Spiroindolines as modulators of chemokine receptors
The present invention relates to a compound of the following formula: where R 1 -R 6 , R 10 , Y, n, m, p, and q are as defined herein. Compounds and compositions of the present invention are useful for the treatment of diseases associated with the overexpression of CCR2.
1. A compound of the following formula:
or a pharmaceutically acceptable salt thereof or an enantiomer thereof;
where each R 1 is independently halo, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, OCF 3 , CN, C 1 -C 6 -alkyl-C(O)—NH—, C 1 -C 6 -alkyl-NH—C(O)—, —CH 2 —N(R 7 ) 2 , —CH 2 —O—R 8 , C 1 -C 4 —S(O) r —, COOH, or heteroaryl;
R 2 is H, C 1 -C 4 -alkyl, —CH 2 C(O)OR 9 , or CH 2 C(O)N(R 9 ) 2 ;
each R 3 is independently C 1 -C 6 -alkyl or hydroxy-C 1 -C 6 -alkyl;
each R 4 is independently OH, F, Cl, CN, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, or C 1 -C 4 -alkoxy;
Y is —NH— or
R 5 is H, OH, F, Cl, CN, CF 3 , C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy;
each R 6 is independently halo, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, OCF 3 , benzyloxy, or CN;
each R 7 is independently H, C 1 -C 4 -alkyl, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group;
R 8 is H, C 1 -C 6 -alkyl, benzyl, or phenyl;
each R 9 is independently H, C 1 -C 6 -alkyl, or benzyl;
each R 10 is independently OH, F, Cl, CN, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, or C 1 -C 4 -alkoxy;
n is 0, 1, or 2;
m is 0, 1, 2, or 3;
p is 0, 1, or 2;
q is 0, 1, or 2;
r is 0, 1, or 2; and
s is 0, 1, or 2.
2. The compound of claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof or an enantiomer thereof, wherein
each R 1 is independently Cl, F, Br, CF 3 , CN, CH 3 , OCF 3 , C 1 -C 4 —S(O) r —, or methoxy;
each R 6 is independently F, Cl, Br, CF 3 , CH 3 , benzyloxy, or OCH 3 ;
m is 1 or 2;
n is 0, 1, or 2;
q is 0 or 1; and
s is 0 or 1.
3. The compound of either of claim 1 or 2 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof or an enantiomer thereof, wherein R 4 is CH 3 or OH; and R 5 is H or OH.
4. The compound of any of claims 1 to 3 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof or an enantiomer thereof;
where each R 1 is independently CH 3 , F, Cl, or CN;
each R 6 is independently F or Cl;
R 10 is CH 3 or OH;
n is 0, 1, or 2; and
s is 0 or 1.
5. The compound of claim any of claims 1 to 4 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl, CH 3 , or CN; and s is 0 or 1.
6. The compound of any of claims 1 to 4 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl, CH 3 , or CN; and s is 0 or 1.
7. The compound of claim 1 which is 2-(6-chloro-1,2-dihydro-1H-spiro[indole-3,4′-piperidin]-1′-yl)-1-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol;
1′-((2R)-2-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-hydroxy-4-piperidinyl}-2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-6-carbonitrile;
1′-((2S)-2-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-6-carbonitrile;
6-chloro-1′-(2-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-hydroxy-4-piperidinyl}-2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-3′-ol;
6-chloro-1′-(2-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-3′-ol;
1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-{2-[(3R,3′R)-3′,6-dimethyl-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl]-1-hydroxyethyl}-4-piperidinol;
or 1-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-(3′-methyl-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)ethanol;
or a pharmaceutically acceptable salt thereof or an enantiomer thereof.
8. A compound which is (1S)-2-(6-chloro-1,2-dihydro-1H-spiro[indole-3,4′-piperidin]-1-yl)-1-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol or a pharmaceutically acceptable salt thereof.
9. A pharmaceutically acceptable salt of the compound of claim 8 , wherein the salt is a benzoate salt.
10. A composition that comprises a) the compound of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.