US2003055266A1PendingUtilityA1
Small molecule modulators of G protein-coupled receptors
Priority: Jul 31, 1998Filed: May 6, 2002Published: Mar 20, 2003
Est. expiryJul 31, 2018(expired)· nominal 20-yr term from priority
Inventors:Nigel Robert Arnold BeeleyDominic P. BehanDerek T. ChalmersFrédérique MenzaghiSonja Strah-Pleynet
C07D 233/42C07D 405/12G01N 2333/726G01N 33/68C07D 409/12A61P 43/00C07D 403/12C07D 413/12C07D 513/04G01N 2500/00C07D 401/12
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Claims
Abstract
Disclosed herein are small molecule modulators of the G protein coupled receptor six, methods of making such compounds, and methods of using such compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A small molecule, GPR6 inverse agonist.
2 . A method for modulating by inverse agonism the G protein-coupled receptor, GPR6, comprising the step of contacting GPR6 with a small molecule GPR6 inverse agonist.
3 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following: H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 2 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (N 13 R 14 ), CNR 15 (SR 12 ), COOR 12 ,COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position on said aryl, each said position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 SC 5l H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 , SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring, said aryl ring being substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N and S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 , SC 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 ; or
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
4 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 , R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 ,R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl andr alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position on said aryl, each said position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 ,CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring, said aryl ring being substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N and S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H, 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 ; or
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
5 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 ) SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 may form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
6 . The method of claim 2 wherein the GPR6 inverse agonist is structurally represented as follows:
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 2 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylallyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 1 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 may form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SCH 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl;
7 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein at least one of V, W, X, Y and Z is selected from N and each of V, W, X, Y, and Z that is/are not N are independently selected from CR 1 , CR 2 , CR 3 , CR 4 , and CR 5 , with the proviso that at least two of V, W, X, Y and Z are other than N;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 2 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3 s cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
8 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein at least one of V, W, X, Y and Z is selected from N and each of V, W, X, Y, and Z that is/are not N are independently selected from CR 1 , CR 2 , CR 3 , CR 4 , and CR 5 , with the proviso that at least two of V, W, X, Y and Z are other than N;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 13 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
9 . The small molecule, GPR6 inverse agonist of claim 1 , structurally represented as follows:
wherein at least one of V, W, X, Y and Z is selected from N and each of V, W, X, Y, and Z that is/are not N are independently selected, from CR 1 , CR 2 , CR 3 , CR 4 , and CR 5 , with the proviso that at least two of V, W, X, Y and Z are other than N;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 5 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) m NR 13 R 14 , (CH 2 ) n SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
10 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein at least one of V, W, X, Y and Z is selected from N and each of V, W, X, Y, and Z that is/are not N are independently selected from CR 1 , CR 2 , CR 3 , CR 4 , and CR 5 , with the proviso that at least two of V, W, X, Y and Z are other than N;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 6 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NCH 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
11 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein Z is selected from NR 4 , O and S;
W, X, or Y are independently selected from N, CR 1 , CR 2 , and CR 3 , with the provisio that when Z is O and Y is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 2 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 3 R 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-9 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, L CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
12 . The method of claim 2 wherein said small mlecule, GPR6 inverse agonist is structurally represented as follows:
wherein Z is selected from NR 4 , O and S;
W, X, or Y are independently selected from N, CR 1 , CR 2 , and CR 3 , with the provisio that when Z is O and Y is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5, NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
13 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein Z is selected from NR 4 , O and S;
W, X, or Y are independently selected from N, CR 1 , CR 2 , and CR 3 , with the provisio that when Z is O and Y is N, then W is CR 1 and X is CR 2 ;
R 1 , R 12 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 2 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 2 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, (CH 2 ) m CO 2 H wherein n is 2 through 6 or m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
14 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein Z is selected from NR 4 , O and S;
W, X, or Y are independently selected from N, CR 1 , CR 2 , and CR 3 , with the proviso that when Z is O and Y is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain allyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, (CH 2 ) m CO 2 H wherein n is 2 through 6 or m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
15 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein Y is selected from NR 4 , O or S;
W, X, or Z are each independently selected from N or CR 1 , CR 2 , or CR 3, with the proviso that when Y is O and Z is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R6 and R 7 are each independently selected from H. C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H. C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4 9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 ,NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
16 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein Y is selected from NR 4 , O or S;
W, X, or Z are each independently selected from N or CR 1 , CR 2 , or CR 3 with the proviso that when Y is O and Z is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 2 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 3 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 ( 3 R 14 ) CNRR 5 (SR 12 ) COOR 12 COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) n SO 3 H, and (CH 2 ) m CO 2 H, where in n is 2 through 6 an d m is I through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
17 . The small molecule, GPR6 inverse agonist of claim 1 structurally represented as follows:
wherein Y is selected from NR 4 , O or S;
W, X, or Z are each independently selected from N or CR 1 , CR 2 , or CR 3 with the proviso that when Y is O and Z is N, then W is CR 1 and X is CR 2 ;
R 1 , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 R 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 13 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R 5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 1 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloakyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CC 13 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
18 . The method of claim 2 wherein the small molecule, GPR6 inverse agonist is structurally represented as follows:
wherein Y is selected from NR 4 , O or S;
W, X, or Z are each independently selected from N or CR 1 , CR 2 , or CR 3 with the proviso that when Y is O and Z is N, then W is CR 1 and X is CR 2 ;
R , R 2 , and R 3 are each independently selected from the following:
H, F, Cl, Br, I, R 12 , CF 3 , CF 2 R 12 , CF 2 CF 2 , CCl 3 , CCl 2 R 12 , CCl 2 CCl 2 R 12 , NR 13 R 14 , NR 15 COR 12 , NR 15 SO 2 R 12 , OR 12 , OCF 3 , OCF 2 R 12 , OCF 2 CF 2 R 12 , OCOR 12 , OSO 2 R 12 , OPO(OR 12 ) 2 , SR 12 , SCF 3 , SCF 2 R 12 , SCF 2 CF 2 R 12 , SCOR 12 , SO 3 R 12 , SO 2 NR 13 R 14 , PO(OR 12 ) 3 , PO(OR 12 ) 2 R 12 , NO 2 , CN, CNR 15 (NR 13 R 14 ), CNR 15 (SR 12 ), COOR 12 , COSR 12 , CONR 3 R 14 , and
wherein any two adjacent positions of R 1 , R 2 , R 3 , R 4 , and R5 can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure;
R 4 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5 , CSR 5 , and SO 2 R 5 ;
R 5 , R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl;
R 6 and R 7 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl and alkylaryl
R 8 , R 9 , R 10 , and R 11 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2 g alkenyl, aryl and alkylaryl;
R 12 is selected from H, C 1-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2 ) n NR 13 R 14 , (CH 2 ) m SO 3 H, and (CH 2 ) m CO 2 H, wherein n is 2 through 6 and m is 1 through 6;
R 13 and R 14 are each independently selected from H, C 1-8 straight chain alkyl, branched alkyl, C 2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH 2 aryl, wherein each said aryl group or said aryl portion of said CH 2 aryl group may be optionally substituted by up to four substituents in any position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and/or R 14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, or OCH 2 CH 2 O to form a bi-cyclic structure; or
R 13 and R 14 form part of a 5, 6 or 7 membered saturated cyclic structure or 5,6 or 7 membered unsaturated cyclic structure, each such structure optionally containing up to four heteroatoms selected from O, N and S and wherein each said cyclic structure may be optionally substituted by up to four substituents in any position, each position independently selected from:
F, Cl, Br, I, CF 3 , CCl 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC 2 H 5 , N(C 2 H 5 ) 2 , NHC 3 H 7 , N(C 3 H 7 ) 2 , NHC 4 H 9 , N(C 4 H 9 ) 2 , NHCOH, NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 4 H 9 , NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 3 H 7 , NHSO 2 C 4 H 9 , OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OC 4 H 7 , OC 4 H 9 , OC 5 H 9 , OC 5 H 11 , OC 6 H 11 , OC 6 H 13 , OCF 3 , OCOCH 3 , OCOC 2 H 5 , OCOC 3 H 7 , OCOC 4 H 9 , OSO 2 CH 3 , OSO 2 C 2 H 5 , OSO 2 C 3 H 7 , OSO 2 C 4 H 9 , SH, SCH 3 , SC 2 H 5 , SC 3 H 7 , SC 4 H 7 , SC 4 H 9 , SC 5 H 9 , SC 5 H 11 , SC 6 H 11 , SC 6 H 13 ,, SCF 3 , SCOCH 3 , SCOC 2 H 5 , SCOC 3 H 7 , SCOC 4 H 9 , SO 3 CH 3 , SO 3 C 2 H 5 , SO 3 C 3 H 7 , SO 3 C 4 H 9 , SO 2 NH 2 , SO 2 NHCH 3 , SO 2 N(CH 3 ) 2 , SO 2 NHC 2 H 5 , SO 2 N(C 2 H 5 ) 2 , SO 2 NHC 3 H 7 , SO 2 N(C 3 H 7 , SO 2 N(C 3 H 7 ) 2 , SO 2 NHC 4 H 9 , SO 2 N(C 4 H 9 ) 2 , NO 2 , CN, COOCH 3 , COOC 2 H 5 , COOC 3 H 7 , COOC 4 H 9 , COSCH 3 , COSC 2 H 5 , COSC 3 H 7 , COSC 4 H 9 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CONHC 2 H 5 , CON(C 2 H 5 ) 2 , CONHC 3 H 7 , CON(C 3 H 7 ) 2 , CONHC 4 H 9 , CON(C 4 H 9 ) 2 , and
wherein when R 13 and R 14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH 2 CH 2 CH 2 CH 2 , CHCHCH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 , SCH 2 S, SCH 2 CH 2 S, OCH 2 O, and OCH 2 CH 2 O to form a bi-cyclic structure; and
R 15 is selected from H, C 3-8 straight chain alkyl, branched alkyl, C 3-8 cycloalkyl, C 4-9 alkylcycloalkyl or cycloalkylalkyl, and C 2-8 alkenyl.
19 . A small molecule, GPR6 inverse agonist selected from the group consisting of the e following structures:
20 . A method for modulating by inverse agonism the G protein-coupled receptor, GPR6, comprising the step of contacting GPR6 with a small molecule GPR6 inverse agonist selected from the group consisting of:Join the waitlist — get patent alerts
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