Urea derivatives as integrin a4 antagonists

Abstract

Novel antagonists of α4β1 integrin and/or α4β7 integrin are described in this application.

1 - 23 . (canceled)  
   
   
       24 . A pharmaceutical composition comprising an effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier  
     
       
         
         
             
             
         
       
       wherein:  
       A represents a —CH— group or a nitrogen atom;  
       R1 is C 3-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-10 alkyl, C 3-10 cycloalkyl-C 2-10 alkenyl, C 3-10 cycloalkyl-C 2-10 alkynyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-10 alkyl, 3- to 10-membered heterocyclyl-C 2-10 alkenyl, 3- to 10-membered heterocyclyl-C 2-10 alkynyl, C 6-10 aryl, C 6-10 aryl-C 1-10 alkyl, C 6-10 aryl-C 2-10 alkenyl, C 6-10 aryl-C 2-10 alkynyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-10 alkyl, 5- to 10-membered heteroaryl-C 2-10 alkenyl, or 5- to 10-membered heteroaryl-C 2-10 alkynyl; wherein said alkyl, alkenyl, and alkynyl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra; and wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Rb;  
       R2 is hydrogen, C 1-6 alkyl, C 0-2 alkyl-C 3-10 cycloalkyl, C 0-2 alkyl-C 6-10 aryl or C 0-2 alkyl-5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 0-2 alkyl, C 6-10 aryl-C 0-2 alkyl or 5- to 10-membered-heteroaryl-C 0-2  alkyl, wherein said aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra;  
       R5 is C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra; and wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Rb;  
       L1 is —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(S)—, —N(Rc)-, —CH 2 —, —CH 2 N(Rc)-, —CON(Rc)-, —CSN(Rc)-, —N(Rc)CO—, —N(Rc)CS—, —S(O) 2 N(Rc)- or —N(Rc)S(O) 2 —;  
       L2 is a covalent bond, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —N(Rc)-, —CON(Rc)-, —OC(O)N(Rc), —CSN(Rc)-, —N(Rc)CO—, —N(Rc)C(O)O—, —N(Rc)CS—, —S(O) 2 N(Rc)-, —N(Rc)S(O) 2 —, —N(Rc)CON(Rc)-, or —N(Rc)CSN(Rc)-, wherein if two Rc substituents are present, these may be the same or different;  
       W is O, S, NH, N(Rc), or NCN;  
       Z is —C(O)ORd, —P(O) 2 ORd, —S(O) 2 ORd, —S(O) 2 N(Rd)(Rd), —S(O) 2 N(Re)C(O)Rd, -5-tetrazolyl, or —C(O)Rd; wherein if two Rd groups are present these may be the same or different;  
       Ra is —ORe, —NO 2 , halogen, —S(O)Re, —S(O) 2 Re, —SRe, —S(O) 2 ORe, S(O)NReRe —S(O) 2 NReRe, —NReRe, —O(CReRe) m NReRe, —C(O)Re, —CO 2 Re, —CO 2 (CReRe) m CONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH 2 , —CF 2 H, or —CF 3 ; wherein if two or more Re groups are present these may be the same or different;  
       Rb is a group selected from —ORe, —NO 2 , halogen, —S(O)Re, —S(O) 2 Re, —SRe, —S(O) 2  ORe, —S(O)NReRe —S(O) 2 NReRe, —NReRe, —O(CReRe) m NReRe, —C(O)Re, —CO 2 Re, —CO 2 (CReRe) m CONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH 2 , —CF 2 H, —CF 3 , C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are independently selected from Ra;  
       Rc is hydrogen, C 1-10  alkyl or C 3-10 cycloalkyl; wherein said alkyl or cycloalkyl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are selected from Ra;  
       Rd is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are independently selected from Ra;  
       Re is hydrogen, or C 1-4 alkyl;  
       p is an integer from 0 to 4; and  
       m is an integer from 1 to 6.  
     
   
   
       25 . (canceled)  
   
   
       26 . A method for treating a subject afflicted with a pathological condition susceptible to amelioration by antagonism of α4β1 and/or α4β7 integrins, which comprises administering to said subject an effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof  
     
       
         
         
             
             
         
       
       wherein:  
       A represents a —CH— group or a nitrogen atom;  
       R1 is C 3-10  alkyl, C 3-10 alkenyl, C 3-10  alkynyl, C 3-10 cycloalkyl, C 3-10  cycloalkyl-C 1-10 alkyl, C 3-10  cycloalkyl-C 2-10 alkenyl, C 3-10 cycloalkyl-C 2-10 alkynyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-10 alkyl, 3- to 10-membered heterocyclyl-C 2-10 alkenyl, 3- to 10-membered heterocyclyl-C 2-10 alkynyl, C 6-10 aryl, C 6-10 aryl-C 1-10 alkyl, C 6-10 aryl-C 2-10 alkenyl, C 6-10 aryl-C 2-10 alkynyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C 1-10 alkyl, 5- to 10-membered heteroaryl-C 2-10 alkenyl, or 5- to 10-membered heteroaryl-C 2-10 alkynyl; wherein said alkyl, alkenyl, and alkynyl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra; and wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Rb;  
       R2 is hydrogen, C 1-6 alkyl, C 0-2 alkyl-C 3-10 cycloalkyl, C 0-2 alkyl-C 6-10 aryl or C 0-2 alkyl-5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 0-2 alkyl, C 6-10 aryl-C 0-2 alkyl or 5- to 10-membered-heteroaryl-C 0-2  alkyl, wherein said aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra;  
       R5 is C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Ra; and wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents, which may be the same or different and are independently selected from Rb;  
       L1 is —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(S)—, —N(Rc)-, —CH 2 —, —CH 2 N(Rc)-, —CON(Rc)-, —CSN(Rc)-, —N(Rc)CO—, —N(Rc)CS—, —S(O) 2 N(Rc)- or —N(Rc)S(O) 2 —;  
       L2 is a covalent bond, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —N(Rc)-, —CON(Rc)-, —OC(O)N(Rc), —CSN(Rc)-, —N(Rc)CO—, —N(Rc)C(O)O—, —N(Rc)CS—, —S(O) 2 N(Rc)-, —N(Rc)S(O) 2 —, —N(Rc)CON(Rc)-, or —N(Rc)CSN(Rc)-, wherein if two Rc substituents are present, these may be the same or different;  
       W is O, S, NH, N(Rc), or NCN;  
       Z is —C(O)ORd, —P(O) 2 ORd, —S(O) 2 ORd, —S(O) 2 N(Rd)(Rd), —S(O) 2 N(Re)C(O)Rd, -5-tetrazolyl, or —C(O)Rd; wherein if two Rd groups are present these may be the same or different;  
       Ra is —ORe, —NO 2 , halogen, —S(O)Re, —S(O) 2 Re, —SRe, —S(O) 2 ORe, S(O)NReRe —S(O) 2 NReRe, —NReRe, —O(CReRe) m NReRe, —C(O)Re, —CO 2 Re, —CO 2 (CReRe) m CONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH 2 , —CF 2 H, or —CF 3 ; wherein if two or more Re groups are present these may be the same or different;  
       Rb is a group selected from —ORe, —NO 2 , halogen, —S(O)Re, —S(O) 2 Re, —SRe, —S(O) 2  ORe, —S(O)NReRe —S(O) 2 NReRe, —NReRe, —O(CReRe) m NReRe, —C(O)Re, —CO 2 Re, —CO 2 (CReRe) m CONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH 2 , —CF 2 H, —CF 3 , C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are independently selected from Ra;  
       Rc is hydrogen, C 1-10  alkyl or C 3-10 cycloalkyl; wherein said alkyl or cycloalkyl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are selected from Ra;  
       Rd is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1-4 alkyl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups or moieties are unsubstituted or substituted with one to four substituents which may be the same or different and are independently selected from Ra;  
       Re is hydrogen, or C 1-4 alkyl;  
       p is an integer from 0 to 4; and  
       m is an integer from 1 to 6.  
     
   
   
       27 . A method according to  claim 26 , wherein the pathological condition is susceptible to amelioration by the inhibition or prevention of cell adhesion processes mediated by α4β1 and/or α4β7 integrins.  
   
   
       28 . A method according to any one of claims  26  or  27   claim 26 , wherein the pathological condition is an immune or inflammatory disease or disorder susceptible to amelioration by antagonism of α4β1 and/or α4β7 integrins.  
   
   
       29 . A method according to any one of claims  26  or  27   claim 26 , wherein the pathological condition or disease is chosen from multiple sclerosis, asthma, allergic rhinitis, allergic conjunctivitis, an inflammatory lung disease, rheumatoid arthritis, polydermatomyositis, septic arthritis, type I diabetes, organ transplantation rejection, restenosis, autologous bone marrow transplantation, inflammatory sequelae of viral infections, atopic dermatitis, myocarditis, inflammatory bowel disease including ulcerative colitis and Chron's disease, Geftain type toxic and immune-based nephritis, contact dermal hypersensitivity, psoriasis, tumor metastasis, atherosclerosis sand cerebral ischemia.  
   
   
       30 . A method according to  claim 26 , wherein the inflammatory bowel disease is chosen from ulcerative colitis and Chron's disease.