-hand terminus of said compound of Formula (1.0.0) is represented by the following partial Formulas (1.8.1) through (1.8.72):

10. A compound according to claim 1 wherein B² and the substituents R¹ and R² are selected in such a way that this portion of the right-hand terminus of said compound of Formula (1.0.0) is represented by the following partial Formulas (3.0.1) through (3.0.47):

11. A compound according to claim 1 wherein B¹ and B² are independently phenyl or pyridyl;

m is 1;

n is 1;

A is a moiety of partial Formula (1.1.1) where R⁷ is —

H, or —

CH₃ or phenyl independently substituted by 0 or 1 R¹⁰ where R¹⁰ is phenyl or pyridyl substituted by 0-2 of —

F, —

Cl, —

OCH₃, —

CN, —

NO₂, or —

NR¹⁶R¹⁷where R¹⁶ and R¹⁷ are —

H or —

CH₃;

or R¹⁰is —

F, —

Cl, —

CF₃, —

CN, —

OCH₃, —

NO₂, or —

C(═

O)OR¹⁶, —

NR¹⁶R¹⁷, or —

S(═

O)₂NR¹⁶R¹⁷ where R¹⁶ and R¹⁷ are —

H or —

CH₃;

R⁹ is —

H or —

CH₃;

W is —

O—

;

Y is ═

C(R¹_a)—

;

R¹_a is —

H, or —

F;

R^A and R^B are independently —

H or —

CH₃;

or R^A and R^B are taken together to form a —

(C₃-C₇) cycloalkyl-spiro moiety;

one of R^C and R^D is —

H and the other is —

H or —

CH₃;

R¹ and R² are —

H, —

F, or —

OCH₃;

R³ is —

H or —

CH₃; and

R⁴, R⁵ and R⁶ are —

H provided that R⁵ and R⁶ are not both —

H at the same time, —

F, —

Cl, —

OCH₃, —

CN;

—

NO₂, or —

C(═

O)R³ or —

C(═

O)OR³ where R³ is —

CH₃;

or R⁵ and R⁶ are taken together to form a moiety of partial Formula (1.3.1), (1.3.2), 1.3.3), (1.3.11), (1.3.12), or (1.3.15).

12. A compound according to claim 11 wherein R⁷ is —

H;

R⁹ is —

H;

R^A and R^B are both —

CH₃, or taken together are a cyclopropyl-spiro moiety;

R^C and R^D are both —

H;

R³ is —

H;

R⁴ is —

H;

R⁵ is —

H, —

F, —

Cl, —

CN, —

OCH₃, —

C(═

O)CH₃, or —

NO₂;

R⁶ is —

H, provided that R⁵ and R⁶ are not both —

H at the same time, or —

F;

or R⁵ and R⁶ are taken together to form a moiety of partial Formula (1.3.1), or partial Formula (1.3.11) where R²³ and R²⁴ are both absent.

13. A compound according to claim 1 wherein B¹ and B² are independently phenyl or pyridyl;

m is 1;

n is 1;

A is a moiety of partial Formula (1.1.3) where R⁷ is —

H, or —

CH₃ or phenyl independently substituted by 0 or 1 R¹⁰ where R¹⁰ is pyridyl or phenyl substituted by 0-2 of —

F, —

Cl, —

OCH₃, —

CN, —

NO₂, or —

NR¹⁶R¹⁷ are —

H or —

CH₃;

or R¹⁰ is —

F, —

Cl, —

CF₃, —

CN, —

OCH₃ , —

NO₂, —

C(═

O)OR¹⁶, —

NR¹⁶R¹⁷, or —

S(═

O)₂NR¹⁶R¹⁷ where R¹⁶ and R¹⁷ are —

H or —

CH₃;

R⁹ is —

H or —

CH₃;

W is —

O—

;

Y is ═

C(R¹_a)—

;

R¹_a is —

H;

or —

F;

R^A and R^B are independently —

H or —

CH₃;

or R^A and R^B are taken together to form a —

(C₃-C₇) cycloalkyl-spiro moiety;

one of R^C and R^D is —

H and the other is —

H or —

CH₃;

R¹ and R² are —

H, —

F, or —

OCH₃;

R³ is —

H or —

CH₃; and

R⁴, R⁵ and R⁶ are —

H provided that R⁵ and R⁶ are not both —

H at the same time, —

F, —

Cl, —

OCH₃, —

CN;

—

NO₂, or —

C(═

O)R³ or —

C(═

O)OR³ where R³ is —

CH₃;

or R⁵ and R⁶ are taken together to form a moiety of partial Formula (1.3.1), (1.3.2), (1.3.3), (1.3.11), (1.3.12), or (1.3.15), where for partial Formulas (1.3.11), (1.3.12), and (1.3.15), R²³ and R²⁴ are both absent.

14. A compound according to claim 13 wherein R⁷ is —

H;

R⁹ is —

H;

R^A and R^B are taken together to form a cyclopropyl-spiro or cyclobutyl-spiro moiety;

R^C and R^D are both —

H;

R³ is -H;

R⁴ and R⁵ are both -H, and R⁶ is —

F;

or R⁵ and R⁸ are taken together to form a moiety of partial Formula (1.3.1) or (1.3.11).

15. A compound according to claim 1 wherein B¹ and B² are independently phenyl or pyridyl;

m is 1;

n is 1;

A is a moiety of partial Formula (1.1.4) where v is 0 or 1, and R⁸ is tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-on-5-yl, 1,2,3-triazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazolidin-2-on-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-on-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-on-5-yl, 1,3,4-oxadiazolyl, 1,3,4-oxadiazol-2-on-5-yl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, succinimidyl, glutarimidyl, pyrrolidonyl, 2-piperidonyl, 2-pyridonyl, 4-pyridonyl, pyridazin-3-onyl, thiadiazolyl, parathiazinyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, all of which are independently substituted by 0 or 1 R¹⁴ where R¹⁴ is —

(C₁-C₃) alkyl, phenyl, or pyridyl, each of which is independently substituted by 0-2 of —

F, —

Cl, —

OCH₃, —

CN, —

NO₂, or —

NR¹⁶R¹⁷ where R¹⁶ and R¹⁷ are —

H or —

CH₃;

or R¹⁴ is —

F, —

Cl, —

CF₃, —

CN, —

OCH₃, —

NO₂, or —

C(═

O)OR¹⁶, —

NR¹⁶R¹⁷, or —

S(═

O)₂NR¹⁶R¹⁷ where R¹⁶ and R¹⁷ are —

H or —

CH₃;

R⁹ is —

H or —

CH₃;

W is —

O—

;

Y is ═

C(R¹_a);

R¹_a is —

H;

or —

F;

R^A and R^B are independently —

H or —

CH₃;

or R^A and R^B are taken together to form a —

(C₃-C₇) cycloalkyl-spiro moiety;

one of R^C and R^D is —

H and the other is —

H or —

CH₃;

R¹ and R² are —

H, —

F, or —

OCH₃;

R³ is —

H or —

CH₃; and

R⁴, R⁵ and R⁶ are —

H provided that R⁵ and R⁶ are not both —

H at the same time, —

F, —

Cl, —

OCH₃, —

CN;

—

NO₂, or —

C(═

O)R³ or —

C(═

O)OR³ where R³ is —

CH₃;

or R⁵ and R⁶ are taken together to form a moiety of partial Formula (1.3.1), (1.3.2), (1.3.3), (1.3.11), (1.3.12), or (1.3.15).

16. A compound according to claim 15 wherein v is 0, R⁸ is tetrazol-5-yl, 1,2,3-triazol-5-yl, or pyridyl;

R^C and R^D are both —

H;

R³ is —

H;

R⁴ and R⁵ are both —

H, and R⁶ is —

F;

or R⁵ and R⁶ are taken together to form a moiety of partial Formula (1.3.1) or (1.3.11).

17. A compound according to claim 1 wherein said compound is a member selected from the group consisting of the following:

[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid methyl ester of Formula (6.0.30);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid methyl ester of Formula (6.0.31);

2-[4-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid methyl ester of Formula (6.0.32);

[3-Fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid methyl ester of Formula (6.0.35);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-cyclobutanecarboxylic acid ethyl ester of Formula (6.0.36);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-cyclopropanecarboxylic acid ethyl ester of Formula (6.0.37);

[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-acetic acid methyl ester of Formula (6.0.38);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl ]-cyclopropanecarboxylic acid ethyl ester of Formula (6.0.39);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid of Formula (6.5.1);

2-[4-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid of Formula (6.5.2);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-cyclobutanecarboxylic acid of Formula (6.5.3);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-2-methyl-propionic acid of Formula (6.5.4);

2-[3-Fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl ]-methyl-propionic acid of Formula (6.5.5);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl ]-cyclopropanecarboxylic acid of Formula (6.5.6);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-propionic acid of Formula (6.5.7);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-methoxy-phenyl]-2-methyl-propionic acid of Formula (6.5.8);

2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino }-methyl)-3-methoxy-phenyl]-2-methyl-propionic acid of Formula (6.5.9);

2-[4-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-3-methoxy-phenyl]-2-methyl-propionic acid of Formula (6.5.10);

[3-Fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid of Formula (6.5.11);

[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid of Formula (6.5.12);

1-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-cyclopropanecarboxylic acid of Formula (6.5.13);

[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-acetic acid of Formula (6.5.14);

[4-({[2-(3-Cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-acetic acid of Formula (6.5.15);

[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-acetic acid of Formula (6.5.16);

2-[4-({[2-(Benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino }-methyl)-phenyl]2-methyl-propionic acid of Formula (6.5.17);

2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-1-methyl-ethyl)-benzyl]-nicotinamide of Formula (6.5.18);

2-(Benzo[1,3]dioxol-5-yloxy)-N-(4-carbamoylmethyl-benzyl)-nicotinamide of Formula (6.5.19);

N-(4-Carbamoylmethyl-2-fluoro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide of Formula (6.5.20);

2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-1-methyl-ethyl)-2-fluoro-benzyl ]-nicotinamide of Formula (6.5.21);

N-[4-(1-Carbamoyl-1-methyl-ethyl)-2-fluoro-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide of Formula (6.5.22);

2-(4-Fluoro-phenoxy)-N-[2-fluoro-4-(1H-tetrazol-5-ylmethyl)-benzyl]-nicotinamide of Formula (6.5.23);

2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-methyl-1-methylcarbamoyl-ethyl)-benzyl ]-nicotinamide of Formula (6.5.24);

2-(Benzo[1,3]dioxol-5-yloxy)-N-{4-[1-(cyclopropylmethyl-carbamoyl)-1-methyl-ethyl ]-benzyl}-nicotinamide of Formula (6.5.25);

2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-ethylcarbamoyl-1-methyl-ethyl)-benzyl]-nicotinamide of Formula (6.5.26);

2-(4-Fluoro-phenoxy)-N-[4-(1H-tetrazol-5-yl)-benzyl]-nicotinamide of Formula (6.5.27);

2-(4-Fluoro-phenoxy)-N-{4-[l -methyl-1-(1H-tetrazol-5-yl)-ethyl]-benzyl}-nicotinamide of Formula (6.5.28);

N-{2-Fluoro-4-[1-methyl-1-(1H-tetrazol-5-yl )-ethyl]-benzyl}-2-(4-fluoro-phenoxy)-nicotinamide of Formula (6.5.29);

5-Chloro-2-(4-fluoro-phenoxy)-N-{4-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-benzyl }-nicotinamide of Formula (6.5.30);

2-(Benzo[1,3]dioxol-5-yloxy)-5-chloro-N-{4-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-benzyl}-nicotinamide of Formula (6.5.31); and

2-(Benzo[1,3]dioxol-5-yloxy)-N-{4-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-benzyl}-nicotinamide of Formula (6.5.32).

19. A pharmaceutical composition for use in treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme whereby it regulates the activation and degranulation of eosinophils, comprising a therapeutically effective amount of a compound of Formula (1.0.0) as defined in claim 1 together with a pharmaceutically acceptable carrier therefor.

20. A method according to claim 18 wherein said disease, disorder, or condition comprises one or more members selected from the group consisting of:

asthma of whatever type, etiology, or pathogenesis;

or asthma that is a member selected from the group consisting of atopic asthma;

non-atopic asthma;

allergic asthma;

atopic, bronchial, IgE-mediated asthma;

bronchial asthma;

essential asthma;

true asthma;

intrinsic asthma caused by pathophysiologic disturbances;

extrinsic asthma caused by environmental factors;

essential asthma of unknown or inapparent cause;

non-atopic asthma;

bronchitic asthma;

emphysematous asthma;

exercise-induced asthma;

occupational asthma;

infective asthma caused by bacterial, fungal, protozoal, or viral infection;

non-allergic asthma;

incipient asthma;

wheezy infant syndrome;

chronic or acute bronchoconstriction;

chronic bronchitis;

small airways obstruction; and

emphysema;

obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis;

or an obstructive or inflammatory airways disease that is a member selected from the group consisting of asthma;

pneumoconiosis;

chronic eosinophilic pneumonia;

chronic obstructive pulmonary disease (COPD);

COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith;

COPD that is characterized by irreversible, progressive airways obstruction;

adult respiratory distress syndrome (ARDS), and exacerbation of airways hyper-reactivity consequent to other drug therapy;

pneumoconiosis of whatever type, etiology, or pathogenesis;

or pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers'"'"' disease;

anthracosis or miners'"'"' asthma;

asbestosis or steam-fitters'"'"' asthma;

chalicosis or flint disease;

ptilosis caused by inhaling the dust from ostrich feathers;

siderosis caused by the inhalation of iron particles;

silicosis or grinders'"'"' disease;

byssinosis or cotton-dust asthma; and

talc pneumoconiosis;

bronchitis of whatever type, etiology, or pathogenesis;

or bronchitis that is a member selected from the group consisting of acute bronchitis;

acute laryngotracheal bronchitis;

arachidic bronchitis;

catarrhal bronchitis;

croupus bronchitis;

dry bronchitis;

infectious asthmatic bronchitis;

productive bronchitis;

staphylococcus or streptococcal bronchitis; and

vesicular bronchitis;

bronchiectasis of whatever type, etiology, or pathogenesis;

or bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis;

sacculated bronchiectasis;

fusiform bronchiectasis;

capillary bronchiectasis;

cystic bronchiectasis;

dry bronchiectasis; and

follicular bronchiectasis;

seasonal allergic rhinitis;

or perennial allergic rhinitis;

or sinusitis of whatever type, etiology, or pathogenesis;

or sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis;

acute or chronic sinusitis; and

ethmoid, frontal, maxillary, or sphenoid sinusitis;

rheumatoid arthritis of whatever type, etiology, or pathogenesis;

or rheumatoid arthritis that is a member selected from the group consisting of acute arthritis;

acute gouty arthritis;

chronic inflammatory arthritis;

degenerative arthritis;

infectious arthritis;

Lyme arthritis;

proliferative arthritis;

psoriatic arthritis; and

vertebral arthritis;

gout, and fever and pain associated with inflammation;

an eosinophil-related disorder of whatever type, etiology, or pathogenesis;

or an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia;

pulmonary infiltration eosinophilia;

Loffler'"'"'s syndrome;

chronic eosinophilic pneumonia;

tropical pulmonary eosinophilia;

bronchopneumonic aspergillosis;

aspergilloma;

granulomas containing eosinophils;

allergic granulomatous angiitis or Churg-Strauss syndrome;

polyarteritis nodosa (PAN); and

systemic necrotizing vasculitis;

atopic dermatitis;

or allergic dermatitis;

or allergic or atopic eczema;

urticaria of whatever type, etiology, or pathogenesis;

or urticaria that is a member selected from the group consisting of immune-mediated urticaria;

complement-mediated urticaria;

urticariogenic material-induced urticaria;

physical agent-induced urticaria;

stress-induced urticaria;

idiopathic urticaria;

acute urticaria;

chronic urticaria;

angioedema;

cholinergic urticaria;

cold urticaria in the autosomal dominant form or in the acquired form;

contact urticaria;

giant urticaria; and

papular urticaria;

conjunctivitis of whatever type, etiology, or pathogenesis;

or conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis;

acute catarrhal conjunctivitis;

acute contagious conjunctivitis;

allergic conjunctivitis;

atopic conjunctivitis;

chronic catarrhal conjunctivitis;

purulent conjunctivitis; and

vernal conjunctivitis;

uveitis of whatever type, etiology, or pathogenesis;

or uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea;

anterior uveitis;

iritis;

cyclitis;

iridocyclitis;

granulomatous uveitis;

nongranulomatous uveitis;

phacoantigenic uveitis;

posterior uveitis;

choroiditis; and

chorioretinitis;

psoriasis;

multiple sclerosis of whatever type, etiology, or pathogenesis;

or multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis; and

relapsing remitting multiple sclerosis;

autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis;

or an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders;

hemolytic anemia;

aplastic anemia;

pure red cell anemia;

idiopathic thrombocytopenic purpura;

systemic lupus erythematosus;

polychondritis;

scleroderma;

Wegner'"'"'s granulomatosis;

dermatomyositis;

chronic active hepatitis;

myasthenia gravis;

Stevens-Johnson syndrome;

idiopathic sprue;

autoimmune inflammatory bowel diseases;

ulcerative colitis;

Crohn'"'"'s disease;

endocrin opthamopathy;

Grave'"'"'s disease;

sarcoidosis;

alveolitis;

chronic hypersensitivity pneumonitis;

primary biliary cirrhosis;

juvenile diabetes or diabetes mellitus type I;

anterior uveitis;

granulomatous or posterior uveitis;

keratoconjunctivitis sicca;

epidemic keratoconjunctivitis;

diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis;

idiopathic pulmonary fibrosis;

cystic fibrosis;

psoriatic arthritis;

glomerulonephritis with and without nephrotic syndrome;

acute glomerulonephritis;

idiopathic nephrotic syndrome;

minimal change nephropathy;

inflammatory/hyperproliferative skin diseases;

psoriasis;

atopic dermatitis;

contact dermatitis;

allergic contact dermatitis;

benign familial pemphigus;

pemphigus erythematosus;

pemphigus foliaceus; and

pemphigus vulgaris;

prevention of allogeneic graft rejection following organ transplantation;

inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis;

or inflammatory bowel disease that is a member selected from the group consisting of ulcerative colitis (UC);

collagenous colitis;

colitis polyposa;

transmural colitis; and

Crohn'"'"'s disease (CD);

.

septic shock of whatever type, etiology, or pathogenesis;

or septic shock that is a member selected from the group consisting of renal failure;

acute renal failure;

cachexia;

malarial cachexia;

hypophysial cachexia;

uremic cachexia;

cardiac cachexia;

cachexia suprarenalis or Addison'"'"'s disease;

cancerous cachexia; and

cachexia as a consequence of infection by the human immunodeficiency virus (HIV);

liver injury;

pulmonary hypertension; and

hypoxia-induced pulmonary hypertension;

bone loss diseases;

primary osteoporosis; and

secondary osteoporosis;

central nervous system disorders of whatever type, etiology, or pathogenesis;

or a central nervous system disorder that is a member selected from the group consisting of depression;

Parkinson'"'"'s disease;

learning and memory impairment;

tardive dyskinesia;

drug dependence;

arteriosclerotic dementia; and

dementias that accompany Huntington'"'"'s chorea, Wilson'"'"'s disease, paralysis agitans, and thalamic atrophies;

infection, especially infection by viruses wherein such viruses increase the production of TNF-α

in their host, or wherein such viruses are sensitive to upregulation of TNF-α

in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1, HIV-2, and HIV-3;

cytomegalovirus, CMV;

influenza;

adenoviruses; and

Herpes viruses, including Herpes zoster and Herpes simplex;

yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF-α

or elicit TNF-α

production in their host, when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but not limited to, polymixins, Polymycin B;

imidazoles, clotrimazole, econazole, miconazole, and ketoconazole;

triazoles, fluconazole and itranazole; and

amphotericins, Amphotericin B and liposomal Amphotericin B; and

ischemia-reperfusion injury;

autoimmune diabetes;

retinal autoimmunity;

chronic lymphocytic leukemia;

HIV infections;

lupus erythematosus;

kidney and ureter disease;

urogenital and gastrointestinal disorders; and

prostate diseases.

21. A method of treatment according to claim 20 wherein said disease, disorder, or condition is a member selected from the group consisiting of (1) inflammatory diseases and conditions comprising:

joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn'"'"'s disease;

(2) respiratory diseases and conditions comprising;

asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease, and silicosis;

(3) infectious diseases and conditions comprising;

sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza;

(4) immune diseases and conditions comprising;

autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and

(5) other diseases and conditions comprising;

bone resorption diseases;

reperfusion injury;

cachexia secondary to infection or malignancy;

cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC);

keloid formation;

scar tissue formation;

type 1 diabetes mellitus; and

leukemia.

22. The combination of a compound of Formula (1.0.0) as defined in claim 1 together with one or more members selected from the group consisting of the following:

(a) Leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors, and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton;

ABT-761;

fenleuton;

tepoxalin;

Abbott-79175;

Abbott-85761;

N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8);

2,6-di-tert-butylphenol hydrazones of Formula (5.2.10);

Zeneca ZD-2138 of Formula (5.2.11);

SB-210661 of Formula (5.2.12);

pyridinyl-substituted 2-cyanor naphthalene compound L-739,010;

2-cyanoquinoline compound L-746,530;

indole and quinoline compounds MK-591, MK-886, and BAY ×

1005;

(b) Receptor antagonists for leukotrienes LTB₄, LTC₄, LTD₄, and LTE₄ selected from the group consisting of phenothiazin-3-one compound L-651,392;

amidino compound CGS-25019c;

benzoxazolamine compound ontazolast;

benzenecarboximidamide compound BIIL 284/260;

compounds zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY ×

7195;

(c) PDE4 inhibitors;

(d) 5-Lipoxygenase (5-LO) inhibitors; and

5-lipoxygenase activating protein (FLAP) antagonists;

(e) Dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF);

(f) Leukotriene antagonists (LTRAs) of LTB₄, LTC₄, LTD₄, and LTE₄;

(g) Antihistaminic H₁ receptor antagonists cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine;

(h) Gastroprotective H₂ receptor antagonists;

(i) α

₁- and α

₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally or topically for decongestant use, selected from the group consisting of propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride;

(j) one or more α

₁- and α

₂-adrenoceptor agonists as recited in (i) above in combination with one or more inhibitors of 5-lipoxygenase (5-LO) as recited in (a) above;

(k) Anticholinergic agents ipratropium bromide;

tiotropium bromide;

oxitropium bromide;

pirenzepine; and

telenzepine;

(l) β

₁- to β

₄-adrenoceptor agonists selected from the group consisting of metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol, and pirbuterol;

(m) Theophylline and aminophylline;

(n) Sodium cromoglycate;

(o) Muscarinic receptor (M1, M2, and M3) antagonists;

(p) COX-1 inhibitors (NSAIDs); and

nitric oxide NSAIDs;

(q) COX-2 selective inhibitor rofecoxib;

(r) Insulin-like growth factor type I (IGF-1) mimetics;

(s) Ciclesonide;

(t) Inhaled glucocorticoids with reduced systemic side effects selected from the group consisting of prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate;

(u) Tryptase inhibitors;

(v) Platelet activating factor (PAF) antagonists;

(w) Monoclonal antibodies active against endogenous inflammatory entities;

(x) IPL 576;

(y) Anti-tumor necrosis factor (TNFα

) agents selected from the group consisting of etanercept, infliximab, and D2E7;

(z) DMARDs selected from the group consisting of leflunomide;

(aa) TCR peptides;

(bb) Interleukin converting enzyme (ICE) inhibitors;

(cc) IMPDH inhibitors;

(dd) Adhesion molecule inhibitors including VLA-4 antagonists;

(ee) Cathepsins;

(ff) MAP kinase inhibitors;

(gg) Glucose-6 phosphate dehydrogenase inhibitors;

(hh) Kinin-B₁- and B₂-receptor antagonists;

(ii) Gold in the form of an aurothio group in combination with hydrophilic groups;

(jj) Immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate;

(kk) Anti-gout agents selected from the group consisting of colchicine;

(ll) Xanthine oxidase inhibitors selected from the group consisting of allopurinol;

(mm) Uricosuric agents selected from the group consisting of probenecid, sulfinpyrazone, and benzbromarone;

(nn) Antineoplastic agents that are antimitotic drugs selected from the group consisting of vinblastine and vincristine;

(oo) Growth hormone secretagogues;

(pp) Inhibitors of matrix metalloproteases (MMPs) that are selected from the group consisting of the stromelysins, the collagenases, the gelatinases, aggrecanase, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11);

(qq) Transforming growth factor (TGFβ

);

(rr) Platelet-derived growth factor (PDGF);

(ss) Fibroblast growth factor selected from the group consisting of basic fibroblast growth factor (bFGF);

(tt) Granulocyte macrophage colony stimulating factor (GM-CSF);

(uu) Capsaicin;

(vv) Tachykinin NK₁, and NK₃ receptor antagonists selected from the group consisting of NKP-608C;

SB-233412 (talnetant); and

D-4418;

(ww) Elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and

(xx) Adenosine A2a receptor agonists.

18. A method of treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme whereby it regulates the activation and degranulation of eosinophils, comprising administering to said subject in need of said treatment a therapeutically effective amount of a compound of Formula (1.0.0).