Bissulfonamide Compounds As Agonists Of GalR1, Compositions, And Methods Of Use

Abstract

Embodiments of the present invention provide bissulfonamide compounds that are agonists of GalR1. The present invention further provides compositions comprising bissulfonamide compounds that are agonists of GalR1, and methods of use of such compounds and compositions.

1 . A method comprising administering to a subject a pharmaceutical composition comprising a compound of Formula (I)
   Ar 2 —SO 2 NH—Ar 1 —NHSO 2 —Ar 3   (I)   
     wherein 
     Ar 1  is selected from the group consisting of an arylene, heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene, fused cycloalkylheteroarylene and fused heterocyclylheteroarylene group optionally substituted 1 to 4 times, wherein the substituents of Ar 1  are selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -alkyl; 
 g) -aryl; 
 h) -heteroaryl; 
 i) -cycloalkyl; 
 j) -L-aryl; 
 k) -L-arylene-aryl; 
 l) -L-arylene-alkyl; 
 m) -Q-alkyl; 
 n) -Q-aryl; 
 o) -Q-alkylene-aryl; 
 p) -Q-arylene-alkyl; 
 q) -L-Q-alkylene-aryl; 
 r) -arylene-Q-alkyl; 
 s) -L-Q-alkyl; 
 t) -L-Q-aryl; 
 u) -L-Q-heteroaryl; 
 v) -L-Q-cycloalkyl; 
 w) -L-Q-arylene-alkyl; 
 x) -D 4 -alkylene-NR 1 R 2 ; 
 y) -D 4 -NR 1 R 2 ; 
 z) -D 4 -alkyl; and 
 aa) -D 4 -H; 
 wherein
 D 4  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 4 )—, —C(O)—, —CON(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )CON(R 4′ )—, —N(R 4 )C(O)O—, —OC(O)N(R 4 )—, —N(R 4 )SO 2 —, —SO 2 N(R 4 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 4 )SO 2 N(R 4 )— and —N═N—;
 wherein
 R 4  and R 4′  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and -alkylene-aryl; 
 
 
 R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 1  and R 2  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 1  and R 2  are attached,
 wherein
 o and p are, independently, 1, 2, 3, or 4 and the sum of the values of o and p is less than or equal to 6, 
 Z 4  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 31 )—, —N(C(O)R 31 )—, —N(C(O)NHR 31 )—, —N(C(O)NR 31 R 32 )—, —N(S(O) 2 NHR 31 )—, —N(SO 2 R 31 )— and —N(C(O)OR 31 )—; 
  wherein 
  R 31  and R 32  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 
 
 L is selected from the group consisting of a direct bond, -alkylene, -alkenylene and -alkynylene; and 
 Q is selected from the group consisting of a direct bond, —CH 2 —, —O— and —S—; 
 
     Ar 2  and Ar 3  are independently selected from the group consisting of an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at least one of Ar 2  and Ar 3  comprise an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the —NHSO 2 -group, and Ar 2  and Ar 3  may be optionally substituted 1 to 5 times with a substituent selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -alkyl; 
 f) -aryl; 
 g) -cycloalkyl; 
 h) -heterocyclyl; 
 i) -alkylene-cycloalkyl; 
 j) -perhaloalkyl; 
 k) heteroaryl; 
 l) -alkylene-aryl; 
 m) -D 1 -H; 
 n) -D 1 -R 3 ; 
 o) -D 1 -alkyl; 
 p) -D 1 -aryl; 
 q) -D 1 -perhaloalkyl; 
 r) -D 1 -alkylene-R 3 ; 
 s) -D 1 -alkylene-aryl; 
 t) -D 1 -alkylene-D 2 -R 3 ; 
 u) -D 1 -cycloalkyl; 
 v) -D 1 -heterocyclyl; 
 w) -D 1 -aryl; 
 x) -D 1 -heteroaryl; 
 y) -D 1 -arylene-D 2 -R 3 ; 
 z) -D 1 -heteroarylene-D 2 -R 3 ; 
 aa) -D 1 -alkylene-heteroaryl; 
 bb) -D 1 -alkylene-heterocyclyl; 
 cc) -D 1 -alkylene-aryl; 
 aa) -D 1 -alkylene-arylene-D 2 -R 3 ; 
 bb) -D 1 -alkylene-heteroarylene-D 2 -R 3 ; 
 ff) -D 1 -alkylene-NR 5 R 6 ; 
 gg) -D 1 -arylene-NR 5 R 6 ; and 
 hh) -acid isostere;
 wherein
 D 1  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 7 )—, —C(O)—, —CON(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )CON(R 8 )—, —N(R 7 )C(O)O—, —OC(O)N(R 7 )—, —N(R 7 )SO 2 —, —SO 2 N(R 7 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 7 )SO 2 N(R 8 )— and —N═N—;
 wherein 
  R 7  and R 8  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 3  is selected from the group consisting of -hydrogen, -alkyl, -aryl, -heterocyclyl and -heteroaryl; and 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 5  and R 6  may be taken together to form a ring having the formula —(CH 2 ) o -Z 1 -(CH 2 ) p — bonded to the nitrogen atom to which R 5  and R 6  are attached,
 wherein 
  o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6, 
  Z 1  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 9 )—, —N(C(O)R 9 )—, —N(C(O)NHR 9 )—, —N(C(O)NR 9 R 10 )—, —N(S(O) 2 NHR 9 )—, —N(SO 2 R 9 )— and —N(C(O)OR 9 )—; 
  wherein 
  R 9  and R 10  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 D 2  is selected from the group consisting of -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O) 2 —, —S(O) 2 -alkylene, —O—, —N(R 11 )—, —C(O)—, —CON(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )CON(R 12 )—, —N(R 1 )C(O)O—, —OC(O)N(R 11 )—, —N(R 11 )SO 2 —, —SO 2 N(R 11 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 — and —N(R 11 )SO 2 N(R 12 )—,
 wherein 
  R 11  and R 12  are independently selected from the group consisting of -hydrogen, -alkyl and -aryl; 
 
 
 
 
     and wherein 
     the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl in Ar 2 , Ar 3 , R 1  through R 32  may be optionally substituted 1 to 4 times with a substituent selected from the group consisting of
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -A-perhaloalkyl 
 g) -A-R 40 ; 
 h) -A-alkyl; 
 i) -A-aryl; 
 j) -A-alkylene-aryl; 
 k) -A-alkylene-NR 41 R 42 ; and 
 l) -A-alkyl-E-R 43 ; 
 
     wherein
 A and E are independently selected from the group consisting of —CH 2 —, —O—, —N(R 44 )—, —C(O)—, —CON(R 44 )—, —N(R 44 )C(O)—, —N(R 44 )CON(R 45 )—, —N(R 44 )C(O)O—, —OC(O)N(R 44 )—, —N(R 44 )SO 2 —, —SO 2 N(R 44 )—, —C(O)—O—, —O—C(O)— and —N(R 44 )SO 2 N(R 45 )—,
 wherein R 44  and R 45  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 40  and R 43  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and 
 R 41  and R 42  are independently selected from the group consisting of hydrogen, aryl and alkyl, wherein R 41  and R 42  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 41  and R 42  are attached,
 wherein
 o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6,
 Z 4  is selected from the group consisting of a direct bond a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 46 )—, —N(C(O)R 46 )—, —N(C(O)NHR 46 )—, —N(C(O)NR 46 R 47 )—, —N(S(O) 2 NHR 46 )—, —N(SO 2 R 46 )— and —N(C(O)OR 46 )—; 
  wherein 
  R 46  and R 47  are independently selected from the group consisting of hydrogen, aryl, alkyl and -alkylene-aryl; 
 
 
 
 
     or a pharmaceutically acceptable salt thereof,
 wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose for which an analgesic effect is observed in a subject. 
 
   
   
       2 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds to at least one peripheral GalR1 while substantially unable to cross the blood-brain barrier in the subject. 
   
   
       3 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dosage level at about or below 1000 mg/kg of the body weight of the subject. 
   
   
       4 . The method of  claim 1 , wherein the dose is an amount sufficient to increase activity of GalR1 receptors in the subject. 
   
   
       5 . The method of  claim 1 , wherein the dose is in an amount sufficient to stimulate peripheral GalR1 receptors in the subject, wherein the compound is partially or completely excluded from the brain of the subject. 
   
   
       6 . A method comprising administering a pharmaceutical composition to a subject having a disorder ameliorated by the activation of a GalR1 receptor, wherein the pharmaceutical composition comprises a compound of Formula (I)
   Ar 2 —SO 2 NH—Ar 1 —NHSO 2 —Ar 3   (I)   
     wherein 
     Ar 1  is selected from the group consisting of an arylene, heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene, fused cycloalkylheteroarylene and fused heterocyclylheteroarylene group optionally substituted 1 to 4 times, wherein the substituents of Ar 1  are selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -alkyl; 
 g) -aryl; 
 h) -heteroaryl; 
 i) -cycloalkyl; 
 j) -L-aryl; 
 k) -L-arylene-aryl; 
 l) -L-arylene-alkyl; 
 m) -Q-alkyl; 
 n) -Q-aryl; 
 o) -Q-alkylene-aryl; 
 p) -Q-arylene-alkyl; 
 q) -L-Q-alkylene-aryl; 
 r) -arylene-Q-alkyl; 
 s) -L-Q-alkyl; 
 t) -L-Q-aryl; 
 u) -L-Q-heteroaryl; 
 v) -L-Q-cycloalkyl; 
 w) -L-Q-arylene-alkyl; 
 x) -D 4 -alkylene-NR 1 R 2 ; 
 y) -D 4 -NR 1 R 2 ; 
 z) -D 4 -alkyl; and 
 aa) -D 4 -H;
 wherein
 D 4  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 4 )—, —C(O)—, —CON(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )CON(R 4 )—, —N(R 4 )C(O)O—, —OC(O)N(R 4 )—, —N(R 4 )SO 2 —, —SO 2 N(R 4 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 4 )SO 2 N(R 4 )— and —N═N—;
 wherein 
  R 4  and R 4′  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and -alkylene-aryl; 
 
 R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 1  and R 2  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 1  and R 2  are attached,
 wherein 
  o and p are, independently, 1, 2, 3, or 4 and the sum of the values of o and p is less than or equal to 6, 
  Z 4  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 31 )—, —N(C(O)R 31 )—, —N(C(O)NHR 31 )—, —N(C(O)NR 31 R 32 )—, —N(S(O) 2 NHR 31 )—, —N(SO 2 R 31 )— and —N(C(O)OR 31 )—; 
  wherein 
  R 31  and R 32  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 
 L is selected from the group consisting of a direct bond, -alkylene, -alkenylene and -alkynylene; and 
 Q is selected from the group consisting of a direct bond, —CH 2 —, —O— and —S—; 
 
 
     Ar 2  and Ar 3  are independently selected from the group consisting of an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at least one of Ar 2  and Ar 3  comprise an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the —NHSO 2 -group, and Ar 2  and Ar 3  may be optionally substituted 1 to 5 times with a substituent selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -alkyl; 
 f) -aryl; 
 g) -cycloalkyl; 
 h) -heterocyclyl; 
 i) -alkylene-cycloalkyl; 
 j) -perhaloalkyl; 
 k) heteroaryl; 
 l) -alkylene-aryl; 
 m) -D 1 -H; 
 n) -D 1 -R 3 ; 
 o) -D 1 -alkyl; 
 p) -D 1 -aryl; 
 q) -D 1 -perhaloalkyl; 
 r) -D 1 -alkylene-R 3 ; 
 s) -D 1 -alkylene-aryl; 
 t) -D 1 -alkylene-D 2 -R 3 ; 
 u) -D 1 -cycloalkyl; 
 v) -D 1 -heterocyclyl; 
 w) -D 1 -aryl; 
 x) -D 1 -heteroaryl; 
 y) -D 1 -arylene-D 2 -R 3 ; 
 z) -D 1 -heteroarylene-D 2 -R 3 ; 
 aa) -D 1 -alkylene-heteroaryl; 
 bb) -D 1 -alkylene-heterocyclyl; 
 cc) -D 1 -alkylene-aryl; 
 aa) -D 1 -alkylene-arylene-D 2 -R 3 ; 
 bb) -D 1 -alkylene-heteroarylene-D 2 -R 3 ; 
 ff) -D 1 -alkylene-NR 5 R 6 ; 
 gg) -D 1 -arylene-NR 5 R 6 ; and 
 hh) -acid isostere;
 wherein
 D 1  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 7 )—, —C(O)—, —CON(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )CON(R 8 )—, —N(R 7 )C(O)O—, —OC(O)N(R 7 )—, —N(R 7 )SO 2 —, —SO 2 N(R 7 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 7 )SO 2 N(R 8 )— and —N═N—;
 wherein 
  R 7  and R 8  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 3  is selected from the group consisting of -hydrogen, -alkyl, -aryl, -heterocyclyl and -heteroaryl; and 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 5  and R 6  may be taken together to form a ring having the formula —(CH 2 ) o -Z 1 -(CH 2 ) p — bonded to the nitrogen atom to which R 5  and R 6  are attached,
 wherein 
  o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6, 
  Z 1  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)-20, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 9 )—, —N(C(O)R 9 )—, —N(C(O)NHR 9 )—, —N(C(O)NR 9 R 10 )—, —N(S(O) 2 NHR 9 )—, —N(SO 2 R 9 )— and —N(C(O)OR 9 )—; 
  wherein 
  R 9  and R 10  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 D 2  is selected from the group consisting of -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O) 2 —, —S(O) 2 -alkylene, —O—, —N(R 11 )—, —C(O)—, —CON(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )CON(R 12 )—, —N(R 11 )C(O)O—, —OC(O)N(R 11 )—, —N(R 11 )SO 2 —, —SO 2 N(R 11 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 — and —N(R 11 )SO 2 N(R 12 )—,
 wherein 
  R 11  and R 12  are independently selected from the group consisting of -hydrogen, -alkyl and -aryl; 
 
 
 
 
     and wherein 
     the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl in Ar 2 , Ar 3 , R 1  through R 32  may be optionally substituted 1 to 4 times with a substituent selected from the group consisting of
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -A-perhaloalkyl 
 g) -A-R 40 ; 
 h) -A-alkyl; 
 i) -A-aryl; 
 j) -A-alkylene-aryl; 
 k) -A-alkylene-NR 41 R 42 ; and 
 l) -A-alkyl-E-R 43 ; 
 
     wherein
 A and E are independently selected from the group consisting of —CH 2 —, —O—, —N(R 44 )—, —C(O)—, —CON(R 44 )—, —N(R 44 )C(O)—, —N(R 44 )CON(R 45 )—, —N(R 44 )C(O)O—, —OC(O)N(R 44 )—, —N(R 44 )SO 2 —, —SO 2 N(R 44 )—, —C(O)—O—, —O—C(O)— and —N(R 44 )SO 2 N(R 45 )—,
 wherein R 44  and R 45  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 40  and R 43  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and 
 R 41  and R 42  are independently selected from the group consisting of hydrogen, aryl and alkyl, wherein R 41  and R 42  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 41  and R 42  are attached,
 wherein
 o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6,
 Z 4  is selected from the group consisting of a direct bond a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 46 )—, —N(C(O)R 46 )—, —N(C(O)NHR 46 )—, —N(C(O)NR 46 R 47 )—, —N(S(O) 2 NHR 46 )—, —N(SO 2 R 46 )— and —N(C(O)OR 46 )—; 
  wherein 
  R 46  and R 47  are independently selected from the group consisting of hydrogen, aryl, alkyl and -alkylene-aryl; 
 
 
 
 
     or a pharmaceutically acceptable salt thereof,
 wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to increase activity of GalR1 receptors in a subject. 
 
   
   
       7 . The method of  claim 6 , wherein the disorder is selected from the group consisting of seizure disorders, neuroendocrine disorders, gastrointestinal disorders, musculoskeletal disorders, psychotic behavior, schizophrenia, migraine, morphine tolerance, drug addition, opiate addiction, pain, neuropathic pain, inflammatory pain, chronic pain, sleep disorders, eating/body weight disorders, bulimia, bulimia nervosa, anorexia nervosa, metabolic wasting disorders, cachexia, neuropathological disorders, diabetes, dyslipidemia, hypertension, memory loss, depression, anxiety, cerebral hemorrhage, and diarrhea. 
   
   
       8 . The method of  claim 6 , wherein the disorder is selected from the group consisting of neuropathic pain, inflammatory pain, chronic pain and allodynia. 
   
   
       9 . The method of  claim 6 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dosage level at about or below 1000 mg/kg of the body weight of the subject. 
   
   
       10 . The method of  claim 1 , wherein the dose is in an amount sufficient to stimulate peripheral GalR1 receptors in the subject, wherein the compound is partially or completely excluded from the brain of the subject. 
   
   
       11 . A method comprising:
 administering to a subject suffering from pain a GalR1 agonist in an amount sufficient to stimulate peripheral GalR1 receptors, wherein the GalR1 agonist is partially or completely excluded from the brain.   
   
   
       12 . The method of  claim 11 , wherein the GalR1 agonist comprises a compound of Formula (I)
   Ar 2 —SO 2 NH—Ar 1 —NHSO 2 —Ar 3   (I)   
     wherein 
     Ar 1  is selected from the group consisting of an arylene, heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene, fused cycloalkylheteroarylene and fused heterocyclylheteroarylene group optionally substituted 1 to 4 times, wherein the substituents of Ar 1  are selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -alkyl; 
 g) -aryl; 
 h) -heteroaryl; 
 i) -cycloalkyl; 
 j) -L-aryl; 
 k) -L-arylene-aryl; 
 l) -L-arylene-alkyl; 
 m) -Q-alkyl; 
 n) -Q-aryl; 
 o) -Q-alkylene-aryl; 
 p) -Q-arylene-alkyl; 
 q) -L-Q-alkylene-aryl; 
 r) -arylene-Q-alkyl; 
 s) -L-Q-alkyl; 
 t) -L-Q-aryl; 
 u) -L-Q-heteroaryl; 
 v) -L-Q-cycloalkyl; 
 w) -L-Q-arylene-alkyl; 
 x) -D 4 -alkylene-NR 1 R 2 ; 
 y) -D 4 -NR 1 R 2 ; 
 z) -D 4 -alkyl; and 
 aa) -D 4 -H; 
 wherein
 D 4  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 4 )—, —C(O)—, —CON(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )CON(R 4′ )—, —N(R 4 )C(O)O—, —OC(O)N(R 4 )—, —N(R 4 )SO 2 —, —SO 2 N(R 4 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 4 )SO 2 N(R 4 )— and —N═N—;
 wherein
 R 4  and R 4′  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and -alkylene-aryl; 
 
 
 R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 1  and R 2  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 1  and R 2  are attached,
 wherein
 and p are, independently, 1, 2, 3, or 4 and the sum of the values of o and p is less than or equal to 6, 
 Z 4  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)-20, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 31 )—, —N(C(O)R 31 )—, —N(C(O)NHR 31 )—, —N(C(O)NR 31 R 32 )—, —N(S(O) 2 NHR 31 )—, —N(SO 2 R 31 )— and —N(C(O)OR 31 )—; 
  wherein 
  R 31  and R 32  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 
 
 L is selected from the group consisting of a direct bond, -alkylene, -alkenylene and -alkynylene; and 
 Q is selected from the group consisting of a direct bond, —CH 2 —, —O— and —S—; 
 
     Ar 2  and Ar 3  are independently selected from the group consisting of an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at least one of Ar 2  and Ar 3  comprise an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the —NHSO 2 -group, and Ar 2  and Ar 3  may be optionally substituted 1 to 5 times with a substituent selected from the group consisting of:
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -alkyl; 
 f) -aryl; 
 g) -cycloalkyl; 
 h) -heterocyclyl; 
 i) -alkylene-cycloalkyl; 
 j) -perhaloalkyl; 
 k) heteroaryl; 
 l) -alkylene-aryl; 
 m) -D 1 -H; 
 n) -D 1 -R 3 ; 
 o) -D 1 -alkyl; 
 p) -D 1 -aryl; 
 q) -D 1 -perhaloalkyl; 
 r) -D 1 -alkylene-R 3 ; 
 s) -D 1 -alkylene-aryl; 
 t) -D 1 -alkylene-D 2 -R 3 ; 
 u) -D 1 -cycloalkyl; 
 v) -D 1 -heterocyclyl; 
 w) -D 1 -aryl; 
 x) -D 1 -heteroaryl; 
 y) -D 1 -arylene-D 2 -R 3 ; 
 z) -D 1 -heteroarylene-D 2 -R 3 ; 
 aa) -D 1 -alkylene-heteroaryl; 
 bb) -D 1 -alkylene-heterocyclyl; 
 cc) -D 1 -alkylene-aryl; 
 aa) -D 1 -alkylene-arylene-D 2 -R 3 ; 
 bb) -D 1 -alkylene-heteroarylene-D 2 -R 3 ; 
 ff) -D 1 -alkylene-NR 5 R 6 ; 
 gg) -D 1 -arylene-NR 5 R 6 ; and 
 hh) -acid isostere;
 wherein
 D 1  is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 7 )—, —C(O)—, —CON(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )CON(R 8 )—, —N(R 7 )C(O)O—, —OC(O)N(R 7 )—, —N(R 7 )SO 2 —, —SO 2 N(R 7 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 7 )SO 2 N(R 8 )— and —N═N—;
 wherein 
  R 7  and R 8  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 3  is selected from the group consisting of -hydrogen, -alkyl, -aryl, -heterocyclyl and -heteroaryl; and 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl and aryl, wherein R 5  and R 6  may be taken together to form a ring having the formula —(CH 2 ) o -Z 1 -(CH 2 ) p — bonded to the nitrogen atom to which R 5  and R 6  are attached,
 wherein 
  o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6, 
  Z 1  is selected from the group consisting of a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, NHS(O) 2 NH—, —OC(O)—, —N(R 9 )—, —N(C(O)R 9 )—, —N(C(O)NHR 9 )—, —N(C(O)NR 9 R 10 )—, —N(S(O) 2 NHR 9 )—, —N(SO 2 R 9 )— and —N(C(O)OR 9 )—; 
  wherein 
  R 9  and R 10  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl and -alkylene-aryl; 
 
 D 2  is selected from the group consisting of -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O) 2 —, —S(O) 2 -alkylene, —O—, —N(R 1 )—, —C(O)—, —CON(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )CON(R 12 )—, —N(R 11 )C(O)O—, —OC(O)N(R 11 )—, —N(R 11 )SO 2 —, —SO 2 N(R 11 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 — and —N(R 11 )SO 2 N(R 12 )—,
 wherein 
  R 11  and R 12  are independently selected from the group consisting of -hydrogen, -alkyl and -aryl; 
 
 
 
 
     and wherein 
     the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl in Ar 2 , Ar 3 , R 1  through R 32  may be optionally substituted 1 to 4 times with a substituent selected from the group consisting of
 a) -hydrogen; 
 b) -halo; 
 c) -cyano; 
 d) -nitro; 
 e) -perhaloalkyl; 
 f) -A-perhaloalkyl 
 g) -A-R 40 ; 
 h) -A-alkyl; 
 i) -A-aryl; 
 j) -A-alkylene-aryl; 
 k) -A-alkylene-NR 41 R 42 ; and 
 l) -A-alkyl-E-R 43 ; 
 
     wherein
 A and E are independently selected from the group consisting of —CH 2 —, —O—, —N(R 44 )—, —C(O)—, —CON(R 44 )—, —N(R 4 )C(O)—, —N(R 44 )CON(R 45 )—, —N(R 44 )C(O)O—, —OC(O)N(R 44 )—, —N(R 44 )SO 2 —, —SO 2 N(R 44 )—, —C(O)—O—, —O—C(O)— and —N(R 44 )SO 2 N(R 45 )—,
 wherein R 44  and R 45  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; 
 
 R 40  and R 43  are independently selected from the group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and 
 R 41  and R 42  are independently selected from the group consisting of hydrogen, aryl and alkyl, wherein R 41  and R 42  may be taken together to form a ring having the formula —(CH 2 ) o -Z 4 -(CH 2 ) p — bonded to the nitrogen atom to which R 41  and R 42  are attached,
 wherein
 o and p are, independently, 1, 2, 3, or 4 and the value of the sum of o and p is less than or equal to 6,
 Z 4  is selected from the group consisting of a direct bond a direct bond, —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O) 2 N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 46 )—, —N(C(O)R 46 )—, —N(C(O)NHR 46 )—, —N(C(O)NR 46 R 47 )—, —N(S(O) 2 NHR 46 )—, —N(SO 2 R 46 )— and —N(C(O)OR 46 )—; 
  wherein 
  R 46  and R 47  are independently selected from the group consisting of hydrogen, aryl, alkyl and -alkylene-aryl; 
 
 
 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       13 . The method of  claim 11 , wherein the pain is inflammatory pain. 
   
   
       14 . The method of  claim 11 , wherein the pain is allodynia. 
   
   
       15 . The method of  claim 11 , wherein the pain is neuropathic pain. 
   
   
       16 . The method of  claim 11 , further comprising modulating peripheral GalR1 receptors in the subject at the level of the dorsal root ganglia (DRG), wherein the GalR1 agonist is substantially unable to cross the blood-brain barrier in the subject at doses for which an analgesic effect is observed in the subject.