Urea derivatives as integrin α4 antagonists

A compound of the general Formula Ia:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• A represents a —CH— group or a nitrogen atom;
• R1 is C3-10alkyl, C3-10alkenyl, C3-10alkynyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-10alkyl, C3-10cycloalkyl-C2-10alkenyl, C3-10cycloalkyl-C2-10alkynyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-10alkyl, 3- to 10-membered heterocyclyl-C2-10alkenyl, 3- to 10-membered heterocyclyl-C2-10alkynyl, C6-10aryl, C6-10aryl-C1-10alkyl, C6-10aryl-C2-10alkenyl, C6-10aryl-C2-10alkynyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C1-10alkyl, 5- to 10-membered heteroaryl-C2-10alkenyl, or 5- to 10-membered heteroaryl-C2-10alkynyl;
• 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, C1-6-alkyl, C0-2alkyl-C3-10cycloalkyl, C0-2alkyl-C6-10aryl, or C0-2alkyl-5- to 10-membered heteroaryl, C3-10cycloalkyl-C0-2alkyl, C6-10aryl-C0-2alkyl or 5- to 10-membered heteroaryl-C0-2 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 C1-6-alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-4alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C1-4alkyl;
• 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)—, —CH2—, —CH2N(Rc)—, —CON(Rc)—, —CSN(Rc)—, —N(Rc)CO—, —N(Rc)CS—, —S(O)2N(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)2N(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)2ORd, —S(O)2ORd, —S(O)2N(Rd)(Rd), —S(O)2N(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, —NO2, halogen, —S(O)Re, —S(O)2Re, —SRe, —S(O)2ORe, —S(O)NReRe —S(O)2NReRe, —NReRe, —O(CReRe)mNReRe, —C(O)Re, —CO2Re, —CO2(CReRe)mCONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH2, —CF2H, or —CF3;
• wherein if two or more Re groups are present these may be the same or different;
• Rb is a group selected from —ORe, —NO2, halogen, —S(O)Re, —S(O)2Re, —SRe, —S(O)2ORe, —S(O)NReRe —S(O)2NReRe, —NReRe, —O(CReRe)mNReRe, —C(O)Re, —CO2Re, —CO2(CReRe)mCONReRe, —OC(O)Re, —CN, —C(O)NReRe, —NReC(O)Re, —OC(O)NReRe, —NReC(O)ORe, —NReC(O)NReRe, —CRe(N—ORe), —CFH2, —CF2H, —CF3, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-4alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl-C1-4alkyl;
• 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, C1-10alkyl or C3-10cycloalkyl;
• 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, C1-6alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-4alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5–10-membered heteroaryl, or 5- to 10-membered heteroaryl-C1-4alkyl;
• 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 C1-4alkyl;
• p is an integer from 0 to 4;
• and
• m is an integer from 1 to 6.