US2005090533A1PendingUtilityA1
Dual NK1/NK3 receptor antagonists
Priority: Jul 3, 2003Filed: Jul 2, 2004Published: Apr 28, 2005
Est. expiryJul 3, 2023(expired)· nominal 20-yr term from priority
A61P 25/00A61P 25/18C07D 451/04A61K 31/541A61K 31/444A61K 31/46A61K 31/551A61K 31/5377C07D 513/08A61K 31/44A61K 31/4418A61K 31/4995C07D 401/04C07D 413/04C07D 497/10C07D 495/10A61K 31/4439A61K 31/5386C07D 419/04C07D 213/75A61K 31/554C07D 491/10A61K 31/496A61K 31/4427C07D 487/08C07D 417/04A61K 31/547
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Claims
Abstract
The present invention provides a method for the treatment of schizophrenia which comprises administering a compound of formula wherein the substituents are as described herein or a pharmaceutically active acid-addition salt thereof. In particular, the invention provides methods for treating both positive and negative symptoms of schizophrenia through dual inhibition of NK1 and NK3 receptors. The invention also provides novel compounds with formula I and methods for preparing compounds of the invention.
Claims
exact text as granted — not AI-modified1 . A method of treating schizophrenia comprising administering to an individual an effective amount of a compound of formula I
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl,
—S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl, selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a -alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′R″,
—(CH 2 ) c NR′C(O)-alkyl,
—(CH 2 ) c NR′S(O) 2 -alkyl,
—(CH 2 ) d S(O)-alkyl,
—(CH 2 ) d S-alkyl,
—(CH 2 ) d S(O) 2 -alkyl, or
—(CH 2 ) d S(O) 2 —NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) o OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) e -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″; or with
—(CH 2 ) 2 —S(O) 2 N(CH 3 )—CH 2 , or with
—S(O)—O—(CH 2 ) 2,3 —;
or —NR 4 R 5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
2 . The method of claim 1 , wherein the compound of formula I is a compound of formula IA
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH, or —(CR′R″) l —(CR′R″) l —(CR′R″) a -alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other and are hydrogen, or
C b -alkyl;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl;
a is 0 or 1;
b is 1 or 2; and
d is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof.
3 . The method of claim 1 , wherein the compound of formula I is a compound of formula IB
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently hydrogen, —(CH 2 ) 2 SCH 3 , —(CH 2 ) 2 S(O) 2 CH 3 , —(CH 2 ) 2 S(O) 2 NHCH 3 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 NHS(O) 2 CH 3 , or —(CH 2 ) 2 NHC(O)CH 3 ;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2; and
d is 0, 1, 2, or 3;
or a pharmaceutically active acid-addition salt thereof.
4 . The method of claim 1 , wherein the compound of formula I is a compound of formula IC
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 is hydrogen;
R 5 is —(CH 2 ) 0 -cycloalkyl, unsubstituted or substituted by hydroxy;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl,
—S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2; and
d is 0, 1, 2, or 3;
or a pharmaceutically active acid-addition salt thereof.
5 . The method of claim 1 , wherein the compound of formula I is a compound of formula ID
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e -, which is unsubstituted or substituted by one or more substituents selected from the group consisting of —(CR′R″) d OH;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl,
—S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2;
d is 0, 1, 2, or 3; and
e is 3, 4, or 5;
or a pharmaceutically active acid-addition salt thereof.
6 . The method of claim 1 , wherein the compound of formula I is a compound of formula IE
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3; and
e is 3, 4, or 5;
or a pharmaceutically active acid-addition salt thereof.
7 . The method of claim 1 , wherein the compound of formula I is a compound of formula IF
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ; and
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl,
—S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3; and
e is 3, 4, or 5;
or a pharmaceutically active acid-addition salt thereof.
8 . The method of claim 1 , wherein the compound of formula I is a compound of formula IG
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O) 2 -alkyl;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) c —S(O) f —(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with —(CH 2 ) d , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, 3 or 4;
e is 3, 4, or 5; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
9 . The method of claim 1 , wherein the compound of formula I is a compound of formula IH
wherein
R 1 is heteroaryl selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a — alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′R″,
—(CH 2 ) c NR′C(O)-alkyl,
—(CH 2 ) c NR′S(O) 2 -alkyl,
—(CH 2 ) d S(O)-alkyl,
—(CH 2 ) d S-alkyl,
—(CH 2 ) d S(O) 2 -alkyl, or
—(CH 2 ) d S(O) 2 —NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) o OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) c —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″; or with
—(CH 2 ) 2 —S(O) 2 N(CH 3 )—CH 2 , or with
—S(O)—O—(CH 2 ) 2,3 —;
or —NR 4 R 5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d iso, 1, 2, or 3;
e is 3, 4, or 5; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
10 . The method of claim 1 , wherein the compound of formula I is a compound of formula I J,
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl, selected from the group, consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
—NR 4 R 5 are
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl;
b is 1 or 2;
d is 0, 1, 2, or 3; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
11 . The method of claim 1 , wherein the compound of formula I is a compound of formula I-1
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN,
S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl, selected from the groups consisting of pyridin-2-or 3-yl, imidazolyl or oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(C+R′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a -lower alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′C(O)-lower alkyl,
—(CH 2 ) c NR′S(O) 2 -lower alkyl, or
—(CH 2 ) d S(O) 2 -lower alkyl;
R′ is hydrogen, lower alkyl, —(CH 2 ) o OH, —C(O)H, —C(O)-lower alkyl, —C(O)-cycloalkyl, —S(O) 2 -lower alkyl;
R″ is hydrogen or lower alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) e -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -lower alkyl,
—(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -lower alkyl,
—(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with
—(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -loewr alkyl,
—(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with
—(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -lower alkyl,
—(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R″) d OH, ═O, and —NR′R″, wherein R′ and R″ may form together with the N-atom to which they are attached a ring with
—(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -lower alkyl,
—(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″;
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
12 . A compound selected from the group consisting of
N-[6-(2-acetylamino-ethylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide, 2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[ethyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-propyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifuoromethyl-phenyl)-N-[6-[butyl-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2,3-dihydroxy-propyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(1-hydroxymethyl-3-methyl-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-2-methyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-butylamino)-pyrin-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-{6-[bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxyethyl)-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[(2-hydroxy-ethyl)-propyl-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-propyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-propyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifuoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1′-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1R,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1S,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[hexyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-pentyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, and 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-1-hydroxymethyl-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide.
13 . A composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.
14 . A compound of formula IB
wherein
R 1 is phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl;
R and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently hydrogen, —(CH 2 ) 2 SCH 3 , —(CH 2 ) 2 S(O) 2 CH 3 , —(CH 2 ) 2 S(O) 2 NHCH 3 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 NHS(O) 2 CH 3 or —(CH 2 ) 2 NHC(O)CH 3 ;
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl;
R″ is hydrogen or alkyl;
b is 1 or 2; and
d is 0, 1, 2, or 3;
or a pharmaceutically active acid-addition salt thereof.
15 . A composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.
16 . A compound selected from the group consisting of
trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide, trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide, trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide, trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1RS,2RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide, (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide, and (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide.
17 . A composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.
18 . A compound selected from the group consisting of
(S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide, (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide, (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrol idin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-difluoro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-difluoro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrol idin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-dimethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide, (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide, (S)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (3R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, and (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.
19 . A composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
20 . A compound selected from the group consisting of
(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2R,5R)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-dimethylamino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,5-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-4-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-amino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methylsulfanyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methanesulfonyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-2-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-4-yl]-benzamide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrol idin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, and (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.
21 . A composition comprising a compound of claim 20 and a pharmaceutically acceptable carrier.
22 . A compound selected from the group consisting of
(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-cyano-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy- 2 -hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrol idin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrol idin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-,bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-difluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide, (3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide and (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide.
23 . A composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier.
24 . A compound selected from the group consisting of
(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (RS)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-methanesulfonyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (R)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide, (S)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[6-[2-(acetylamino-methyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-dimethyl-carbamic acid 1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-pyrrolidin-2-ylmethyl ester, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, N-[4-amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, N-[4-acetylamino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, and (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-azetidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,5-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (3S,5R)-5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-2-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide, (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide, (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide and (2RS,3RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.
25 . A composition comprising a compound of claim 24 and a pharmaceutically acceptable carrier.
26 . A compound selected from the group consisting of
N-[6-(4-acetyl-piperazin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-(4-acetyl-[1,4]diazepan-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-oxo-[1,4]diazepan-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-imidazolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, N-[6-(3-acetyl-imidazolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-chloromethanesulfonyl-piperazin-1-y)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-dimethylsulfamoyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(-4-methanesulfonyl-3-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2RS,5SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (2S,6R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,6-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (3S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-formyl-2-hydroxymethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-cyclopropanecarbonyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-N-[6-(4-acetyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-hydroxymethyl-phenyl)-6-(-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, and 2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.
27 . A composition comprising a compound of claim 26 and a pharmaceutically acceptable carrier.
28 . A compound selected from the group consisting of
(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (R)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide and 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide.
29 . A composition comprising a compound of claim 28 and a pharmaceutically acceptable carrier.
30 . A compound selected from the group consisting of
(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-lλ 6 -thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-lλ 6 -thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiazolidin-3-yl-pyridin-3-yl]-N-methyl-isobutyramide, (1RS,4RS)- or (1RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-lλ 4 -thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (1RS,4SR)- or (1RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-lλ 4 -thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1,1-dioxo-lλ 6 -thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide, (+)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-l□ 6 -thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (−)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-l□ 6 -thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-lλ 4 -[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-lλ 6 -[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-lλ 6 -[1,3]thiazinan-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, and (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.
31 . A composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier.
32 . A compound of formula IH
wherein
R 1 is heteroaryl selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a -alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′R″,
—(CH 2 ) c NR′C(O)-alkyl,
—(CH 2 ) c NR′S(O) 2 -alkyl,
—(CH 2 ) d S(O)-alkyl,
—(CH 2 ) d S-alkyl,
—(CH 2 ) d S(O) 2 -alkyl;
—(CH 2 ) d S(O) 2 —NR′R″
R′ is hydrogen, alkyl, —(CH 2 ) c OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″; or with
—(CH 2 ) 2 —S(O) 2 N(CH 3 )—CH 2 , or with
—S(O)—O—(CH 2 ) 2,3 —;
or —NR 4 R 5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5;
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
33 . A composition comprising a compound of claim 32 and a pharmaceutically acceptable carrier.
34 . A compound of formula IJ,
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN, S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl,
or is heteroaryl, selected from the group, consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
—NR 4 R 5 are
R′ is hydrogen, alkyl, —(CH 2 ) d OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl;
b is 1 or 2;
d is 0, 1, 2, or 3; and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.
35 . A composition comprising a compound of claim 34 and a pharmaceutically acceptable carrier.
36 . A process for preparing a compound of formula I
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN,
S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl, selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a -alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′R″,
—(CH 2 ) c NR′C(O)-alkyl,
—(CH 2 ) c NR′S(O) 2 -alkyl,
—(CH 2 ) d S(O)-alkyl,
—(CH 2 ) d S-alkyl,
—(CH 2 ) d S(O) 2 -alkyl, or
—(CH 2 ) d S(O) 2 —NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) c OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N-di-alkyl,
R″ is hydrogen or alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) e -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″; or with
—(CH 2 ) 2 —S(O) 2 N(CH 3 )—CH 2 , or with
—S(O)—O—(CH 2 ) 2,3 —;
or —NR 4 R 5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5; and
f is 0, 1, or 2;
which process comprises reacting a compound of formula
with a compound of formula
NHR 4 R 5 III
to produce a compound of formula
wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
37 . A process for preparing a compound of formula I
wherein
R 1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH 2 ) d OH, —C(O)H, CF 3 , CN,
S-alkyl, —S(O) b -alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O) 2 -alkyl, or
is heteroaryl, selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF 2 , OCH 2 F, OCF 3 or CF 3 ;
R 4 and R 5 are each independently
hydrogen,
—(CR′R″) l —(CR′R″) l —(CR′R″) a —OH or —(CR′R″) l —(CR′R″) l —(CR′R″) a -alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
C b -alkyl,
—C(O)H,
—(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy,
—(CH 2 ) c NR′R″,
—(CH 2 ) c NR′C(O)-alkyl,
—(CH 2 ) c NR′S(O) 2 -alkyl,
—(CH 2 ) d S(O)-alkyl,
—(CH 2 ) d S-alkyl,
—(CH 2 ) d S(O) 2 -alkyl; or
—(CH 2 ) d S(O) 2 —NR′R″;
R′ is hydrogen, alkyl, —(CH 2 ) o OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O) 2 -alkyl, —S(O) 2 -halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O) 2 —N′-di-alkyl,
R″ is hydrogen or alkyl; or
R 4 and R 5 form together with the N-atom to which they are attached a ring
with —(CH 2 ) e -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl, or —C(O)NR′R″, or with
—(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—(CH 2 ) c —S(O) f —(CH 2 ) c -, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″, or with
—CH 2 CH═CH—CH 2 —, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R″) d OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or
by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R″, —(CH 2 ) d —S(O) 2 -alkyl, —(CH 2 ) d —S(O)-alkyl, —(CH 2 ) d —S-alkyl, —(CH 2 ) d —S(O) 2 —NR′R″, —(CH 2 ) d -pyrrolidinyl or —C(O)NR′R″;
or with
—(CH 2 ) 2 —S(O) 2 N(CH 3 )—CH 2 , or with
—S(O)—O—(CH 2 ) 2,3 —;
or —NR 4 R 5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5; and
f is 0, 1, or 2;
which process comprises reacting a compound of formula
with a compound of formula
R 1 —B(OH) 2
or a compound of formula
or a compound of formula
R 1 —ZnCl
to produce a compound of formula
wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.Join the waitlist — get patent alerts
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