Therapeutically active compounds based on indazole bioisostere replacement of catechol in PDE4 inhibitors

Abstract

Therapeutically active compositions of matter are described which are useful for treating or preventing diseases and conditions comprising inflammatory diseases including joint inflammation, Crohn's disease, and inflammatory bowel disease; respiratory diseases such as chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema; infectious diseases including endotoxic shock and toxic shock syndrome; immune diseases including systemic lupus erythematosis and psoriasis; and other diseases including bone resorption diseases and reperfusion injury; wherein said composition of matter comprises a compound which is an inhibitor of phosphodiesterase isozyme 4 (PDE4) and wherein an indazole is one essential component of said compound's overall chemical structure, and wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said therapeutic activity and the same remaining said components of its overall chemical structure. Included are compounds of Formula (IA) or (IB): wherein R 2 a and R 2 b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R 2 a and R 2 b must be independently selected as hydrogen, wherein said substituents comprise moieties including the following:

What is claimed is:  
     
         1 . A therapeutically active composition of matter useful for treating or preventing one or more members selected from the group of diseases and conditions consisting essentially of (1) inflammatory comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn's disease; (2) respiratory comprising: acute respiratory distress syndrome, bronchitis, chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis and pulmonary emphysema, and silicosis; (3) infectious 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 comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) general 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) infectioin, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; 
 wherein said composition of matter comprises a compound which is an inhibitor of phosphodiesterase isozyme 4 (PDE4) and wherein an indazole is one essential component of said compound's overall chemical structure, and wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having said therapeutic activity and the same remaining said components of its overall chemical structure.    
     
     
         2 . A therapeutically active composition of matter according to  claim 1  comprising a compound of Formula (IA) or (IB):  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein: 
 R is a member independently selected from the group consisting essentially of hydrogen, (C 1 -C 9 ) alkyl; —(CH 2 ) n (C 3 -C 10 ) cycloalkyl wherein n is an integer selected from 0, 1, and 2; (C 1 -C 6 ) alkoxy(C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; —(CH 2 ) n (C 3 -C 9 ) heterocyclyl wherein n is an integer selected from 0, 1, and 2; and —(Z 1 ) b (Z 2 ) c (C 6 -C 10 ) aryl wherein b and c are integers independently selected from 0 and 1, Z 1  is (C 1 -C 6 ) alkylene or (C 2 -C 6 ) alkenylene, and Z 2  is O, S, SO 2 , or NR 119 ; and further wherein said heterocyclyl is a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; wherein said aryl is a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties defining said R groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; (C 1 -C 5 ) alkyl; (C 2 -C 5 ) alkenyl; (C 1 -C 5 ) alkoxy; (C 3 -C 6 ) cycloalkoxy; mono-, di-, and ti-fluoromethyl; nitro; —C(═O)OR 119 , —C(═O)NR 119 R 120 , —NR 119 R 120  and —S(═O) 2 NR 119 R 120 ;  
 R 1  is a member independently selected from the group consisting essentially of hydrogen; (C 1 -C 9 ) alkyl; (C 2 -C 3 ) alkenyl; phenyl; (C 3 -C 7 ) cycloalkyl; and (C 3 -C 7 ) cycloalkyl(C 1 -C 2 ) alkyl; wherein said alkyl, alkenyl and phenyl moieties defining said R 1  groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro; and  
 R 2   a  and R 2   b  are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R 2   a  and R 2   b  must be independently selected as hydrogen, wherein said substituents comprise moieties of the groups (I) through (V):  
 (-I-)  
 a moiety of partial Formulas (IC), (ID), (IE), or (IF):  
                     
 
       wherein the dashed lines in formulas (IC) and (ID) independently and optionally represent a single or double bond, provided that in formula (IC) both dashed lines cannot both represent double bonds at the same time;  
       m is an integer selected from 0, 1, 2, 3, and 4, and when 2, may apply to a single carbon atom on the ring;  
       R 113  is a member selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; (C 2 -C 4 ) alkynyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of phenyl, pyridyl and pyrimidinyl; (C 1 -C 4 ) alkyl substituted by 0 to 6 bromo, chloro, or fluoro; —CH 2 NHC(═O)C(═O)NH 2 ; cyclopropyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of R 121 ; R 127 ; CH 2 OR 119 ; NR 119 R 120 ; CH 2 NR 119 R 120 ; C(═O)OR 119 ; C(═O)NR 119 R 120 ; C≡—CR 11 ; C(Z)H; and —CH═CR 121 R 121 ; provided that R 113  is H in Formula (IC) when the dashed line for the ring carbon of R 113  attachment represents a double bond; 
 R 114  is a member selected from the group consisting essentially of H; R 116 ; C(Y)R 124 ; C(═O)OR 124 ; C(Y)NR 127 R 124 ; CN; C(NR 127 )NR 127 R 124 ; C(NOR 119 )R 124 ; C(═O)NR 119 NR 119 C(═O)R 119 ; C(═O)NR 119 NR 127 R 124 ; C(NOR 124 )R 119 ; C(NR 119 )NR 127 R 124 ; C(NR 124 )NR 119 R 120 ; C(NCN)NR 127 R 124 , C(NCN)S(C 1 -C 4 ) alkyl; CR 119 R 120 OR 124 , CR 119 R 120 SR 124 , CR 119 R 120 S(O) n R 125  where n is an integer selected from 0, 1, and 2; CR 119 R 120 NR 124 R 127 ; CR 119 R 120 NR 127 S(═O) 2 R 15 ; CR 119 R 120 NR 127 C(Y)R 124 ; CR 119 R 120 NR 127 C(═O)OR 125 ; CR 119 R 120 NR 127 C(Y)NR 127 R 124 ; CR 119 R 120 NR 127 C(NCN)NR 127 R 124 ; CR 119 R 120 NR 127 C(CR 119 NO 2 )S(C 1 -C 4 ) alkyl; CR 119 R 120 C(═O)OR 125 ; CR 119 R 120 C(Y)NR 127 R 124 ; CR 119 R 120 C(NR 127 )NR 127 R 124 ; CR 119 R 120 CN; CR 119 R 120 C(NOR 120 )R 124 ; CR 119 R 120 C(NOR 124 )R 120 ; CR 119 R 120 NR 127 C(NR 127 )S(C 1 -C 4 ) alkyl; CR 119 R 120 NR 127 C(NR 127 )NR 127 R 124 ; CR 119 R 120 NR 127 C(═O)C(═O)NR 127 R 124 ; CR 119 R 120 NR 127 C(═O)C(═O)OR 124 ; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; CR 119 R 120 (tetrazolyl); CR 119 R 120 (thiazolyl); CR 19 R 120 (imidazolyl); CR 119 R 120 (imidazolidinyl); CR 119 R 120 (pyrazolyl); CR 119 R 120 (thiazolidinyl); CR 119 R 120 (oxazolyl); CR 119 R 120 (oxazolidinyl); CR 119 R 120 (triazolyl); CR 119 R 120 (isoxazolyl); CR 119 R 120 (oxadiazolyl); CR 119 R 120 (thiadiazolyl); CR 119 R 120 (morpholinyl); CR 119 R 120 (piperidinyl); CR 119 R 120 (piperazinyl); and CR 119 R 120 (pyrrolyl); said heterocyclic groups being substituted by 0 to 3 substituents R 124 ;  
 R 115  is a member selected from the group consisting essentially of R 119 ; OR 119 ; —CH 2 OR 119 ; cyano; C(═O)R 119 ; C(═O)OR 119 ; C(═O)NR 119 R 120 ; and NR 119 R 120 ; provided that R 115  is absent when the dashed line in Formula (9.2) represents a double bond;  
 or R 114  and R 115  are taken together to form ═O or ═R 118 ;  
 or R 115  is hydrogen and R 114  is OR 124 ; SR 124 ; S(O) n R 125 , where n is an integer selected from 0, 1, and 2; S(═O) 2 NR 127 R 124 ; NR 127 R 124 ; NR 124 C(═O)R 119 ; NR 127 C(Y)R 124 ; NR 127 C(═O)OR 125 ; NR 127 C(Y)NR 127 R 124 ; NR 127 S(═O) 2 NR 127 R 124 ; NR 127 C(NCN)NR 127 R 124 ; NR 127 S(═O) 2 R 125 ; NR 127 C(CR 119 NO 2 )NR 127 R 124 ; NR 127 C(NCN)S(C 1 -C 4 ) alkyl; NR 127 C(CR 119 NO 2 )S(C 1 -C 4 ) alkyl; NR 127 C(NR 127 )NR 127 R 124 ; NR 127 C(═O)C(═O)NR 127 R 124 ; or NR 127 C(═O)C(═O)OR 124 ;  
 R 116  is a member independently selected from the group consisting essentially of methyl and ethyl substituted by 0 to 5 bromo, chloro, or fluoro, wherein m may be 2 with respect to a single ring carbon atom to which R 116  is attached;  
 R 117  is a member independently selected from the group consisting essentially of OR 124 ; SR 124 ; SO 2 NR 127 R 124 ; NR 127 R 124 ; NR 124 C(═O)R 119 ; NR 127 C(Y)R 124 ; NR 127 C(═O)OR 125 ; S(O) n R 12  where n is an integer selected from 0, 1, and 2; OS(═O) 2 R 122 ; OR 122 ; OC(═O)NR 123 R 122 ; OC(═O)R 123 ; OC(═O)OR 123 ; O(CR 122 R 123 ) m OR 122  where m is an integer selected from 0, 1, and 2; CR 119 R 120 OR 124 ; CR 119 R 120 NR 127 R 124 ; C(Y)R 124 ; C(═O)OR 124 ; C(Y)NR 127 R 124 ; CN; C(NR 127 )NR 127 R 124 ; C(NOR 119 )R 124 ; C(═O)NR 119 NR 119 C(═O)R 119 ; C(═O)NR 119 NR 127 R 124 ; C(NOR 124 )R 119 ; C(NR 119 )NR 127 R 124 ; C(NR 124 )NR 119 R 120 ; C(NCN)NR 127 R 124 ; C(NCN)S(C 1 -C 4 ) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; and thiadiazolyl; where the recited heterocyclic groups are substituted by 0 to 3 substituents where said substituent is R 124 ;  
 R 118  is a member selected from the group consisting essentially of —NR 125 ; —NCR 119 R 120 (C 2 -C 6 ) alkenyl; —NOR 124 ; —NOR 129 ; —NOCR 119 R 120 (C 2 -C 6 ) alkenyl; —NNR 119 R 124 ; —NNR 119 R 129 ; —NCN; —NNR 119 C(Y)NR 119 R 124 ; —C(CN) 2 ; —CR 124 CN; —CR 124 C(═O)OR 119 ; —CR 124 C(═O)NR 119 R 124 ; —C(CN)NO 2 ; —C(CN)C(═O)O(C 1 -C 4 ) alkyl; —C(CN)OC(═O)O(C 1 -C 4 ) alkyl; —C(CN)(C 1 -C 4 ) alkyl; —C(CN)C(═O)NR 119 R 124 ; 2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane); dimethyl ketal and diethyl ketal;  
 R 119  and R 120  are each a member independently selected from the group consisting essentially of hydrogen and (C 1 -C 4 ) alkyl substituted by 0 to 3 fluorine atoms;  
 R 121  is fluoro; or R 120 ;  
 R 122  is a member selected from the group consisting essentially of (C 1 -C 6 ) alkyl; (C 2 -C 3 ) alkenyl; (C 3 -C 7 ) cycloalkyl; (C 3 -C 7 ) cycloalkyl(C 1 -C 2 ) alkyl; (C 6 -C 10 ) aryl; and (C 3 -C 9 ) heterocyclyl; where said aryl and heterocyclyl are as defined under R A   5  above; and where said R 122  groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro;  
 R 123  is a member independently selected from the group consisting essentially of hydrogen and R 122 ;  
 R 124  is a member independently selected from the group consisting essentially of hydrogen and R 125 ; or when R 124  and R 127  appear together as NR 127 R 124  then R 127  and R 124  may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring optionally containing one additional heteroatom selected from O, N and S;  
 R 125  is a member independently selected from the group consisting essentially of (C 1 -C 6 ) alkyl and —(CR 119 R 120 ) n R 126 , where n is an integer selected from 0, 1, and 2 and R 126  and said (C 1 -C 6 ) alkyl are substituted by 0 to 3 substituents where each said substituent is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; NR 120 R 127 ; C(═O)R 119 ; OR 119 ; C(═O)NR 120 R 127 ; OC(═O)NR 120 R 127 ; NR 127 C(═O)NR 127 R 120 ; NR 127 C(═O)R 120 ; NR 17 C(═O)O(C 1 -C 4 ) alkyl; C(NR 127 )NR 127 R 120 ; C(NCN)NR 127 R 120 ; C(NCN)S(C 1 -C 4 ) alkyl; NR 127 C(NCN)S(C 1 -C 4 ) alkyl; NR 127 C(NCN)NR 127 R 120 ; NR 127 S(═O) 2 (C 1 -C 4 ) alkyl; S(O) n (C 1 -C 4 ) alkyl; where n is an integer selected from 0, 1, and 2; NR 127 C(═O)C(═O)NR 127 R 120 , NR 127 C(═O)C(═O)R 127 ; thiazolyl; imidazolyl; oxazolyl; pyrazolyl; triazolyl; tetrazolyl; and (C 1 -C 2 ) alkyl substituted with 0 to 3 fluorine atoms;  
 R 126  is a member independently selected from the group consisting essentially of (C 3 -C 7 ) cycloalkyl; pyridyl; pyrimidyl; pyrazolyl; imidazolyl; triazolyl; pyrrolyl; piperazinyl; piperidinyl; morpholinyl; furanyl; thienyl; thiazolyl; quinolinyl; naphthyl; and phenyl;  
 R 127  is a member independently selected from the group consisting essentially of OR 119  and R 120 ;  
 R 128  is a member independently selected from the group consisting essentially of H; C(Y)R 124 ; C(═O)OR 124 ; C(Y)NR 127 R 124 ; CN; C(NR 127 )NR 127 R 124 ; C(NOR 119 )R 124 ; C(═O)NR 119 NR 119 C(═O)R 119 ; C(═O)NR 119 NR 127 R 124 ; C(NOR 124 )R 119 ; C(NR 119 )NR 127 R 124 ; C(NR 124 )NR 119 R 120 ; C(NCN)NR 127 R 124 ; C(NCN)S(C 1 -C 4 ) alkyl; CR 119 R 120 OR 124 ; CR 119 R 120 SR 124 ; CR 119 R 120 S(O) n R 125 , where n is an integer selected from 0, 1, and 2; CR 119 R 120 NR 124 R 127 ; CR 119 R 120 NR 127 S(═O) 2 R 125 ; CR 119 R 120 NR 127 C(Y)R 124 ; CR 119 R 120 NR 127 C(═O)OR 125 ; CR 119 R 120 NR 127 C(Y)NR 127 R 124 ; CR 119 R 120 NR 127 C(NCN)NR 127 R 124 ; CR 119 R 120 NR 127 C(CR 9 NO 2 )S(C 1 -C 4 ) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; wherein said recited heterocyclic groups are substituted by 0 to 3 substituents where each said substituent is independently selected from the group consisting essentially of R 124 ;  
 R 129  is a member independently selected from the group consisting essentially of —C(═O)R 12 ; —C(═O)NR 119 R 124 ; —S(═O) 2 R 125 ; and —S(═O) 2 NR 119 R 124 ;  
 Y is O or S; and,  
 Z is O; NR 127 ; NCN; C(—CN) 2 ; CR 119 CN; CR 119 NO 2 ; CR 119 C(═O)OR 119 ; CR 119 C(═O)NR 119 R 120 ; C(—CN)C(═O)O(C 1 -C 4 ) alkyl); and C(—CN)C(═O)NR 119 R 120 ; 
 —OR, said substituents defining R 2   a  and R 2   b  comprise:-  
 (-II-)  
 
 a member selected from the group consisting essentially of R 229 ; —C(═O)NR 222 (CHR 222 ) m C(═O)NR 222 O(CH 2 ) q (C 6 -C 10 ) aryl); —C(═NR 242 )NH(CH 2 ) p (C 6 -C 10 ) aryl; —C(═O)NR 218 (CHR 222 ) m C(═O)NR 222 (CH 2 ) p OR 222 ; —C(═O)NR 222 (CHR 222 ) m S(C 1 -C 4 ) alkyl; —C[═NOC(═O)R 235 ]R 236 ; —CR 227 R 228 CHR 238 NR 219 SO 2 (CH 2 ) p A; —CR 227 R 228 CHR 238 NR 219 P(═O)(OR 222 )C(═O)(C 1 -C 4 ) alkyl; —CR 227 R 238 CHR 238 NR 219 P(═O)[(C 1 -C 4 ) alkoxy] 2 , —Z 3 —R 217 ; and —(CR 227 R 228 ) m NR 219 (C(O)) q R 220  wherein p is an integer selected from 0, 1, and 2; m is an integer selected from 1, 2, 3, 4, 5, and 6; and q is an integer selected from 1 and 2; 
 —OR, said substituents defining R 2   a  and R 2   b  comprise a moiety of partial Formulas (IIA) through (III), inclusive:— 
                     
 
 wherein in said partial Formulas (IIA)-(III), the structures of partial Formulas (IIF) and (IIG) are attached to the nucleus of Formula (IA) or (IB) at carbons 5, 6, or 7 of said partial Formulas (IIF) and (IIG); the dashed line in partial Formulas (IIC) and (IID) indicates a single bond or double bond, except that R 316  is absent in formulas (IIC) and (IID) where said dashed line indicates a double bond; n is an integer selected from 0, 1, and 2; p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and m is an integer selected from 0, and 1;  
 R 213  is a member independently selected from the group consisting essentially of —C(═O)N(CH 3 )(OCH 3 ) and —(CH 2 ) n OH, where n is an integer selected from 0, 1, 2, 3, and 4;  
 R 214  and R 215  are independently selected from the group consisting essentially of H; ethyl; —CO 2 H; and —C(═O)NHOH;  
 R 216  is a member independently selected from the group consisting essentially of H; hydroxy; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; —OC(═O)(C 1 -C 6 ) alkyl and —OC(═O)(C 6 -C 10 ) aryl;  
 R 217  is a member independently selected from the group consisting essentially of (C 1 -C 10 ) aryl and a 5- to 10-membered heterocyclyl, wherein said R 217  groups are substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluroro; trifluoromethyl; cyano; nitro; —CO 2 R 222 , (C 1 -C 4 ) alkoxy; —OC(═O)(C 1 -C 4 ) alkyl; —NR 222 C(═O)(C 1 -C 4 ) alkyl; —C(═O)NH 2 ; —C(═O)NHOH; —C(═O)O(C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkyl; —S(O) n R 222  where n is an integer selected from 0, 1, and 2; benzoyl; —NR 222 R 223 , —OR 222 , (C 1 -C 6 ) alkanoyl; —Y 1 —(C 6 -C 10 ) aryl; —C(═O)O(C 6 -C 10 ) aryl; —NH(C 6 -C 10 ) aryl; —C(═O)NH(C 6 -C 10 ) aryl; —C(═O)NR 222 O(CH 2 ) n (C 6 -C 10 ) aryl, where n is an integer selected from 1, 2, and 3; and —SO 2 NH(C 6 -C 10 ) aryl;  
 R 218  is a member independently selected from the group consisting essentially of H; (C 1 -C 6 ) alkyl; and —(CH 2 ) n (C 6 -C 10 ) aryl, where n is an integer selected from 0, 1, 2, 3, and 4;  
 R 219  is a member independently selected from the group consisting essentially of H; —OR 222 ; —(CH 2 ) m A; and —CH 2 O(CH 2 ) m A, where m is an integer selected from 0, 1, and 2;  
 R 220  is a member independently selected from the group consisting essentially of (C 1 -C 4 ) alkyl; —OR 222 , —CR 222 R 223 OR 222 ; —CR 222 R 223 NR 222 R 223 ; —CR 222 (OR 223 )CR 222 R 223 OR 222 ; 2,2-dimethyl-1,3-dioxolan-4-yl; —NR 222 C(═O)NR 222 R 223 , —S(CR 222 R 223 ) n CH 3  where n is an integer selected from 0, 1, 2, 3, 4, and 5; —NR 222 (CH 2 ) q (pyridyl) where q is an integer selected from 0 and 1; —P(═O)[(C 1 -C 4 ) alkoxy)] 2 ; —NR 222 R 223 ; —NR 222 OR 223 ; —NR 222 NR 223 R 221 , —NR 222 CH 2 R 224 ; —OCH 2 NR 222 C(═O)R 224 ; —OCH 2 C(═O)NR 225 R 226 , —OCHR 222 OC(═O)(C 1 -C 4 ) alkyl; —OCHR 222 C(═O)(C 1 -C 3 ) alkoxy; —O(CH 2 ) m R 221 ; and —NR 222 (CH 2 ) m R 221  where m is an integer selected from 0, 1, and 2;  
 R 222  is a member independently selected from the group consisting essentially of H and A;  
 each R 222  and R 223  is a member independently selected from the group consisting essentially of H and (C 1 -C 4 ) alkyl;  
 R 224  is a member independently selected from the group consisting essentially of methyl and phenyl;  
 R 225  is a member independently selected from the group consisting essentially of H; methyl; ethyl; and —CH 2 CH 2 OH;  
 R 226  is a member independently selected from the group consisting essentially of H; methyl; ethyl; —CH 2 C(═O)NH 2 ; and —CH 2 CH 2 OH;  
 each R 227  is a member independently selected from the group consisting essentially of H; hydroxy; cyano; halo; (C 1 -C 3 ) alkyl; (C 1 -C 3 ) alkoxy; —NR 222 R 223 ; —C(═O)OR 222 ; —C(═O)R 222 ; —CH═CR 222 R 223 ; —C≡CR 222 ; —CH 2 NR 222 R 223 ; —CH 2 OR 222 ; —C(═O)NR 222 R 223 ; —C(Y 5 )H; and —CH 2 NR 12 C(═O)C(═O)NR 222 R 223 ; provided that when R 227  is hydroxy then R 228  is H or (C 1 -C 4 ) alkyl;  
 each R 228  is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C 1 -C 4 ) alkyl; where said methyl is substituted by 0 to 3 substituents each comprising a fluorine atom;  
 or R 227  and R 228  are taken together to form an oxo (═O) moiety;  
 R 229  is a member independently selected from the group consisting essentially of phenyl; naphthyl; pyrrolyl; furanyl; thienyl; oxazolyl; pyridinyl; pyrimidinyl; pyridazinyl; quinolinyl; isoquinolinyl; 5,6,7,8-tetrahydroquinolinyl; and 5,6,7,8-tetrahydroisoquinolinyl, where said R 229  groups, except said phenyl, are substituted by 0 to 3 substituents R 233 , and wherein said phenyl R 229  group is substituted by 0 to 3 substituents independently selected from R 233  and R 234 ;  
 R 230  is a member independently selected from the group consisting essentially of —C(═O)R 231 ; —C(═O)C(═O)R 231 , —C(═O)C(Y 2 )C(═O)R 231  and a moiety of partial Formula (IIJ):  
                     
 wherein  
 R 231  is a member independently selected from the group consisting essentially of H; —OR 232 ; —NHR 232 ; —NHOH; —NHNH 2 ; —(CH 2 ) n Y 3 (phenyl) and —(CH 2 ) n Y 3 (pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;  
 R 232  is a member independently selected from the group/consisting essentially of H; (C 1 -C 8 ) alkyl; —(CH 2 ) n Y 3 (phenyl) and —(CH 2 ) n Y 3 (pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;  
 each R 233  is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C 1 -C 6 ) alkyl; (C 1 -C 7 ) alkoxy; (C 2 -C 6 ) alkylenedioxy; trifluoromethyl; —NR 222 R 223 ; nitro; —C(NR 222 )NR 222 R 223 ; —C(═O)NR 223 R 223 C(═O)R 222 ; —C(NOR 222 )R 223 ; —C(NCN)NR 222 R 223 ; —C(NCN)SR 222 ; —(CH 2 ) m (CN) where m is an integer selected from 0, 1, 2, and 3; hydroxy; —C(═O)R 222 , —C(═O)NR 222 OR 223 ; —C(═O)NR 222 NR 222 R 223 ; —OC(═O)NR 222 R 223 ; —NR 222 C(═O)R 222 ; —C(═O)C(═O)NR 222 R 223 ; —CO 2 R 222 ; —SO 2 R 222 ; —SO 2 NR 222 R 223 ; —C(═O)NR 222 R 223 ; —NR 222 SO 2 R 223 ; and —NR 222 C(═O)NR 222 R 223 ;  
 each R 234  is a member independently selected from the group consisting essentially of imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl, where each of said foregoing R 234  substituents is substituted by 0 to 3 substituents R 233 ;  
 R 235  is a member independently selected from the group consisting essentially of —NR 222 R 223 ; —NH(C 6 -C 10 ) aryl; (C 1 -C 6 ) alkoxy; and (C 6 -C 10 ) aryloxy;  
 R 236  is a member independently selected from the group consisting essentially of H; (C 1 -C 6 ) alkyl and —(CH 2 ) m Y 4 (phenyl) where m is an integer selected from 0, 1, 2, 3, and 4 and the phenyl moiety of said —(CH 2 ) m Y 4 (phenyl)R 236  group is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; —OR 222 ; (C 1 -C 6 ) alkanoyloxy; (C 6 -C 10 ) aryloxy; —NR 222 R 223 ; —NH(C 6 -C 10 ) aryl; and —NHC(═O)(C 1 -C 4 ) alkyl;  
 each R 237  is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; —(CH 2 ) p NR 222 C(═O)CH 3  where p is an integer selected from 1, 2, 3, 4, and; (C 1 -C 4 ) alkoxy; nitro; cyano; —NR 222 R 223 ; —CO 2 R 222 ; —OR 222 ; —C(Y 1 )NR 222 R 223 ; —NR 222 C(NCN)S(C 1 -C 3 ) alkyl; —NR 222 C(NCN)NR 222 R 223 ; —NR 222 C(═O)NR 222 R 223 ; —NR 222 C(═O)C(═O)NR 222 R 223 ; —C(═NR 222 )NR 222 R 223 ; —S(O) m CH 3  where m is an integer selected from 0, 1, and 2; —C(═NR 222 )S(C 1 -C 3 ) alkyl; —NR 222 SO 2 (C 1 -C 3 ) alkyl; —OC(═O)R 222 ; —OC(═O)NR 222 R 223 ; —NR 222 SO 2 CF 3 ; —NR 222 C(═O)C(═O)OR 222 ; —NR 222 C(═O)R 222 ; —NR 222 C(═O)OR 222 ; imidazolyl; thiazolyl; oxazolyl; pyrazolyl; triazolyl; and tetrazolyl;  
 R 238  is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C 1 -C 2 ) alkyl, where said alkyl is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; —C(═O)NR 222 R 223 ; and —C(═O)OR 222 ;  
 R 239  is a member independently selected from the group consisting essentially of phenyl substituted by 0 to 2 substituents independently selected from —NR 222 R 223 , nitro, halo, —OR 222 , —NHR 240 , —NR 240 R 241 , and —C(═O)OR 222 ;  
 each R 240  and R 241  is a member independently selected from the group consisting essentially of (C 1 -C 8 ) alkyl and (C 2 -C 8 ) alkenyl;  
 R 242  is pyridin-4-yl substituted by 0 to 2 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; and (C 1 -C 4 ) alkyl;  
 each A is a member independently selected from the group consisting essentially of (C 1 -C 6 ) alkyl; pyridyl; morpholinyl; piperidinyl; imidazolyl; thienyl; pyrimidyl; thiazolyl; triazolyl; quinolinyl; phenyl; and naphthyl; wherein the foregoing A groups are substituted with 0 to 3 substituents R 237 ; or A is —(CH 2 ) q S(C 1 -C 4 ) alkyl wherein q is an integer selected from 1 and 2;  
 W is a member independently selected from the group consisting essentially of O; NOH; NNH 2 ; NOC(═O)CH 3 ; and NNHC(═O)CH 3 ;  
 Y 1  is O or S;  
 Y 2  is O, NOH or H 2 ;  
 Y 3  is a bond or —CH═CH—;  
 Y 4  is a bond, O, S, or —NH—;  
 Y 5  is a member independently selected from the group consisting essentially of O; NR 222 ; NOR 222 ; NCN; C(CN) 2 ; CR 222 NO 2 ; CR 222 C(═O)OR 222 ; CR 222 C(═O)NR 222 R 223 ; C(CN)NO 2 ; C(CN)C(═O)OR 222 ; and C(CN)C(═O)NR 222 R 223 ; and  
 Z 3  is a member independently selected from the group consisting essentially of —NR 222 —; —(CH 2 ) m —; —CH 2 C(═O)NH—; —NHCH 2 C(═O)—; —CH 2 C(Y 1 )CH 2 —; —CH═CH—; —C≡C—; —CH(Y 1 H)—; —C(Y 1 )—; —CH 2 C(Y 1 )—; —C(Y 1 )CH 2 —; —C(Y 1 )C(Y 1 )—; —CH 2 NR 222 —; —CH 2 -Y 1 —; —C(Y 1 )NR 218 (CHR 222 ) n —; —NR 218 C(Y 1 )(CHR 222 ) n —; —NHCH 2 —; —Y 1 —CH 2 —; —SOCH 2 —; —CH 2 SO—; —SO 2 CH 2 —; —CH 2 SO 2 —; —OC(Y 1 )—; —N═N—; —NHSO 2 —; —SO 2 NH—; —C(Y 1 )C(Y 1 )NH—; —NHC(═O)O—; —OC(═O)NH—; and —NHC(═O)NH—; wherein for said Z 3  moieties n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 1, 2, and 3; 
 —OR said substituents defining R 2   a  and R 2   b  comprise:— 
 (-III-)  
 
 a member independently selected from the group consisting essentially of 2-oxo-4-pyrrolyl; pyrazolyl; 2-oxo-3,4-dihydro-5-pyrimidyl; 2-oxo-3,4-dihydro-4-pyrimidyl; 2-oxo-tetrahydro-pyrimidyl; 2-oxo-tetrahyro-5-pyrimidyl; 2-oxo-4-pyrimidyl; and 2-oxo-5-pyrimidyl; wherein each of said R 2   a  and R 2   b  groups is substituted by 0, 1, 2, 3, or 4 R 236  groups;  
                                                         
 wherein, in said partial Formulas (IIIA)-(IIIT), q is an integer selected from 0 and 1 in partial Formula (IIIB); n is an integer selected from 0, 1, and 2 in partial Formula (IIIC); and the dashed lines appearing in formulas (IIIB), (IIID), (IIG), (IIIH), (III), (IIIJ) and (IIIO) represent a double bond or a single bond;  
 X 1  is O or S;  
 X 2 , in formula (IIIK) and where the dashed line in formula (IIIJ) represents a double bond, is a member independently selected from the group consisting essentially of CR 335 ; CR 336 ; CR 346 ; and COC(═O)NR 339 R 342 ; or, where the dashed line in formula (IIIJ) represents a single bond, X 2  is a member independently selected from the group consisting essentially of CR 335 R 339 ; CR 336 R 339 ; and CR 346 R 339 ;  
 X 3  is a member independently selected from the group consisting essentially of C(═Z 3 ); C(S); and CR 336 R 340 ;  
 X 4  is a member independently selected from the group consisting essentially of —(CH 2 ) m — where m is an integer selected from 0, 1, and 2;  
 X 5  is a bond or —CH 2 —;  
 X 6  is a member independently selected from the group consisting essentially of —CH 2 — and —C(═O)—;  
 R 333  is a member independently selected from the group consisting essentially of H; hydroxy; (C 1 -C 4 ) alkoxy; CHR 337 (O) q (CH 2 ) m A where q is an integer selected from 0 and 1, and m is an integer selected from 0, 1, and 2;  
 R 334  is a member independently selected from the group consisting essentially of H; hydroxy; (C 1 -C 4 ) alkyl; (C 1 -C 2 ) alkoxy; —OC(═O)CH 3 ; (C 2 -C 3 ) alkenyl; and phenyl(C 1 -C 2 ) alkyl-;  
 R 335  is a member independently selected from the group consisting essentially of H; hydroxy; —(CH 2 ) m A where m is an integer selected from 0, 1, and 2; (C 1 -C 6 ) alkyl; and (C 2 -C 3 ) alkanoyl; where said alkyl group is substituted by 0 to 3 subtituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; —NR 340 R 341 ; —CO 2 R 340 ; —OR 340 ; —OC(═O)R 340 ; —C(═O)R 340 ; cyano; —C(═Y)NR 340 R 341 ; —NR 340 C(═Y)NR 340 R 341 , —NR 340 C(═Y)R 340 ; —NR 340 C(═O)OR 340 ; —C(NR 340 )NR 340 R 341 ; —C(NCN)NR 340 R 341 ; —C(NCN)SR 340 ; —NR 340 SO 2 R 340 ; —S(O) m R 340 , where m is an integer selected from 0, 1, and 2; —NR 340 SO 2 CF 3 ; —NR 340 C(═O)C(═O)NR 340 R 341 ; —NR 340 C(═O)C(═O)OR 340 ; imidazolyl; and 1-(NHR 340 )-2-imidazolyl;  
 each R 336  is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; R 343 ; cyclopropyl substituted by 0 or 1 substituent independently selected from the group consisting essentially of R 339 ; —OR 340 ; —CH 2 OR 340 ; —NR 340 R 342 ; —CH 2 NR 340 R 342 ; —C(═O)OR 340 ; —C(═O)NR 340 R 342 ; —CH═CR 339 R 339 ; —C≡CR 339 ; and —C(═Z 3 )H;  
 R 337  is a member independently selected from the group consisting essentially of H; —C(═O)R 338 ; imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl;  
 each R 338  is a member independently selected from the group consisting essentially of —OR 340 ; —NR 340 R 342 ; and —R 343 ;  
 each R 339  is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; and (C 1 -C 4 ) alkyl substituted by 0 to 3 fluorine atoms;  
 each R 340  and R 341  is a member independently selected from the group consisting essentially of hydrogen and (C 1 -C 4 ) alkyl;  
 each R 342  is a member independently selected from the group consisting essentially of —OR 340  and —R 340 ;  
 R 343  is (C 1 -C 4 ) alkyl;  
 each R 344  is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; —NR 340 R 346 ; —NR 346 R 342 ; —C(═Z 3 )R 338 ; —S(O) m R 343  where m is an integer selected from 0, 1, and 2; —OR 342 ; —OC(═O)NR 340 R 342 ; —C(NR 342 )NR 340 R 342 ; —C(NR 340 )SR 343 , —OC(═O)CH 3 ; —C(NCN)NR 340 R 342 ; —C(S)NR 340 R 342 ; —NR 342 C(═O)R 347 ; —C(═O)R 347 ; oxazolyl; imidazolyl; thiazolyl; pyrazolyl; triazolyl; and tetrazolyl;  
 each R 345  is a member independently selected from the group consisting essentially of hydrogen and (C 1 -C 4 ) alkyl substituted by 01 to 3 fluorine atoms;  
 each R 346  is a member independently selected from the group consisting essentially of H; —R 343 ; —C(═O)R 343 ; —C(═O)C(═O)R 338 ; —C(═O)NR 340 R 342 ; —S(O) m R 343  where m is an integer selected from 0, 1, and 2; —C(NCN)SR 343 ; —C(NCN)R 343 ; —C(NR 342 )R 343 ; —C(NR 342 )SR 343 ; and —C(NCN)NR 340 R 342 ;  
 each R 347  is a member independently selected from the group consisting essentially of —R 343 ; —C(═O)R 343 ; oxazolidinyl; oxazolyl; thiazolyl; pyrazolyl; triazolyl; tetrazolyl; imidazolyl; imidazolidinyl; thiazolidinyl; isoxazolyl; oxadiazolyl; thiadiazolyl; morpholinyl; piperidinyl; piperazinyl; and pyrrolyl; where each of said recited R 347  heterocyclic groups is substituted by 0 to 2 (C 1 -C 2 ) alkyl groups;  
 R 348  is a member independently selected from the group consisting essentially of H; (C 1 -C 5 ) alkyl; (C 2 -C 5 ) alkenyl; benzyl; and phenethyl;  
 R 349  is a member independently selected from the group consisting essentially of H; (C 1 -C 5 ) alkyl; (C 1 -C 5 ) alkanoyl; and benzoyl;  
 R 350  is a member independently selected from the group consisting essentially of H; (C 1 -C 4 ) alkyl; carboxy; aminocarbonyl; (C 1 -C 6 ) alkyl substituted by 0 or 1 carboxy, —(CH 2 ) m C(═O)(C 1 -C 6 ) alkoxy; or —(CH 2 ) m (C 6 -C 10 ) aryl; where m is an integer selected from 0, 1, and 2;  
 R 351  is a member independently selected from the group consisting essentially of H; (C 1 -C 6 ) alkyl; —C(═Y)R 352 ; —C(═Y)NH35; —C(═O)OR 352 ; and —(CH 2 ) n X 7 (pyridyl) where n is an integer selected from 0, 1, 2, 3, 4, and to 5; and X 7  is a bond or —CH═CH—; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;  
 R 352  is a member independently selected from the group consisting essentially of (C 1 -C 6 ) alkyl (C 3 -C 8 ) cycloalkyl; —(CH 2 ) m (C 6 -C 10 ) aryl; and —(CH 2 ) n X 7 (pyridyl) where n is an integer selected from 0, 1, 2, 3, 4, and 5; and X 7  is a bond or —CH═CH—; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;  
 R 353  is a member independently selected from the group consisting essentially of H; —R 345 ; (C 1 -C 3 ) alkyl substituted by 0 or 1 substituent hydroxy, or (C 1 -C 3 ) alkyoxy(C 1 -C 3 ) alkyl;  
 R 354  is a member independently selected from the group consisting essentially of H; —R 345 ; carboxy; (C 1 -C 3 ) alkyoxy(C 1 -C 3 ) alkyl-; (C 3 -C 7 ) cycloalkyl; and (C 1 -C 5 ) alkyl substituted by 0 or 1 —NR 340 R 341 ;  
 or R 353  and R 354  are taken together to form —CH 2 OCH 2 OCH 2 —;  
 R 355  is a member independently selected from the group consisting essentially of H; hydroxy; (C 1 -C 4 ) alkyl substituted by 0 or 1 substituent comprising a member independently selected from the group consisting essentially of hydroxy; —C(═O)R 340 ; —NR 340 R 341 ; —(CH 2 ) m NHC(═O)R 340 ; —(CH 2 ) m NHC(═O)R 343 ; —(CH 2 ) m CO 2 R 340 , —(CH 2 ) m C(═O)NR 340 R 341 ; —(CH 2 ) m C(═O)N(OH)R 340 ; —(CH 2 ) m SO 2 NR 340 R 341 ; —(CH 2 ) m PO 3 H 2 ; —(CH 2 ) m SO 2 NHC(═O)R 343 ; and —(CH 2 ) m SO 2 NHC(═O)(phenyl), where m is an integer selected from 0, 1, 2, 3, and 4;  
 R 356  is a member independently selected from the group consisting essentially of H; (C 1 -C 4 ) alkyl; phenyl; —NR 340 R 341 ; and —NR 340 (C 1 -C 4 ) alkanoyl;  
 R 357  is a member independently selected from the group consisting essentially of —R 340 ; —CH 2 CO 2 R 343 ; and —CH 2 C(═O)NR 340 R 341 ;  
 R 358  is a member independently selected from the group consisting essentially of —C(═O)R 340 ; —C(═O)(C 6 -C 10 ) aryl; —C(═O)(C 3 -C 9 ) heteroaryl; —CO 2 R 340 ; —C(═O)NR 340 R 341 ; cyano; nitro; —CH 2 OH; —NR 340 SO 2 R 340 ; —NHSO 2 (C 6 -C 10 ) aryl; —NHCO 2 (C 1 -C 4 ) alkyl; —NR 340 C(═O)R 340 ; and —NHCO 2 (C 6 -C 10 ) aryl;  
 R 359  is a member independently selected from the group consisting essentially of —R 345 ; cyano; carboxy; formyl; —C(═O)R 340 ; and (C 1 -C 4 ) alkanoyl;  
 R 360  is a member independently selected from the group consisting essentially of cyano; —NR 340 R 341 ; —SO 2 (C 1 -C 4 ) alkyl; —SO 2 (C 6 -C 10 ) aryl; —C(═O)R 340 ; —C(═O)(C 6 -C 10 ) aryl; —C(═O)(C 3 -C 9 ) heteroaryl; —C(═O)NR 340 R 341 ; and —CO 2 R 340 ;  
 R 361  and R 362  is each a member independently selected from the group consisting essentially of H; cyano; nitro; —CO 2 R 340 ; —C(═O)NR 340 R 341 ; —CH 2 OH; —C(═O)R 340 ; —NHCO 2 R 340 ; and —NHSO 2 R 340 ;  
 A is a member independently selected from the group consisting essentially of pyridyl; morpholinyl; piperidinyl; imidazolyl; thienyl; pyrimidyl; thiazolyl; phenyl; and naphthyl; where each of said A groups is substituted by 0 to 2 substituents R 344  or by 1 substituent R 345 ;  
 Z 3  is a member independently selected from the group consisting essentially of O; —NR 342 ; NOR 340 ; N(CN); C(CN) 2 ; CR 340 NO 2 ; CR 340 C(═O)OR 343 ; CR 340 C(═O)NR 340 R 341 ; C(CN)NO 2 ; C(CN)C(═O)OR 343 ; and C(CN)C(═O)NR 340 R 341 ; and,  
 Y is O or S; 
 —OR said substituents defining R 2   a  and R 2   b  comprise a moiety of partial Formula (IV):— 
 (-IV-)  
                     
 
 wherein  
 the broken line indicates a single or double bond;  
 X 1  is —CR 472 R 473 — where said broken line indicates a single bond; or —CR 473 — where said broken line indicates a double bond;  
 X 2  is —CR 475 R 477 R 478 — or —C(═NOR 481 )R 482 — where said broken line indicates a single bond; or —CR 477 R 478  where said broken line indicates a double bond;  
 R 472  is a member independently selected from the group consisting essentially of H; hydroxy; bromo, chloro, or fluoro; and —OR 479 ;  
 each R 473  is a member independently selected from the group consisting essentially of cyano; cyanomethyl; benzyloxy; —R 475 ; —CO 2 R 475 ; —CO 2 (CH 2 ) n (C 6 -C 10 ) aryl; —C(Y)NR 475 R 476 ; —C(Y)NR 475 (CH 2 ) n (C 6 -C 10 ) aryl; —(CH 2 ) n (C 6 -C 10 ) aryl; and —(CH 2 ) n (5- to 10-membered heteroaryl); where n is an integer selected from 0, 1, 2, and 3; each R 473  group is substituted by 0 to 3 substituents R 474 ; and each R 473  group is substituted by 0 or 1 substituent R 480 ;  
 each R 474  is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; cyano; nitro; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; —OR 475 ; (C 3 -C 7 ) cycloalkoxy; —NR 475 R 476 ; —NR 475 OR 476 ; —S(O) m R 475  where m is an integer selected from 0, 1, and 2; —CO 2 R 475 , —C(═O)R 475 ; —SO 2 NR 475 R 476 ; —C(═O)NR 475 R 476 ; —CR 475 R 476 SO 2 NR 475 R 476 ; —CR 475 R 476 C(═O)NR 475 R 476 ; —NHSO 2 R 145 ; —NHSO 2 NR 475 R 476 ; —NHC(═O)NR 475 R 476 ; —NHC(═O)(C 1 -C 6 ) alkyl; and —NHC(═O)O(C 1 -C 6 ) alkyl);  
 each R 475  and R 476  is a member independently selected from the group consisting essentially of H; and (C 1 -C 6 ) alkyl;  
 R 477  is a member independently selected from the group consisting essentially of —R 473 ; 2-oxo-pyridyl; 3-oxo-pyridyl; 4-oxo-pyridyl; 2-oxo-pyrrolyl; 4-oxo-thiazolyl; 4-oxo-piperidyl; 2-oxo-quinolyl; 4-oxo-quinolyl; 1-oxo-isoquinolyl; 4-oxo-oxazolyl; 5-oxo-pyrazolyl; 5-oxo-isoxazolyl; and 4-oxo-isoxazolyl; where each of said R 477  groups is substituted by 0 to 3 substituents R 474 ;  
 R 478  is a member independently selected from the group consisting essentially of —R 475 ; cyano, —(CH 2 ) p (C 6 -C 10 ) aryl; and —(CH 2 ) p (5- to 10-membered heteroaryl); where p is an integer selected from 1, 2, and 3; and where each said R 478  group is substituted by 0 to 3 substituents R 474 ;  
 R 479  is a member independently selected from the group consisting essentially of formyl; carbamoyl; thiocarbamyl; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 1 -C 4 ) alkoxy(C 1 -C 4 ) alkyl-; and (C 1 -C 6 ) alkanoyl; where said alkyl moieties of each of said R 479  groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; and (C 1 -C 4 ) alkoxy;  
 R 480  is a member independently selected from the group consisting essentially of cyclobutyl; cyclopentyl; cyclohexyl; 2-cyclobuten-1-yl; 2-cyclopenten-1-yl; 3-cyclopenten-1-yl; 2,4-cyclopentadien-1-yl; 3,5-cyclohexadien-1-yl; pyrrolyl; pyrrolidinyl; dioxolanyl; imidazolyl; oxazolyl; imidazolidinyl; pyrazolyl; pyrazolidinyl; pyranyl; piperidinyl; 1,4-dioxanyl; morpholinyl; 1,4-dithianyl; thiomorpholinyl; piperazinyl; 1,3,5-trithianyl; oxazinyl; isoxazinyl; oxathiazinyl; and oxadiazinyl; where each of said R 480  groups is substituted by 0 to 2 (C 1 -C 2 ) alkyl;  
 R 481  is a member independently selected from the group consisting essentially of H; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; —C(Y)NR 475 R 476 ; —C(Y)NH(C 6 -C 10 ) aryl; —C(Y)(C 1 -C 6 ) alkoxy; —C(Y)(C 6 -C 10 ) aryloxy; and —C(Y)(C 1 -C 6 ) alkyl);  
 R 482  is a member independently selected from the group consisting essentially of phenyl and pyridinyl; where each of said R 482  groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C 1 -C 4 ) alkyl; hydroxy; (C 1 -C 4 ) alkoxy; —NR 475 R 476 ; and —S(O) m R 475 , where m is an integer selected from 0, 1, and 2; and,  
 Y is O or S; 
 —OR, said substituents defining R 2   a  and R 2   b  comprise a moiety of partial Formulas (VA) through (VM), inclusive:— 
                                       
 
 
     
     
         3 . A therapeutically active composition of matter according to  claim 2  wherein for said compounds of Formula (IA) or (IB), R 2   a  and R 2   b  are as defined under (-IV-); R 1  is ethyl; and R is a member independently selected from the group consisting essentially of cyclopentyl; cyclohexyl; and (C 6 -C 10 ) aryl.  
     
     
         4 . A therapeutically active composition of matter according to  claim 2  wherein for said compounds of Formula (IA) or (IB), R 2   a  and R 2   b  are as defined under (-IV-); and R 473  is —(CH 2 ) n (C 6 -C 10 ) aryl or —(CH 2 ) n (5- to 10-membered heteroaryl), where n is an integer selected from 0, 1, 2, and 3.  
     
     
         5 . A therapeutically active composition of matter according to  claim 4  wherein R 473  is phenyl or pyridin-4-yl.  
     
     
         6 . A therapeutically active composition of matter according to  claim 2  wherein for said compounds of Formula (IA) or (IB), R 2   a  and R 2   b  are as defined under (-I-).  
     
     
         7 . A therapeutically active composition of matter according to  claim 6  wherein R is phenyl substituted by fluoro; R 1  is (C 1 -C 2 ) alkyl; one of R 2   a  and R 2   b  is hydrogen and the other is a substituent of Formula (IC) where the dashed line represents a single bond, R 113  is cyano, and R 115  and R 114  are both hydrogen.  
     
     
         8 . A therapeutically active composition of matter according to  claim 7  wherein R 1  is ethyl.  
     
     
         9 . A therapeutically active composition of matter according to  claim 6  wherein R is a member independently selected from the group consisting essentially of cyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl, phenyl, and 4-fluoro-phenyl.  
     
     
         10 . A therapeutically active composition of matter according to  claim 6  wherein one of R 2   a  and R 2   b  is hydrogen and the other is a group of partial Formula (IC) wherein the dashed line attached to the ring carbon atom to which R 113  is attached represents a single bond; and R 113  and R 114  are cis with respect to each other.  
     
     
         11 . A therapeutically active composition of matter according to  claim 10  wherein R 113  is cyano.  
     
     
         12 . A therapeutically active composition of matter according to  claim 11  wherein m is 0; R 115  is hydrogen; and R 114  is a member independently selected from the group consisting essentially of —OH; —CH 2 OH; —C(CH 3 ) 2 OH; —C(═O)OH; —C(═O)OCH 3 ; —C(═O)OCH 2 CH 3 ; and —CH 2 C(═O)NH 2 .  
     
     
         13 . A therapeutically active composition of matter according to  claim 12  wherein R is a member independently selected from the group consisting essentially of cyclobutyl, cyclopentyl, cyclohexyl, and 4-fluoro-phenyl; R 1  is ethyl; and R 114  is —C(═O)OH.  
     
     
         14 . A therapeutically active composition of matter according to  claim 6  wherein said compound of Formula (IA) or (IB) as defined under (-I-) is a member independently selected from the group consisting essentially of: 
 1(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;  
 Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;  
 Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;  
 Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;  
 Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;  
 Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;  
 Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxymethylcyclohexanecarbonitrile;  
 Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid amide;  
 Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid amide;  
 Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-(1-hydroxy-1-methylethyl)cyclohexanecarbonitrile;  
 Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;  
 Cis-1-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile;  
 Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;  
 Cis-1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;  
 Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;  
 Trans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;  
 Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 Trans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;  
 6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole;  
 4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarboxylic acid ethyl ester;  
 4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid ethyl ester;  
 4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester;  
 4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid ethyl ester;  
 Cis-4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid;  
 4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid; and  
 4-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarboxylic acid.  
 
     
     
         15 . A therapeutically active composition of matter according to  claim 2  wherein said diseases and conditions which may be treated or prevented comprise inflammatory diseases and conditions and respiratory diseases and conditions.  
     
     
         16 . A therapeutically active composition of matter according to  claim 15  wherein said inflammatory diseases and conditions comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, Crohn's disease, and inflammatory bowel disease; and wherein said respiratory diseases and conditions comprise: chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema.  
     
     
         17 . A therapeutically active composition of matter according to  claim 16  wherein said respiratory disease or condition comprises asthma.  
     
     
         18 . A pharmaceutical composition for inhibition of PDE4 or production of TNF in a mammal in need of such treatment comprising a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.  
     
     
         19 . A pharmaceutical composition comprising a therapeutically active composition of matter according to  claim 1  and a pharmaceutically acceptable carrier therefor.  
     
     
         20 . A pharmaceutical composition according to  claim 19  wherein said therapeutically active composition of matter is a compound according to  claim 2 .  
     
     
         21 . A method of treating or preventing a disease or condition in a mammal in need of such treatment wherein said disease or condition responds favorably to inhibition of PDE4 or production of TNF and is a member selected from the group consisting essentially of joint inflammation; rheumatoid arthritis; gouty arthritis; rheumatoid spondylitis; osteoarthritis; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; acute respiratory distress syndrome; cerebal malaria; chronic pulmonary obstructive disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema; silicosis; pulmonary sarcoidosis; bone resorption diseases; reperfusion injury; graft vs. host reaction; allograft rejections; fever and myalgias due to bacterial, viral or fungal infection including influenza; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS); AIDS; HIV infection; ARC (AIDS related complex); keloid formation; scar tissue formation; Crohn's disease; ulcerative colitis; pyresis; multiple sclerosis; type 1 diabetes mellitus; autoimmune diabetes; systemic lupus erythematosis; bronchitis; chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis and pulmonary emphysema; psoriasis; Bechet's disease; anaphylactoid purpura nephritis; chronic glomerulonephritis; inflammatory bowel disease; leukemia; allergic rhinitis; and dermatitis, comprising administering to said mammal a therapeutically effective amount of a compound according to  claim 1 , optionally together with a pharmaceutically acceptable carrier therfor.  
     
     
         22 . A method of treating or preventing a disease or condition according to  claim 21  comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 2.