3-aminopyrrolidine derivatives as modulators of chemokine receptors
The present invention relates to 3-aminopyrrolidine derivatives of the formula I: (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y and X are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as a modulator of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.
1. A method of treating rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, or allergic rhinitis in a patient, the method comprising administering to said patient a compound of formula III:
or an enantiomer, diastereomer, enantiomerically enriched mixture, racemic mixture, crystalline form, non-crystalline form, amorphous form, solvate, or pharmaceutically acceptable salt thereof wherein:
R 1 is independently selected from the group consisting of: a carbocycle, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, hetero-arylalkynyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylcarboxamido, heteroaryl-carboxamido, arylureido, heteroarylureido, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, arylamino and heteroarylamino and wherein said carbocycle, heterocycle, aryl, arylalkyl, heteroaryl or heteroarylalkyl group is substituted with 0-3 R 1a substituents wherein R 1a is independently selected from the group consisting of: halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, hydroxyalkyl, mono-, di- or tri-haloalkyl, mono-, di- or trihalo-alkoxy, nitro, amino, mono- or di-substituted amino, mono- or di-substituted aminoalkyl, aminocarbonyl, mono- or di-substituted aminocarbonyl, cyclic aminocarbonyl, aminosulfonyl, mono- or di-substituted aminosulfonyl, alkylcarbonyl, cyclic alkylcarbonyl, arylcarbonyl, hetero- arylcarbonyl, alkylsulfonyl, cyclic alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxylic acid, esterified carboxylic acid, alkylcarbonylamino, cyclic alkylcarbonylamino, aryl-carbonylamino, heteroarylcarbonylamino, cyano, arylalkyl, heteroarylalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, carbamate, mono- or di-substituted carbamate, R 1b -aryl and R 1b -heteroaryl wherein R 1b is H, halogen, OH, amino, mono- or di-substituted amino, mono-, di- or tri-haloalkyl, alkoxy, mono-, di- or tri-haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, carboxamide, sulfonamide, carbamate, urea or cyano;
R 2 is independently selected from the group consisting of: H, amino, mono- or di-substituted amino, OH, carboxyl, esterified carboxyl, carboxamide, N-monosubstituted carboxamide, and N,N-disubstituted carboxamide, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, thioalkyl, mono-, di- or trihaloalkyl, halogen, aryl and heteroaryl; or,
R 1 and R 2 are bonded to each other to form a spirocycle;
R 3 , R 4 , R 5 , and R 6 are independently selected form the group consisting of: H, amino, OH, alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy and thioalkyl; or,
R 1 and R 3 can be cyclized to form a carbocycle or heterocycle having 0-3 R a substituents wherein R a is selected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamido, cyano, mono, disubstituted, or polysubstituted aryl and heterocycle substituted by 0-3 R b wherein R b is selected from the group consisting of halogen, alkyl, alkoxy, thioalkyl, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, nitro, amino, carboxyl, esterified carboxyl, carboxamido, thiocarboxamido and cyano; or,
R 3 and R 4 or R 5 and R 6 are cyclized to form a bridged bicyclic system having an ethylene bridge; or,
R 3 and R 6 are cyclized to form a bridged bicyclic system having a methylene group or an ethylene group or a heteroatom selected form the group consisting of N, O and S;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, alkoxy, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, alkoxyalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, arylalkoxyalkyl and heteroarylalkoxyalkyl; wherein, C 1 -C 8 alkyl can be interrupted by oxygen or sulfur; or,
R 7 and R 8 can be cyclized to form a spirocarbocycle or spiroheterocycle;
and, m=1-5.
2. The method of claim 1 , wherein the compound is N-(2-{[(3R)-1 -(4-hydroxy-4-pyrimidin-4-ylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidin-4-ylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is N-(2-{[(3R)-1-(4-hydroxy-4-pyrimidin-4-ylcyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide.
5. The method of claim 1 , wherein the compound is N-({(3R)-1-[4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-pyrrolidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is N-({(3R)-1-[4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-pyrrolidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide, or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound is N-({(3R)-1-[4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-pyrrolidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide.
8. The method of claim 2 , wherein the method is for treating rheumatoid arthritis.
9. The method of claim 2 , wherein the method is for treating multiple sclerosis.
10. The method of claim 2 , wherein the method is for treating psoriasis.
11. The method of claim 2 , wherein the method is for treating asthma.
12. The method of claim 2 , wherein the method is for treating allergic rhinitis.
13. The method of claim 2 , wherein the method is for treating rheumatoid arthritis.
14. The method of claim 5 , wherein the method is for treating multiple sclerosis.
15. The method of claim 5 , wherein the method is for treating psoriasis.
16. The method of claim 5 , wherein the method is for treating asthma.
17. The method of claim 5 , wherein the method is for treating allergic rhinitis.