Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors

Abstract

This invention relates to the use of a group of aryl ureas in treating p38 mediated diseases, and pharmaceutical compositions for use in such therapy.

What is claimed is:  
     
         1 . A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: 
       A-D-B  (I) 
       or a pharmaceutically acceptable salt thereof, wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and  
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y ) R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N( 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen; and  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 , with R 7  as defined above.  
 
     
     
         2 . A method as in  claim 1  for the treatment of a cancerous cell growth mediated by p38 kinase.  
     
     
         3 . A method as in  claim 1  for the treatment of a disease other than cancer.  
     
     
         4 . A method as in  claim 1  wherein the condition within a host treated by administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system.  
     
     
         5 . A method as in  claim 1  wherein the condition within a host treated by administering a compound of formula I is rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria ( Plasmodium falciparum  malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement.  
     
     
         6 . A method as in  claim 1  wherein the condition within a host treated by administering a compound of formula I is an an infectious disease selected from the group consisting of tuberculosis,  Helicobacter pylori  infection during peptic ulcer disease, Chaga's disease resulting from  Trypanosoma cruzi  infection, effects of Shiga-like toxin resulting from  E. coli  infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from  Borrelia burgdorferi, Treponema pallidum,  cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).  
     
     
         7 . A method as in  claim 1  wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7 is as defined in  claim 1 .  
     
     
         8 . A method as in  claim 7 , wherein said substituted cyclic moiety L 1  is phenyl, pyridyl or pyrimidinyl.  
     
     
         9 . A method of  claim 1  wherein L 1  is substituted by —C(O)R x  or —SO 2 R x , wherein R x  is NR a R b .  
     
     
         10 . A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: 
       A-D-B  (I) 
       or a pharmaceutically acceptable salt thereof, wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and  
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y ) R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen;  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 ; and  
 wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m , —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is as defined above.  
 
     
     
         11 . A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: 
       A-D-B   (I) 
       or a pharmaceutically acceptable salt thereof, wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a substituted or unsubstituted phenyl or pyridine moiety bound directly to D, L 1  comprises a substituted phenyl, pyridine or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and  
 B is a substituted or unsubstituted phenyl or pyridine group bound directly to D,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y ) R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen;  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 ; with R 7  is as defined above; and  
 wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m , —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is as defined above.  
 
     
     
         12 . A method for the treatment of a disease mediated by p38 kinase other than cancer which comprises administering a compound selected from the group consisting of the 3-tert butyl phenyl ureas: 
 N-(3-tert-butylphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and    N-(3-tert-butylphenyl)-N′-(4-(4-acetylphenoxy)phenyl urea;    the 5-tert-butyl-2-methoxyphenyl ureas:    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea,    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1-oxoisoindolin-5-yloxy)phenyl) urea,    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl) urea and    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea;    the 2-methoxy-5-trifluoromethyl)phenyl ureas:    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;    the 4-chloro-3-(trifluoromethyl)phenyl ureas:    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea;    the 4-bromo-3-(trifluoromethyl)phenyl ureas:    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea; and    the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea.    
     
     
         13 . A pharmaceutical composition for the treatment of a disease within a host mediated by p38 comprising a compound of Formula I, 
       A-D-B  (I) 
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat a disease mediated by p38 and a physiologically acceptable carrier:  
       wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and  
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y )R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen; and  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 , with R 7  as defined above.  
 
     
     
         14 . A pharmaceutical composition as in  claim 13  wherein: 
 R y  is hydrogen, C 1-10  alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatoms, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24  aralkyl, C 7-24  alkaryl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 3-10  cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14  aryl, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24  alkaryl or substituted C 7 -C 24  aralkyl, where R y  is a substituted group, it is substituted by halogen up to per halo,  
 R z  is hydrogen, C 1-10  alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatom, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3 -C 12  hetaryl having 1-3 heteroatoms selected from, S, N and O, C 7-24  alkaryl, C 7-24  aralkyl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 6 -C 14  aryl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from S, N and O, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from N, O and S, substituted C 7-24  alkaryl or substituted C 7 -C 24  aralkyl where R z  is a substituted group, it is substituted by halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C 3 -C 12  hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from N, S and O, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g ,  
 R a  and R b  are, 
 a) independently hydrogen, 
 a carbon based moiety selected from the group consisting of C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3-10  cycloalkyl, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3-12  hetaryl having 1-3 heteroatoms selected from O, N and S, C 3-12  cycloalkyl having 0-3 heteroatoms selected from N, S and O, C 7-24  aralkyl, C 7 -C 24  alkaryl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 3-10  cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C 6-12  aryl, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24  aralkyl, substituted C 7-24  alkaryl, where R a  and R b  are a substituted group, they are substituted by halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteraryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g ; or  
 —OSi(R f ) 3  where R f  is hydrogen, C 1-10  alkyl, C 1  alkoxy, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 6-12  aryl, C 3 -C 12  hetaryl having 1-3 heteroatoms selected from O, S and N, C 7-24  aralkyl, substituted C 1-10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 3 -C 12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C 3 -C 12  heteraryl having 1-3 heteroatoms selected from O, S, and N, substituted C 6-12  aryl, and substituted C 7-24  alkaryl, where R f  is a substituted group it is substituted halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteraryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, halo substituted C 1-6  alkyl up to per halo alkyl, halo substituted C 6 -C 12  aryl up to per halo aryl, halo substituted C 3 -C 12  cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteraryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteraryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g ,  
 
 where R g  is C 1-10  alkyl; —CN, —CO 2 R d , —OR d , —SR d , —NO 2 , —C(O)R e , —NR d R e , —NR d  C(O)OR e  and —NR d  C(O)R e , and R d  and R e  are independently selected from the group consisting of hydrogen, C 1-10 , alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6-12  aryl, C 3 -C 12  hetaryl with 1-3 heteroatoms selected from O, N and S and C 7 -C 24  aralkyl, C 7 -C 24  alkaryl, up to per halo substituted C 1 -C 10  alkyl, up to per halo substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C 6 -C 14  aryl, up to per halo substituted C 3 -C 12  hetaryl having 1-3 heteroatoms selected from  0 , N, and S, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and up to per halo substituted C 7 -C 24  aralkyl,  
 W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 6 -C 14  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 3 -C 12  heteroaryl having 1-3 heteroatoms selected from O, N and S, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C 1 -C 10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 2 -C 20  alkenyl, substituted C 1 -C 10  alkenoyl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C 6 -C 12  aryl, substituted C 3 -C 12  hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C 7 -C 24  aralkyl, substituted C 7 -C 24  alkaryl, substituted C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and —Q—Ar;  
 R 7  is independently selected from H, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6 -C 14  aryl, C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, C 7 -C 14  alkaryl, C 7 -C 24  aralkyl, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 1 -C 10  alkyl, up to per-halosubstituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 6 -C 14  aryl, up to per-halosubstituted C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 7 -C 24  aralkyl, up to per-halosubstituted C 7 -C 24  alkaryl, and up to per-halosubstituted C 4 -C 23  alkheteroaryl; and  
 each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6 -C 14  aryl, C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C 1 -C 10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 2 -C 10  alkenyl, substituted C 1 -C 10  alkenoyl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C 6 -C 12  aryl, substituted C 7 -C 24  alkaryl, substituted C 7 -C 24  aralkyl and substituted C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 .  
 
     
     
         15 . A pharmaceutical composition as in  claim 13  wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7 is as defined in  claim 13 .  
     
     
         16 . A pharmaceutical composition as in  claim 13  wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by —OH.  
     
     
         17 . A pharmaceutical composition as in  claim 13  wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.  
     
     
         18 . A pharmaceutical composition as in  claim 13  wherein B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulphur with the balance of the hetaryl moiety being carbon.  
     
     
         19 . A pharmaceutical composition as in  claim 13  wherein B of Formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl group, a phenyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in  claim 13 , a pyrimidinyl group substituted by a substituted selected from halogen and Wn, wherein W and n are as defined in  claim 13 , or a pyridyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in  claim 13 .  
     
     
         20 . A pharmaceutical composition as in  claim 13 , wherein L, the six member cyclic structure bound directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulphur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wn, wherein W and n are as defined in  claim 13 .  
     
     
         21 . A pharmaceutical composition as in  claim 13 , wherein L, the 6 member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyridyl, unsubstituted pyridyl group, unsubstituted pryimidinyl or substituted prymidinyl.  
     
     
         22 . A pharmaceutical composition as in  claim 13 , wherein said substituted cyclic moiety L 1  comprises a 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulphur.  
     
     
         23 . A pharmaceutical composition as in  claim 13 , wherein said substituted cyclic moiety L 1  is phenyl, pyridyl or pyrimidinyl and M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to pre halo.  
     
     
         24 . A pharmaceutical composition as in  claim 13  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy.  
     
     
         25 . A pharmaceutical composition as in  claim 13  wherein L 1  is substituted by —C(O)R x .  
     
     
         26 . A pharmaceutical composition as in  claim 13  wherein L 1  is substituted by —C(O)R x  or —SO 2 R x , wherein R x  is NR a R b .  
     
     
         27 . A pharmaceutical composition for the treatment of a disease within a host mediated by p38 comprising a compound of Formula I: 
       A-D-B  (I) 
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat a disease mediated by p38 and a physiologically acceptable carrier, wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and  
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y )R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen;  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents are selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7  with R 7  as defined above; and  
 wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, (CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is as defined above.  
 
     
     
         28 . A pharmaceutical composition for the treatment of a disease within a host mediated by p38 comprising a compound of Formula I: 
       A-D-B  (I) 
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat a disease mediated by p38 and a physiologically acceptable carrier, wherein 
 D is —NH—C(O)—NH—,  
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a substituted or unsubstituted phenyl or pyridyl moiety bound directly to D, L 1  comprises a substituted phenyl, pyridyl or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and  
 B is a substituted or unsubstituted phenyl or pyridine group bound directly to D,  
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y ) R z ,  
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and;  
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen, 
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or  
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;  
 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;  
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,  
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, (CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen;  
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7  with R 7  as defined above; and  
 wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, (CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is as defined above.  
 
     
     
         29 . A pharmaceutical composition as in  claim 27  wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.  
     
     
         30 . A pharmaceutical composition as in  claim 27 , wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.  
     
     
         31 . A pharmaceutical composition as in  claim 28 , wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.  
     
     
         32 . A pharmaceutical composition as in  claim 28  wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.  
     
     
         33 . A pharmaceutical composition as in  claim 27  wherein L 1  is substituted by C(O)R x  or SO 2 R x , wherein R x  is NR a R b .  
     
     
         34 . A pharmaceutical composition as in  claim 28  wherein L 1  is substituted by C(O)R x  or SO 2 R x , wherein R x  is NR a R b .  
     
     
         35 . A pharmaceutical composition as in  claim 13  which comprises a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of 
 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and  
 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.  
 
     
     
         36 . A pharmaceutical composition as in  claim 27  which comprises a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of 
 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and  
 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.  
 
     
     
         37 . A pharmaceutical composition as in  claim 28  which comprises a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of 
 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and  
 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.  
 
     
     
         38 . A pharmaceutical composition for the treatment of a disease within a host mediated by p38 comprising a compound selected from the group consisting of the 3-tert butyl phenyl ureas: 
 N-(3-tert-butylphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and    N-(3-tert-butylphenyl)-N′-(4-(4-acetylphenoxy)phenyl urea;    the 5-tert-butyl-2-methoxyphenyl ureas:    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea,    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1-oxoisoindolin-5-yloxy)phenyl) urea,    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl) urea and    N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea;    the 2-methoxy-5-trifluoromethyl)phenyl ureas:    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea,    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;    the 4-chloro-3-(trifluoromethyl)phenyl ureas:    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea,    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)4-pyridyloxy)phenyl) urea,    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl4-pyridyloxy)phenyl) urea and    N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea; ps the 4-bromo-3-(trifluoromethyl)phenyl ureas:    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea,    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea; and    the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and    N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, or a pharmaceutically acceptable salt thereof.