2,4-substituted pyrrolidine derivatives-CCR-3 receptor antagonists

A compound of Formula (Ia):

• wherein
• R1 is hydrogen, alkyl, acyl, heteroalkyl, —CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), —COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or —SO2R6 where R6 is alkyl;
• alk1 is an alkylene chain of 1 to 6 carbon atoms;
• X is —NHCO— or —CONH—;
• Y is —O—(CH2)—, —O—(CH2)2—, —O—(CHCH3)—, —NRb—(CH2)—, —NRb—(CH2)2—, —NRb—(CHCH3)— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)], —S(O)n—(CH2)—, —S(O)n—(CH2)2—, or —S(O)n—(CHCH3)— where n is 0 to 2;
• Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
• Ar2 is aryl;
• alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} or —S(O)n1— wherein n1 is 0 to 2;
• and
• Ar3 is cycloalkyl, aryl or heteroaryl;
• or
• a pharmaceutically acceptable salt thereof.

A compound of Formula (Ib):

• wherein:
• R1 is hydrogen, alkyl, acyl, heteroalkyl, —CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), —COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or —SO2R where R is alkyl;
• alk1 is an alkylene chain of 1 to 6 carbon atoms;
• X is —NHCO— or —CONH—;
• Y is:
• (i) —(CH2)—, —(CH2)2—, —(CH2)3—, —(CHCH3)—, —(CHCH3)—(CH2)—, or —(CH2)—(CHCH3)—;
• or
• (ii) —(CH2)—O—, —(CH2)2—O—, —(CHCH3)—O—, —(CH2)—NRb—, —(CH2)2—NRb—, or —(CHCH3)—NRb— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} when X is —CONH—;
• Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
• Ar2 is aryl;
• alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} or —S(O)n1— wherein n1 is 0 to 2;
• and
• Ar3 is cycloalkyl, aryl or heteroaryl;
• or
• a pharmaceutically acceptable salt thereof.

A compound of Formula (Ib):

• wherein:
• R1 is —COCH2CO2H, —COCH2CO2CH3, or —CO2-tert-butyl;
• alk1 is an alkylene chain of 1 to 6 carbon atoms;
• X is —CONH—;
• Y is:
• (i) —(CH2)—, —(CH2)2—, —(CH2)3—, —(CHCH3)—, —(CHCH3)—(CH2)—, or —(CH2)—(CHCH3)—;
• or
• (ii) —(CH2)—O—, —(CH2)2—O—, —(CHCH3)—O—, —(CH2)—NRb—, —(CH2)2—NRb—, or —(CHCH3)—NRb— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} when X is —CONH—;
• Ar1 is pyrimidin-2-yl;
• Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl of Ar1;
• alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)) or —S(O)n1— wherein n1 is 0 to 2;
• and
• Ar3 is cycloalkyl, aryl or heteroaryl;
• or
• a pharmaceutically acceptable salt thereof.

A compound of the Formula (Ib):

• wherein:
• R1 is —COCH2CO2H, —COCH2CO2CH3, or —CO2-tert-butyl;
• X is —CONH—;
• Y and alk1 are independently methylene or ethylene;
• Ar1 is pyrimidin-2-yl;
• Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl of Ar1;
• alk2 is methylene;
• and
• Ar3 is 3,4-dichiorophenyl;
• or
• a pharmaceutically acceptable salt thereof.