Substituted 4-amino-1-(pyridylmethyl)piperidine and related compounds
This invention provides 4-amino-1-(pyridylmethyl)piperidine and related compounds and pharmaceutically acceptable salts thereof which are useful as muscarinic receptor antagonists. This invention also provides pharmaceutical compositions containing such compounds; processes and intermediates useful for preparing such compounds; and methods for treating disease conditions mediated by muscarinic receptors, such as overactive bladder, irritable bowel syndrome and chronic obstructive pulmonary disease, using such compounds.
1. A compound of formula I:
wherein
W, X, Y and Z are independently selected from the group consisting of CH, CR 4 , N and N→O; provided that at least one and no more than two of W, X, Y and Z are N or N→O;
R 1 is a group of formula (a):
—(CH 2 ) a —(O) b —(CH 2 ) c — (a)
wherein each —CH 2 — group in formula (a) and the —CH 2 — group between the piperidine nitrogen atom and the ring containing W, X, Y and Z in formula I is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-2 alkyl and fluoro; wherein each alkyl group is optionally substituted with 1 to 3 fluoro substituents;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 5 and —(CH 2 ) x —R 6 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 7 and —(CH 2 ) y —R 8 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R 4 is independently selected from the group consisting of C 1-6 alkyl C 2-6 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, —OR 3 and halo; or two adjacent R 4 groups are joined to form C 3-6 alkylene, —O—(C 2-4 alkylene)-, —O—(C 1-4 alkylene)-O—, —(O)C—CH═CH— or —CH═CH—C(O)—; or when Z is CR 4 , —OR 3 and R 4 are joined to form —O—(C 2-5 alkylene)- or —O—(C 1-5 alkylene)-O—; wherein each alkyl, alkylene, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R 5 and R 7 is independently selected from the group consisting of C 3-5 cycloalkyl, C 6-10 aryl, —C(O)(C 6-10 aryl), C 2-9 heteroaryl, —C(O)(C 2-9 heteroaryl) and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k and the aryl and heteroaryl groups are optionally further substituted with a phenyl group, where the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 6 and R 8 is independently selected from the group consisting of —OH, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 9 , C 3-5 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 9 is independently selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, C 6-10 aryl and C 2-9 heteroaryl; wherein the alkyl and cycloalkyl groups are optionally substituted with 1 to 5 fluoro substituents; and the aryl and heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R a and R b is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R a groups or two adjacent R b groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)-O— or —O—(C 1-4 alkylene)-O—; wherein each alkyl, alkylene, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R c and R d is independently selected from the group consisting of C 1-4 alkyl and fluoro; wherein each alkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R e is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 3-6 heterocyclic, —CH 2 —R i and —CH 2 CH 2 —R j ; or both R e groups are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents; and each aryl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R f is independently selected from the group consisting hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R g and R h is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; or R g and R h are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents, and the heterocyclic group is optionally substituted with 1 to 3 substitutents independently selected from C 1-4 alkyl and fluoro;
each R i is independently selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R j is independently selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 3-6 heterocyclic, —OH, —O(C 1-6 alkyl), —O(C 3-6 cycloalkyl), —O(C 6-10 aryl), —O(C 2-9 heteroaryl), —S(C 1-6 alkyl), —S(O)(C 1-6 alkyl), —S(O) 2 (C 1-6 alkyl), —S(C 3-6 cycloalkyl), —S(O)(C 3-6 cycloalkyl), —S(O) 2 (C 3-6 cycloalkyl), —S(C 6-10 aryl), —S(O)(C 6-10 aryl), —S(O) 2 (C 6-10 aryl), —S(C 2-9 heteroaryl), —S(O)(C 2-9 heteroaryl) and —S(O) 2 (C 2-9 heteroaryl); wherein each alkyl group is optionally substituted with 1 to 5 fluoro substitutents; and each aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R k is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R k groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)-O— or —O—(C 1-4 alkylene)-O—; wherein each alkyl, alkylene, alkenyl and alkynyl group is optionally substituted with 1 to 5 fluoro substitutents;
a is an integer from 2 to 7;
b is 0 or 1;
c is an integer from 2 to 7; provided that a+b+c equals 7, 8 or 9;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is 1;
q is an integer from 0 to 4;
r is an integer from 0 to 4;
x is an integer from 2 to 4;
y is an integer from 2 to 4;
or a pharmaceutically-acceptable salt or stereoisomer thereof.
2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 2 —O—(CH 2 ) 4 —, —(CH 2 ) 2 —O—(CH 2 ) 5 —, —(CH 2 ) 2 —O—(CH 2 ) 6 —, —(CH 2 ) 3 —O—(CH 2 ) 3 —, —(CH 2 ) 3 —O—(CH 2 ) 4 —, —(CH 2 ) 3 —O—(CH 2 ) 5 —, —(CH 2 ) 4 —O—(CH 2 ) 2 —, —(CH 2 ) 4 —O—(CH 2 ) 3 —, —(CH 2 ) 4 —O—(CH 2 ) 4 —, —(CH 2 ) 5 —O—(CH 2 ) 2 —, —(CH 2 ) 5 —O—(CH 2 ) 3 — and —(CH 2 ) 6 —O—(CH 2 ) 2 —.
3. The compound according to claim 2 , wherein R 1 is —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 3 —O—(CH 2 ) 3 — or —(CH 2 ) 4 —O—(CH 2 ) 4 —.
4. The compound according to claim 3 , wherein R 1 is —(CH 2 ) 7 —.
5. The compound according to claim 1 , wherein R 2 is C 1-4 alkyl; wherein the alkyl group is optionally substituted with 1 to 3 fluoro substituents.
6. The compound according to claim 5 , wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
7. The compound according to claim 1 , wherein R 2 is —CH 2 —R 5 .
8. The compound according to claim 7 , wherein R 2 is selected from the group consisting of:
(a) —CH 2 —(C 3-5 cycloalkyl); wherein the cycloalkyl group is optionally substituted with 1 to 3 fluoro substituents;
(b) —CH 2 -(phenyl), wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
(c) —CH 2 -(naphthyl); wherein the naphthyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
(d) —CH 2 -(biphenyl), wherein each phenyl ring of the biphenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
(e) —CH 2 -(pyridyl); wherein the pyridyl group is optionally substituted with 1 to 3 substituents independently selected from R k ; and
(f) —CH 2 C(O)-(phenyl), wherein the phenyl ring of the phenacyl group is optionally substituted with 1 to 3 substituents independently selected from R k .
9. The compound according to claim 8 , wherein R 2 is selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 4-cyanobenzyl, 4-methylbenzyl, 4-trifluoromethoxybenzyl, 4-difluoromethoxybenzyl, 4-thiomethoxybenzyl, 4-methanesulfonylbenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, pyridyl-2-ylmethyl, pyrid-3-ylmethyl, napthth-2-ylmethyl, 3-cyanophenacyl, and 3,4-ethylenedioxyphenacyl.
10. The compound according to claim 1 , wherein R 2 is —(CH 2 ) x —R 6 , wherein x is 2, 3 or 4.
11. The compound according to claim 10 , wherein R 2 is selected from the group consisting of:
(a) —(CH 2 ) x —OH;
(b) —(CH 2 ) x —O(C 1-4 alkyl); wherein the alkyl group is optionally substituted with 1 to 3 fluoro substituents;
(c) —(CH 2 ) x —S(C 1-4 alkyl), —(CH 2 ) x —S(O)(C 1-4 alkyl), or —(CH 2 ) x —S(O) 2 (C 1-4 alkyl); wherein the alkyl group is optionally substituted with 1 to 3 fluoro substituents;
(d) —(CH 2 ) x -(phenyl), wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
(e) —(CH 2 ) x —(O-phenyl), wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
(f) —(CH 2 ) x -(naphthyl), wherein the naphthyl group is optionally substituted with 1 to 3 substituents independently selected from R k ; and
(g) —(CH 2 ) x -(indolyl), wherein the indolyl group is optionally substituted with 1 to 3 substituents independently selected from R k .
12. The compound according to claim 11 , wherein R 2 is selected from the group consisting of 2-hydroxyethyl, 2-methoxyethyl, 2-(methylthio)ethyl, 2-ethoxyethyl, 2-(ethylthio)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl, 2-phenethyl, 2-(naphth-1-yl)ethyl, 2-(indol-3-yl)ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-phenylpropyl and 3-phenoxypropyl.
13. The compound according to claim 1 , wherein R 2 is ethyl, n-propyl, isopropyl, cyclopropylmethyl or 2-hydroxyethyl.
14. The compound according to claim 1 , wherein each R 3 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, cyclopropylmethyl and 2-hydroxyethyl; wherein each alkyl group is optionally substituted with 1 to 5 fluoro substituents.
15. The compound according to claim 14 , wherein each R 3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,3-difluoroprop-2-yl, 1,1,3,-trifluoroprop-2-yl, and 1,1,3,3-tetrafluoroprop-2-yl.
16. The compound according to claim 1 , wherein R 4 is selected from the group consisting of C 1-4 alkyl, —OR 3 and halo; wherein the alkyl group is optionally substituted with 1 to 5 fluoro substituents.
17. The compound according to claim 16 , wherein R 4 is methyl, —OR 3 , fluoro or chloro.
18. The compound according to claim 1 , wherein W, X, Y and Z are defined as follows:
(a) W is N; X is CH; Y is CH; and Z is CH;
(b) W is CH or CR 4 ; X is N; Y is CH and Z is CH;
(c) W is CH or CR 4 ; X is CH; Y is N; and Z is CH;
(d) W is CH or CR 4 ; X is CH; Y is CH; and Z is N; or
(e) W is CH; X is N; Y is CH and Z is CH.
19. The compound according to claim 18 , wherein W is CH; X is N; Y is CH and Z is CH.
20. A compound of formula II:
wherein
W, X, Y and Z are independently selected from the group consisting of CH, CR 4 , N and N→O; provided that at least one and no more than two of W, X, Y and Z are N or N→O;
R 1 is a group of formula (a):
—(CH 2 ) a —(O) b —(CH 2 ) c — (a)
wherein each —CH 2 — group in formula (a) and the —CH 2 — group between the piperidine nitrogen atom and the ring containing W, X, Y and Z in formula II is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-2 allyl and fluoro; wherein each alkyl group is optionally substituted with 1 to 3 fluoro substituents;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 -alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 5 and —(CH 2 ) x —R 6 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 -alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 7 and —(CH 2 ) y —R 8 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —OR 3 and halo; or two adjacent R 4 groups are joined to form C 3-6 alkylene, —O—(C 2-4 alkylene)-, —O—(C 1-4 alkylene)-O—, —(O)C—CH═CH— or —CH═CH—C(O)—; or when Z is CR 4 , —OR 3 and R 4 are joined to form —O—(C 2-5 alkylene)- or —O—(C 1-5 alkylene)-O—; wherein each alkyl, alkylene, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R 5 and R 7 is independently selected from the group consisting of C 3-5 cycloalkyl, C 6-10 aryl, —C(O)(C 6-10 aryl), C 2-9 heteroaryl, —C(O)(C 2-9 heteroaryl) and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k and the aryl and heteroaryl groups are optionally further substituted with a phenyl group, where the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 6 and R 8 is independently selected from the group consisting of —OH, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 9 , C 3-5 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 9 is independently selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, C 6-10 aryl and C 2-9 heteroaryl; wherein the alkyl and cycloalkyl groups are optionally substituted with 1 to 5 fluoro substituents; and the aryl and heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R f is independently selected from the group consisting hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyl and C 3-6 cycloalkyl; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R g and R h is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; or R g and R h are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents, and the heterocyclic group is optionally substituted with 1 to 3 substitutents independently selected from C 1-4 alkyl and fluoro;
each R k is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R k groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)-O— or —O—(C 1-4 alkylene)-O—; wherein each alkyl, alkylene, alkenyl and alkynyl group is optionally substituted with 1 to 5 fluoro substitutents;
a is an integer from 2 to 7;
b is 0 or 1;
c is an integer from 2 to 7; provided that a+b+c equals 7, 8 or 9;
x is an integer from 2 to 4;
y is an integer from 2 to 4;
or a pharmaceutically-acceptable salt or stereoisomer thereof.
21. The compound according to claim 20 , wherein R 1 is —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 3 —O—(CH 2 ) 3 — or —(CH 2 ) 4 —O—(CH 2 ) 4 —.
22. The compound according to claim 21 , wherein R 2 is C 1-4 alkyl; wherein the alkyl group is optionally substituted with 1 to 3 fluoro substituents.
23. The compound according to claim 22 , wherein each R 3 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, cyclopropylmethyl and 2-hydroxyethyl; wherein each alkyl group is optionally substituted with 1 to 5 fluoro substituents.
24. The compound according to claim 23 , wherein
R 1 is —(CH 2 ) 7 —;
R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; and
each R 3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,3-difluoroprop-2-yl, 1,1,3,-trifluoroprop-2-yl, and 1,1,3,3-tetrafluoroprop-2-yl.
25. A compound of formula III:
wherein
R 1 is a group of formula (a):
—(CH 2 ) a —(O) b —(CH 2 ) c — (a)
wherein each —CH 2 — group in formula (a) and the —CH 2 — group between the piperidine nitrogen atom and the pyridine ring in formula III is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-2 alkyl and fluoro; wherein each alkyl group is optionally substituted with 1 to 3 fluoro substituents;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 5 and —(CH 2 ) x —R 6 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —R 7 and —(CH 2 ) y —R 8 ; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R 5 and R 7 is independently selected from the group consisting of C 3-5 cycloalkyl, C 6-10 aryl, —C(O)(C 6-10 aryl), C 2-9 heteroaryl, —C(O)(C 2-9 heteroaryl) and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k and the aryl and heteroaryl groups are optionally further substituted with a phenyl group, where the phenyl group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 6 and R 8 is independently selected from the group consisting of —OH, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 9 , C 3-5 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein the cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and the aryl, heteroaryl and heterocyclic groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R 9 is independently selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, C 6-10 aryl and C 2-9 heteroaryl; wherein the alkyl and cycloalkyl groups are optionally substituted with 1 to 5 fluoro substituents; and the aryl and heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from R k ;
each R f is independently selected from the group consisting hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents;
each R g and R h is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; or R g and R h are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substitutents, and the heterocyclic group is optionally substituted with 1 to 3 substitutents independently selected from C 1-4 alkyl and fluoro;
each R k is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R k groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)-O— or —O—(C 1-4 alkylene)-O—; wherein each alkyl, alkylene, alkenyl and alkynyl group is optionally substituted with 1 to 5 fluoro substitutents;
a is an integer from 2 to 7;
b is 0 or 1;
c is an integer from 2 to 7; provided that a+b+c equals 7, 8 or 9;
x is an integer from 2 to 4;
y is an integer from 2 to 4;
or a pharmaceutically-acceptable salt or stereoisomer thereof.
26. The compound according to claim 25 , wherein R 1 is —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 3 —O—(CH 2 ) 3 — or —(CH 2 ) 4 —O—(CH 2 ) 4 —.
27. The compound according to claim 26 , wherein R 2 is C 1-4 alkyl; wherein the alkyl group is optionally substituted with 1 to 3 fluoro substituents.
28. The compound according to claim 27 , wherein each R 3 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, cyclopropylmethyl and 2-hydroxyethyl; wherein each alkyl group is optionally substituted with 1 to 5 fluoro substituents.
29. The compound according to claim 28 , wherein
R 1 is —(CH 2 ) 7 —;
R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; and
R 3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,3-difluoroprop-2-yl, 1,1,3,-trifluoroprop-2-yl, and 1,1,3,3-tetrafluoroprop-2-yl.
30. A compound selected from the group consisting of:
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahept-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(ethyl)amino}-1-(2-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(ethyl)amino}-1-(3-methoxypyrid-2-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahept-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxaoct-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxanon-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxaoct-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxanon-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxahept-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxaoct-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxanon-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxaoct-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxanon-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-7-oxanon-1-yl]-N-(ethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxaoct-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxanon-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahep-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxaoct-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxanon-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxahept-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxaoct-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxanon-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxaoct-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxanon-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-7-oxanon-1-yl]-N-(prop-1-yl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-n-propoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-isopropoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-cyclopropyl-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-{4-(2-hydroxyethoxy)pyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-isobutoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2,4-dimethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino)}-1-(2-fluoro-4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-chloro-4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-methyl-4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-2-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-2-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-2-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-4-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-4-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(isopropyl)amino}-1-(3-methoxypyrid-4-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(isopropyl)amino}-1-(2-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(isopropyl)amino}-1-(2-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxaoct-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxanon-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahep-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxanon-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxaoct-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxanon-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxaoct-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxanon-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-7-oxanon-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxaoct-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxanon-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahep-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxaoct-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxanon-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxahept-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxaoct-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxanon-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxaoct-1-yl]-N-(cyclopropylmethyl)amino)}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxanon-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-7-oxanon-1-yl]-N-(cyclopropylmethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)oct-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)non-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxahept-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxaoct-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-3-oxanon-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxahep-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxaoct-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-4-oxanon-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxahept-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxaoct-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-5-oxanon-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[8-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxaoct-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-6-oxanon-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[9-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)-7-oxanon-1-yl]-N-(2-hydroxyethyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-tert-butoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-hydroxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-ethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-trifluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-difluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-methoxy-2-trifluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-difluoromethoxy-4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-methoxy-4-trifluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-difluoromethoxy-2-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-{2,4-di(trifluoromethoxy)pyrid-3-ylmethyl}piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-{2,4-di(difluoromethoxy)pyrid-3-ylmethyl}piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-ethoxy-4-trifluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2-ethoxy-4-difluoromethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(2,4-diethoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-(N-methylcarbamoyl)-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-(N,N-dimethylcarbamoyl)-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-hydroxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-(N,N-diethylcarbamoyl)-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-hydroxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-(piperidin-1-ylcarbonyl)-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-hydroxypyrid-3-ylmethyl)piperidine;
4-{N-[7-(3-(S)-1-(morpholin-4-ylcarbonyl)-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-hydroxypyrid-3-ylmethyl)piperidine; and
4-{N-[7-(3-(S)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-[4-(2-fluoroethoxy)pyrid-3-ylmethyl]piperidine;
4-{N-[7-(3-(R)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine; and
4-{N-[7-(3-(R)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hep-1-yl]-N-(isopropyl)amino}-1-(4-ethoxypyrid-3-ylmethyl)piperidine;
or a pharmaceutically-acceptable salt or stereoisomer thereof.
31. 4-{N-[7-(3-(S)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(isopropyl)amino}-1-(4-methoxypyrid-3-ylmethyl)piperidine; or a pharmaceutically-acceptable salt thereof.
32. 4-{N-[7-(3-(S)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(isopropyl)amino}-1-(4-ethoxypyrid-3-ylmethyl)piperidine; or a pharmaceutically-acceptable salt thereof.
33. 4-{N-[7-(3-(S)-1-Carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(isopropyl)amino}-1-(4-isopropoxypyrid-3-ylmethyl)piperidine; or a pharmaceutically-acceptable salt thereof.
34. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 - 33 .
35. A process for preparing a compound of formula I:
wherein R 1 , R 2 , R 3 , R a , R b , R c , R d , m, n, p, q, r, W, X, Y and Z are as defined in claim 1 ; or a pharmaceutically-acceptable salt or stereoisomer thereof;
the process comprising reacting a compound of formula Va:
or a salt or stereoisomer or protected derivative thereof; with a compound of formula VIII:
or a salt or protected derivative thereof; and a reducing agent to provide a compound of formula I, or a pharmaceutically-acceptable salt or stereoisomer thereof.
36. The process of claim 35 , wherein the process further comprises the step of forming a pharmaceutically-acceptable salt of the compound of formula I.