Tetrahydropyridine, tetrahydroazepine, and dihydropyrrole derivatives for inflammation and immune-related uses
The invention relates to compounds of structural formula (Ia): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X 1 , X 2 , X 3 , X 4 , X 6 , X 10 , R 1 , Y, Z, L, and n are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.
1. A method of inhibiting IL-2 production in a cell, comprising administering to the cell a compound of structural formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are, independently, CH, CZ, or N;
one of X 3 , X 6 and X 10 is NR 2 , and the others are each, independently, CH 2 , CHR 2 , or C(R 2 ) 2 ;
X 4 is CH 2 , CHR 2 , C(R 2 ) 2 , or CHR 4 , provided that when X 3 is NR 2 , X 4 is CHR 4 ;
L 1 is —NR—C(O)— or —C(O)—NR;
Y is an optionally substituted monocyclic aryl or an optionally substituted heteroaryl;
each Z is independently selected from the group consisting of a C 1-4 alkyl, a C 1-4 haloalkyl, a halo, a C 1-4 alkoxy, a C 1-4 alkyl sulfanyl, cyano, nitro, and C 1-4 haloalkoxy;
R is H or a C 1-4 alkyl;
R 1 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; provided that when R 1 is H, X 4 is CHR 4 , and X 3 is NR 2 ;
R 2 , for each occurrence is, independently, halo, nitro, cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 ;
R 4 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 8 , for each occurrence, is independently —H, a halo, an alkyl, —OR 5 , —NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , or —C(O)NR 6 R 7 ;
R 5 , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 6 and R 7 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
p is 1 or 2;
n is 0, 1 or 2; and
q is 0, 1 or 2,
wherein, unless otherwise specified, an alkyl group has 1-10 carbons, an alkenyl group has 2-10 carbons, an alkynyl group has 2-10 carbons, a cycloalkyl group has 3-14 carbon atoms, a cycloalkenyl group has 5-14 carbon atoms, a heterocyclyl group is a 3-14 membered group having 1 to 8 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl group has 6-14 carbon atoms, and a heteroaryl group is a 5-14 membered group having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur; and
unless otherwise specified, an optionally substituted moiety is substituted with zero, one or more substituents selected from the group consisting of ═O, ═S, ═N—R 22 , an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, —C(O)NR 23 R 24 , —NR 25 C(O)R 26 , halo, —OR 25 , cyano, nitro, haloalkoxy, —C(O)R 25 , —NR 23 R 24 , —SR 25 , —C(O)OR 25 , —OC(O)R 25 , —NR 25 C(O)NR 23 R 24 , —O C(O)NR 23 R 24 , —NR 25 C(O)OR 26 , —S(O) p R 25 , or —S(O) p NR 23 R 24 , wherein R 22 is —H, an alkyl, acetyl, or aralkyl; R 23 and R 24 , for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl; or R 23 and R 24 taken together with the nitrogen to which they are attached is a heterocyclyl or a heteroaryl; and R 25 and R 26 for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl.
2. A method of modulating an ion channel in a cell, wherein the ion channel is a Ca 2+ -release-activated Ca 2+ (CRAC) channel, comprising administering to the cell a compound of structural formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are, independently, CH, CZ, or N;
one of X 3 , X 6 and X 10 is NR 2 , and the others are each, independently, CH 2 , CHR 2 , or C(R 2 ) 2 ;
X 4 is CH 2 , CHR 2 , C(R 2 ) 2 , or CHR 4 , provided that when X 3 is NR 2 , X 4 is CHR 4 ;
L 1 is —NR—C(O)— or —C(O)—NR—;
Y is an optionally substituted monocyclic aryl, or an optionally substituted heteroaryl;
each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, cyano, nitro, or lower haloalkoxy;
R is H or a lower alkyl;
R 1 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; provided that when R 1 is H, X 4 is CHR 4 , and X 3 is NR 2 ;
R 2 , for each occurrence is, independently, halo, nitro, cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 ;
R 4 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 8 , for each occurrence, is independently —H, a halo, an alkyl, —OR 5 , —NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , or —C(O)NR 6 R 7 ;
R 5 , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 6 and R 7 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
p is 1 or 2;
n is 0, 1 or 2; and
q is 0, 1 or 2,
wherein, unless otherwise specified, an alkyl group has 1-10 carbons, an alkenyl group has 2-10 carbons, an alkynyl group has 2-10 carbons, a cycloalkyl group has 3-14 carbon atoms, a cycloalkenyl group has 5-14 carbon atoms, a heterocyclyl group is a 3-14 membered group having 1 to 8 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl group has 6-14 carbon atoms, and a heteroaryl group is a 5-14 membered group having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur; and
unless otherwise specified, an optionally substituted moiety is substituted with zero, one or more substituents selected from the group consisting of ═O, ═S, ═N—R 22 , an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, —C(O)NR 23 R 24 , —NR 25 C(O)R 26 , halo, —OR 25 , cyano, nitro, haloalkoxy, —C(O)R 25 , —NR 23 R 24 , —SR 25 , —C(O)OR 25 , —OC(O)R 25 , —NR 25 C(O)NR 23 R 24 , —O C(O)NR 23 R 24 , —NR 25 C(O)OR 26 , —S(O) p R 25 , or —S(O) p NR 23 R 24 , wherein R 22 is —H, an alkyl, acetyl, or aralkyl; R 23 and R 24 , for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl; or R 23 and R 24 taken together with the nitrogen to which they are attached is a heterocyclyl or a heteroaryl; and R 25 and R 26 for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl.
3. A method for treating transplant rejection or skin graft rejection in a subject in need thereof, comprising administering to the subject a compound of structural formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are, independently, CH, CZ, or N;
one of X 3 , X 6 and X 10 is NR 2 , and the others are each, independently, CH 2 , CHR 2 , or C(R 2 ) 2 ;
X 4 is CH 2 , CHR 2 , C(R 2 ) 2 , or CHR 4 , provided that when X 3 is NR 2 , X 4 is CHR 4 ;
L 1 is —NR—C(O)— or —C(O)—NR—;
Y is an optionally substituted monocyclic aryl, or an optionally substituted heteroaryl;
each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, cyano, nitro, or lower haloalkoxy;
R is H or a lower alkyl;
R 1 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; provided that when R 1 is H, X 4 is CHR 4 , and X 3 is NR 2 ;
R 2 , for each occurrence is, independently, halo, nitro, cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 ;
R 4 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 8 , for each occurrence, is independently —H, a halo, an alkyl, —OR 5 , —NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , or —C(O)NR 6 R 7 ;
R 5 , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R 6 and R 7 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
p is 1 or 2;
n is 0, 1 or 2; and
q is 0, 1 or 2,
wherein, unless otherwise specified, an alkyl group has 1-10 carbons, an alkenyl group has 2-10 carbons, an alkynyl group has 2-10 carbons, a cycloalkyl group has 3-14 carbon atoms, a cycloalkenyl group has 5-14 carbon atoms, a heterocyclyl group is a 3-14 membered group having 1 to 8 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl group has 6-14 carbon atoms, and a heteroaryl group is a 5-14 membered group having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur; and
unless otherwise specified, an optionally substituted moiety is substituted with zero, one or more substituents selected from the group consisting of ═O, ═S, ═N—R 22 , an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, —C(O)NR 23 R 24 , —NR 25 C(O)R 26 , halo, —OR 25 , cyano, nitro, haloalkoxy, —C(O)R 25 , —NR 23 R 24 , —SR 25 , —C(O)OR 25 , —OC(O)R 25 , —NR 25 C(O)NR 23 R 24 , —O C(O)NR 23 R 24 , —NR 25 C(O)OR 26 , —S(O) p R 25 , or —S(O) p NR 23 R 24 , wherein R 22 is —H, an alkyl, acetyl, or aralkyl; R 23 and R 24 , for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl; or R 23 and R 24 taken together with the nitrogen to which they are attached is a heterocyclyl or a heteroaryl; and R 25 and R 26 for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl.
4. The method of claim 3 , wherein the subject is human.
5. The method of claim 1 , wherein the compound is represented by structural formula (VII):
or a pharmaceutically acceptable salt thereof, wherein:
X 3 is NR 2 ;
X 4 is CHR 4 ; and
m is 0, 1, 2, 3, or 4.
6. The method of claim 5 , wherein the compound is represented by structural formula (II):
or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 , wherein Y is selected from the group consisting of an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted furyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted indolizinyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazinyl, an optionally substituted quinolinyl, an optionally substituted isoquniolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted indolizinyl, an optionally substituted imidazopyridinyl, an optionally substituted isothiazolyl, an optionally substituted tetrazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl and an optionally substituted benzo(b)thienyl.
8. The method of claim 7 , wherein Y is an optionally substituted phenyl or an optionally substituted pyridinyl.
9. The method of claim 1 , wherein the compound is represented by structural formula (V):
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein R 2 is cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
11. The method of claim 9 , wherein the compound is represented by structural formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
X 5 is CH or N;
R 12 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and
R 13 is H, a halo, a lower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy.
12. The method of claim 11 , wherein
R 4 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl; and
R 2 is an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
13. The method of claim 1 , wherein the compound is represented by formula (XVI):
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein R 2 is cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
15. The method of claim 13 , wherein the compound is represented by formula (XVII):
or a pharmaceutically acceptable salt thereof, wherein:
X 5 is CH or N;
R 12 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and
R 13 is H, a halo, a lower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy.
16. The method of claim 15 , wherein
R 1 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl; and
R 2 is an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
17. The method of claim 1 , wherein the compound is represented by formula (XVIII):
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; and X 6 is NR 2 .
18. The method of claim 17 , wherein the compound is represented by formula (XXI):
or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 , wherein R 2 is cyano, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
20. The method of claim 18 , wherein the compound is represented by formula (XXII):
or a pharmaceutically acceptable salt thereof, wherein:
X 5 is CH or N;
R 12 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and
R 13 is H, a halo, a lower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy.
21. The method of claim 20 , wherein
R 1 is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl; and
R 2 is an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .
22. A method of inhibiting IL-2 production in a cell, comprising administering to the cell a compound of formula (X):
or a pharmaceutically acceptable salt thereof,
wherein A, W 1 , and W 2 are selected to form a ring selected from optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted pyrazinyl;
L 2 is selected from —NRC(O)— and —C(O)NR—, wherein R is H or lower alkyl;
Y 1 is selected from the group consisting of optionally substituted heterocyclyl, aryl, or heteroaryl, wherein substituents on aryl or heteroaryl groups are selected from the group consisting of halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cyano, and nitro;
R 9 and R 10 together with the carbons to which they are attached form an optionally substituted tetrahydropyridine or tetrahydroazepine; and
R 11 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —OR 5 , —SR 5 , —NR 6 R 7 , —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , or —C(NR 8 )SR 5 .
23. The method of claim 22 , wherein Y 1 is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl.
24. The method of claim 23 , wherein said optionally substituted tetrahydropyridine or tetrahydroazepine is disubstituted.
25. The method of claim 22 , wherein said optionally substituted tetrahydropyridine or tetrahydroazepine is substituted at the 2 position.
26. The method of claim 25 , wherein said optionally substituted tetrahydropyridine or tetrahydroazepine is further substituted at the 5 position.
27. The method of claim 25 , wherein said optionally substituted tetrahydropyridine or tetrahydroazepine is further substituted at the 4 position.
28. The method of claim 23 , wherein said optionally substituted tetrahydropyridine or tetrahydroazepine is tetrahydropyridine.
29. The method of claim 23 , wherein R 11 is selected from the group consisting of a halo, a lower alkyl, a lower alkoxy, a lower alkoxycarbonyl, a haloalkyl, a lower haloalkoxy, and an optionally substituted heteroaryl.
30. The method of claim 1 , wherein the compound is selected from the group consisting of:
N-[4-(1,4-dimethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-2,6-difluoro-benzamide;
5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester;
N-(4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;
N-(4-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;
Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
N-(4-(1,5-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;
Ethyl 4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
2,6-Difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide;
N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;
2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-vinyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid [4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;
N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide, hydrochloride;
N-[4-(1-benzyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
N-{4-[1-(4-nitro-phenyloxycarbonyl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;
N-[4-(1-allyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-cyano-3-ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
2,6-Difluoro-N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
N-[4-(1-ethanesulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
N-[4-(1-phenylsulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;
2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
N-[4-(1-pyridin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
2,6-Difluoro-N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-cyclopropylmethyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyridin-2-yl]-benzamide, hydrochloride;
2,6-Difluoro-N-[4-(1-thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide, dihydrochloride;
2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide, hydrochloride;
2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
5-Methyl-pyrimidine-4-carboxylic acid [4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;
2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide, hydrochloride;
2,6-Difluoro-N-{4-[1-(4-methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
5-Methyl-pyrimidine-4-carboxylic acid {4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide;
2,6-Difluoro-N-{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;
N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;
N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;
2,6-Difluoro-N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
2,6-Difluoro-N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
2,6-Difluoro-N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;
N-[4-(1-pyrimidin-5-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;
2,6-Difluoro-N-[4-(1-thiazol-2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide; and
2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;
or a pharmaceutically acceptable salt thereof.