U.S. patent application number 12/867502 was filed with the patent office on 2011-02-24 for novel imaging agents for detecting neurological dysfunction.
This patent application is currently assigned to SIEMENS MEDICAL SOLUTIONS USA, INC.. Invention is credited to Gang Chen, Kai Chen, Brian A. Duclos, Zhiyong Gao, Farhad Karimi, Dhanalakshmi Kasi, Hartmuth C. Kolb, Qianwa Liang, Vani P. Mocharla, Henry Clifton Padgett, Peter J.H. Scott, Anjana Sinha, Joseph C. Walsh, Eric Wang, Chunfang Xia, Wei Zhang, Tieming Zhao.
Application Number | 20110046378 12/867502 |
Document ID | / |
Family ID | 40627498 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046378 |
Kind Code |
A1 |
Kolb; Hartmuth C. ; et
al. |
February 24, 2011 |
Novel Imaging Agents for Detecting Neurological Dysfunction
Abstract
Disclosed here in are compounds and methods of diagnosing
Alzheimer's Disease or a predisposition thereto in a mammal, the
method comprising administering to the mammal a diagnostically
effective amount of a radiolabeled compound, wherein the compound
is selected from the group consisting of radiolabeled flavones,
coumarins, carbazoles, quinolinones, chromenones, imidazoles and
triazoles derivatives, allowing the compound to distribute into the
brain tissue, and imaging the brain tissue, wherein an increase in
binding of the compound to the brain tissue compared to a normal
control level of binding indicates that the mammal is suffering
from or is at risk of developing Alzheimer's Disease
Inventors: |
Kolb; Hartmuth C.; (Playa
Del Rey, CA) ; Walsh; Joseph C.; (Pacific Palisades,
CA) ; Liang; Qianwa; (Hacienda Heights, CA) ;
Duclos; Brian A.; (Kalamazoo, MI) ; Zhang; Wei;
(Los Angeles, CA) ; Scott; Peter J.H.; (Ypsilanti,
MI) ; Chen; Kai; (Rockville, MD) ; Gao;
Zhiyong; (Wynnewood, PA) ; Zhao; Tieming; (Los
Angeles, CA) ; Mocharla; Vani P.; (Los Angeles,
CA) ; Kasi; Dhanalakshmi; (Los Angeles, CA) ;
Chen; Gang; (Los Angeles, CA) ; Wang; Eric;
(San Diego, CA) ; Sinha; Anjana; (San Diego,
CA) ; Xia; Chunfang; (Los Angeles, CA) ;
Padgett; Henry Clifton; (Hermosa Beach, CA) ; Karimi;
Farhad; (Mansfield, MA) |
Correspondence
Address: |
SIEMENS CORPORATION;INTELLECTUAL PROPERTY DEPARTMENT
170 WOOD AVENUE SOUTH
ISELIN
NJ
08830
US
|
Assignee: |
SIEMENS MEDICAL SOLUTIONS USA,
INC.
Malvern
PA
|
Family ID: |
40627498 |
Appl. No.: |
12/867502 |
Filed: |
February 17, 2009 |
PCT Filed: |
February 17, 2009 |
PCT NO: |
PCT/US09/00961 |
371 Date: |
November 15, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61066101 |
Feb 14, 2008 |
|
|
|
Current U.S.
Class: |
546/86 ; 546/141;
546/150; 546/153; 546/155; 546/171; 546/274.1; 548/247; 548/255;
548/266.4; 548/310.4; 548/420; 548/440; 548/441; 548/444; 549/289;
549/400; 549/403 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
25/24 20180101; C07B 59/002 20130101; A61P 25/00 20180101; A61P
25/22 20180101; A61P 25/18 20180101; A61P 25/20 20180101; A61P
25/28 20180101; A61P 25/08 20180101 |
Class at
Publication: |
546/86 ;
548/310.4; 549/403; 549/400; 548/440; 549/289; 546/141; 548/247;
546/150; 546/171; 548/266.4; 546/153; 548/255; 546/274.1; 548/441;
548/420; 548/444; 546/155 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 235/10 20060101 C07D235/10; C07D 311/30 20060101
C07D311/30; C07D 209/88 20060101 C07D209/88; C07D 311/16 20060101
C07D311/16; C07D 217/24 20060101 C07D217/24; C07D 261/08 20060101
C07D261/08; C07D 217/04 20060101 C07D217/04; C07D 215/38 20060101
C07D215/38; C07D 405/04 20060101 C07D405/04; C07D 215/233 20060101
C07D215/233; C07D 407/04 20060101 C07D407/04; C07D 249/06 20060101
C07D249/06; C07D 401/04 20060101 C07D401/04; C07D 209/80 20060101
C07D209/80; C07D 405/12 20060101 C07D405/12 |
Claims
1. A radiolabeled compound of the Formula I to Formula VI:
##STR00209## wherein: For Formula I: A is N or CR.sup.1; B is N or
CR.sup.2; J is N or CR.sup.3; K is N or CR.sup.4; L is N or
CR.sup.5; M is N or CR.sup.6; P is N or CR.sup.7; and Q is N or
CR.sup.8, provided that no more than two of A, B, J, K, L, M, P and
Q can be N; X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
R.sup.9 is hydrogen or is selected from the group consisting of
halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; provided that the
compound of Formula I is not a compound selected from the group
consisting of 2-fluoroethyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
2-fluoropropyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-thiocarboxylate,
9H-pyrido[3,4-b]indole-3-carboxamide,
9H-pyrido[3,4-b]indole-3-carbimidate,
.beta.-carboline-3-carboxylate, .beta.-carboline-3-thiocarboxylate,
.beta.-carboline-3-carboxamide, .beta.-carboline-3-carbimidate;
(S)-4-(3-(3-(2'-18F]-fluoroethylamino)-2-hydroxypropoxy)-carbazol,
R, S, SS and SR-1'-[18F]-fluorocarazolol (FCAR) and [11C]-carazolol
(CAR),
(S)-(-)-4-(2-hydroxy-3-(1'-[18]fluoroisopropyl)-aminopropoxy)carbazole,
7-(2-fluoroethoxy)-1-methyl-9H-.beta.-carboline,
7-(2-fluoropropoxy)-1-methyl-9H-.beta.-carboline,
7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-.beta.-carboline,
7-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}-1-methyl-9H-.beta.-carboline
and carbazolyl-(4)-oxypropanolamine and their derivatives; wherein
the radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof; For Formula II: X is a bond or is
selected from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
R.sup.9 is hydrogen or is selected from the group consisting of
halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof; For Formula III: Y and Y' are each
independently a bond or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O --; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least one of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is a hydrogen; each R.sup.10 is independently 1-1 or
C.sub.1-6alkyl; R.sup.11 and R.sup.12 are each independently
absent, a hydrogen or are each independently selected from the
group consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; wherein
the radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof; For Formula IV: W is O or
--N--X--R.sup.9; X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--,
--C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; Y and Y' are
each independently a bond or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; or Y is ##STR00210## and
R.sup.12 is absent; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen; R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.o are each independently hydrogen or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; R.sup.9 is hydrogen or is selected from
the group consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; R.sup.11 and
R.sup.12 are each independently absent, a hydrogen or are each
independently selected from the group consisting of halo,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; wherein
the radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof; For Formula V: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.2-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR
.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof; For Formula VI: X is a bond or is
selected from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy;
R.sup.5 and R.sup.6 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; R.sup.11 is a
hydrogen or is selected from the group consisting of halo,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; provided
that at least one of R.sup.1 to R.sup.12 comprises a radiolabel, as
defined herein; wherein the radiolabel comprises a radionuclide
selected from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
2. The radiolabeled compound of claim 1, wherein: For Formula I: A
is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3; K is N or
CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N; and Q is
N or CR.sup.8; X is a bond or is selected from the group consisting
of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O-- and --C(S)O--;
and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; For Formula II: X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O-- and
--C(S)O--; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; For Formula III: Y and Y' are each independently selected
from the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-6alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O --; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; For Formula IV: W is O or --N--X--R.sup.9; R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; For Formula V: X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--,
--C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; R.sup.5 and
R.sup.6 are each independently hydrogen or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; and R.sup.9 is hydrogen or is selected
from the group consisting of halo, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; For
Formula VI: X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy;
R.sup.5 and R.sup.6 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.1-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; R.sup.9 is hydrogen or is selected from
the group consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
R.sup.11 is absent, a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; wherein
the radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof.
3. The compound of claim 2, wherein: For Formula I: A is N or
CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3; K is N or
CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N or
CR.sup.7; and Q is N or CR.sup.8, provided that no more than two of
A, B, J, K, L, M, P and Q can be N; X is a bond or is selected from
the group consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--,
--C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and--N(R.sup.10)S(O).sub.2--; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each independently hydrogen or are each independently selected
from the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula II: X is
a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula III: Y
and Y' are each independently a bond or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5 alkoxy, heteroaryl C.sub.2-5 alkoxy,
C.sub.6-14aryloxy, C.sub.6-10 arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula IV: W is
O or --N--X--R.sup.9; X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--,
--C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; Y and Y' are
each independently a bond or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula V: X is a
bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula VI: X is
a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof.
4. The compound of claim 1, wherein: For Formula I: A is N or
CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3; K is N or
CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N or
CR.sup.7; and Q is N or CR.sup.8, provided that no more than two of
A, B, J, K, L, M, P and Q can be N; X is a bond or is selected from
the group consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--,
--C(O)O--, --X(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each independently hydrogen or are each independently selected
from the group consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; For Formula II: X is a bond or
is selected from the group consisting of C.sub.1-6alkylenyl,
--C(O)--, --C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; For Formula III: Y and Y' are
each independently a bond or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
FCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; For Formula IV: W is O or
--N--X--R.sup.9; X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--,
--C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; Y and Y' are
each independently a bond or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.2-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; For Formula V: X is a bond or
is selected from the group consisting of C.sub.1-6alkylenyl,
--C(O)--, --C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; For Formula VI: X is a bond or
is selected from the group consisting of C.sub.1-6alkylenyl,
--C(O)--, --C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--; wherein the radiolabel
comprises a radionuclide selected from the group consisting of
.sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I,
.sup.125I, .sup.131I and .sup.77Br; and pharmaceutically acceptable
salts thereof.
5. The compound of claim 1, wherein: For Formula I: A is N or
CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3; K is N or
CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N or
CR.sup.7; and Q is N or CR.sup.8, provided that no more than two of
A, B, J, K, L, M, P and Q can be N; X is a bond or is selected from
the group consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--,
--C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each independently hydrogen or are each independently selected
from the group consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula II: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula III: Y and Y' are each
independently a bond or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy, C.sub.6-10
arylC.sub.1-4alkoxy, heteroaryloxy, C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula IV: W is O or --N--X--R.sup.9; X
is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y and Y' are each independently a bond
or are each independently selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula V: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula VI: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(S)--, --C(O)O--, --C(S)O--, --N(R.sup.10)C(O)--,
--N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.2-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and R.sup.5 and R.sup.6 are each
independently hydrogen or are each independently selected from the
group consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; wherein the radiolabel comprises a
radionuclide selected from the group consisting of .sup.11C,
.sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I, .sup.125I,
.sup.131I and .sup.77Br; and pharmaceutically acceptable salts
thereof.
6. The radiolabeled compound of claim 1 wherein: For Formula I and
Formula II: X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
R.sup.9 is hydrogen or is selected from the group consisting of
halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo(CH.sub.2CH.sub.2).sub.1-6--;
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl; For Formula III: Y
and Y' are each independently a bond or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least any two of R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are hydrogens; R.sup.9 is hydrogen or is selected from
the group consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl; For Formula IV: W is
O or --N--X--R.sup.9; X is a bond or is selected from the group
consisting of C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--,
--C(S)O--, --N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--,
--S(O)N(R.sup.10)-- and --N(R.sup.10)S(O).sub.2--; Y and Y' are
each independently a bond or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl, C.sub.6-10aryl
C.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; provided that at least any two of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are hydrogens; R.sup.9 is hydrogen or is selected from
the group consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl; For Formula V: X is
a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and R.sup.5 and R.sup.6 are each
independently each independently hydrogen or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; --R.sup.9 is hydrogen or is selected
from the group consisting of halo, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl; For Formula VI: X is
a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and R.sup.5 and R.sup.6 are each
independently each independently hydrogen or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; --R.sup.9 is hydrogen or is selected
from the group consisting of halo, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl; wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof.
7. The compound of claim 6, wherein: For Formula I and Formula II:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each independently hydrogen or are each independently
selected from the group consisting of amino, halo, cyano, nitro,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(0 CH.sub.2CH.sub.2).sub.1-6O--; For Formula III:
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--; For Formula IV:
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--. For Formula V and
Formula VI: R.sup.5 and R.sup.6 are each independently hydrogen or
are each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--
and C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--. wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof.
8. The compound of claim 1, wherein the halo-moiety of the group
selected from halo-C.sub.1-6alkyl, halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.t-6O--,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.1-5alkylNR.sup.10C(O)-- is selected from the group
consisting of fluoro, iodo and bromo.
9. The compound of claim 6, wherein: For Formula I and Formula II:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each independently hydrogen or are each independently
selected from the group consisting of halo-C.sub.2-5alkoxy,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--; For Formula III: R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--; For Formula IV: R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--; For Formula V and Formula VI:
R.sup.5 and R.sup.6 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--; wherein the radiolabel comprises
a radionuclide selected from the group consisting of .sup.11C,
.sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I, .sup.125I,
.sup.131I and .sup.77Br; and pharmaceutically acceptable salts
thereof.
10. The compound of claim 6, wherein: For Formula I and Formula II:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each independently hydrogen or are each independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula III: R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula IV: R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each independently hydrogen or are each
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--; For Formula V and Formula VI: R.sup.5 and
R.sup.6 are each independently hydrogen or are each independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10-arylC(O)O--; wherein the radiolabel comprises a
radionuclide selected from the group consisting of .sup.11C,
.sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I, .sup.125I,
.sup.131I and .sup.77Br; and pharmaceutically acceptable salts
thereof.
11. The compound of claim 6, wherein: For Formula I and Formula II:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each independently hydrogen or selected from the group
consisting of F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--; For Formula III: R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or
selected from the group consisting of F--C.sub.1-6alkyl,
F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--; For Formula IV: R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen or selected
from the group consisting of F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and F--C.sub.1-5
alkylNR.sup.10C(O)--; For Formula V and Formula VI: R.sup.5 and
R.sup.6 are each independently hydrogen or selected from the group
consisting of F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--; wherein the radiolabel comprises
a radionuclide selected from the group consisting of .sup.11C,
.sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I, .sup.125I,
.sup.131I and .sup.77Br; and pharmaceutically acceptable salts
thereof.
12. The compound of claim 6, wherein: For Formula I and Formula II:
at least four of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are hydrogens; For Formula III: at
least two of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
For Formula IV: at least two of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are hydrogens; For Formula V and Formula VI: at least one
of R.sup.5 or R.sup.6 is a hydrogen; wherein the radiolabel
comprises a radionuclide selected from the group consisting of
.sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I,
.sup.125I, .sup.131I and .sup.77Br; and pharmaceutically acceptable
salts thereof.
13. The compound of claim 1, wherein the amino group is selected
from the group consisting of NH.sub.2--, CH.sub.3NH--,
(CH.sub.3).sub.2N--, C.sub.1-3-alkylNH--, F--C.sub.2-3-alkylNH--,
F--(C.sub.2-3-alkylO).sub.1-4-alkyl-NH--,
(C.sub.1-3-alkyl).sub.2N--, C.sub.1-6alkylNH--,
(C.sub.1-6alkyl).sub.2N--, C.sub.3-6cycloalkylNH--,
(C.sub.3-6cycloalkyl).sub.2N--,
C.sub.3-12cycloalkylC.sub.1-5alkylNH--, C.sub.6-14arylNH--,
C.sub.6-10arylC.sub.1-4alkylNH--, heteroarylNH--,
C.sub.6-14aryloxyNH--, C.sub.6-10arylC.sub.1-4alkoxyNH-- and
heteroaryloxyNH--.
14. The compound of claim 1 of the Formula I, II, V and VI, wherein
X is a bond and R.sup.9 is hydrogen.
15. (canceled)
16. (canceled)
17. A radiolabeled compound of the formula IIa: ##STR00211##
wherein: X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2; R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; provided that at least any two of
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogens, and at least one of R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7, R.sup.8 and R.sup.9 comprises the radiolabel; R.sup.9 is
hydrogen or is selected from the group consisting of halo,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6,
-halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; wherein the
radiolabel comprises a radionuclide selected from the group
consisting of .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br; and pharmaceutically
acceptable salts thereof.
18. The compound of claim 17, wherein: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)O-- and
--N(R.sup.10)C(O)--; R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
C.sub.1-3alkylNH--, halo, cyano, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
heteroarylC.sub.2-5alkoxy, C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; and R.sup.9 is hydrogen or is selected
from the group consisting of halo, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--.
19. The compound of claim 17, wherein: X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(O)O-- and --N(R.sup.10)C(O)--; R.sup.2, R.sup.4, R.sup.6 and
R.sup.8 are each hydrogen; R.sup.3 and R.sup.7 are each
independently selected from the group consisting of
C.sub.1-3alkylNH--, (C.sub.1-3alkyl).sub.2N--,
(halo-C.sub.1-6alkyl)N(C.sub.1-3alkyl)-,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6N(C.sub.1-3alkyl)-,
halo, hydroxyl, halo-C.sub.1-6alkyl, C.sub.6-10arylC.sub.1-4alkyl,
4-(halo-C.sub.1-6alkyl)-triazol-1-yl)C.sub.2-5alkoxy,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylC(O)--; and
R.sup.9 is hydrogen or is selected from the group consisting of
halo, C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--.
20.-28. (canceled)
29. A radiolabel compound of the formula VI: ##STR00212## wherein:
X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; Y is a bond or is selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy) C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy;
R.sup.5 and R.sup.6 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy), C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring; R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; each
R.sup.10 is independently H or C.sub.1-6alkyl; R.sup.11 is a
hydrogen or is selected from the group consisting of halo,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2-(0 CH.sub.2CH.sub.2).sub.1-6(CO)--; provided
that at least one of R.sup.1 to R.sup.11 comprises a radiolabel, as
defined herein; wherein the radiolabel comprises a radionuclide
selected from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
30.-48. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application is a National Stage entry of
PCT/US09/00961, filed Feb. 17, 2009, which claims the priority of
U.S. provisional application No. 60/066,101, filed Feb. 14, 2008.
PCT/US09/00961 and U.S. provisional application No. 60/066,101 are
incorporated herein by reference.
BACKGROUND
[0002] Alzheimer's disease (AD), a leading cause of dementia,
develops in one percent of the population between the ages 65 and
69, and increasing to 40-50% in those 95 years and older. AD
patients exhibit telltale clinical symptoms that include cognitive
impairment and deficits in memory function. In these patients,
heavy senile plaque burden found in the cerebral cortex, verified
by post mortem histopathological examination, confirms the presence
of AD. The mature senile plaques consist of intracellular
neurofibrillary tangles (NFT) derived from filaments of
hyperphosphorylated tau proteins, and extracellular .beta.-amyloid
peptides derived from enzymatic processing of amyloid precursor
protein. Interestingly, despite the development and presence of
senile plaques in elderly persons with normal cognitive function,
the severity of NFT and senile plaque deposition purportedly
correlates with a loss of cognitive function and neuronal circuitry
deterioration.
[0003] Despite Alzheimer's disease being the fourth leading cause
of death in the United States, pharmaceutical intervention has yet
to commercialize a curative therapy. Instead, clinicians currently
prescribe cholinesterase inhibitors to cognitively impaired
patients. Rivastigmine, a therapeutic treatment for both AD and
Parkinson disease patients, inhibits both acetylcholinesterase and
butyrylcholinesterase, preventing the breakdown of acetyl- and
butyrylcholine. Galantamine, a naturally derived
acetylcholinesterase inhibitor, increases nicotinic cholinergic
receptors to release acetylcholine into the brain. As a final
example, the acetylcholinesterase inhibitor Aricept slows
progression of AD in patients by inhibiting acetylcholinesterase
and thus increasing cortical acetylcholine. In a recent clinical
trial, Aricept's effectiveness slowed AD progression in patients
but the therapeutic effects disappeared after 36 months. The effect
of treating AD patients with a therapeutic combination of both
Aricept and memantine caused an increased cognitive function in
those AD patients relative to those who just received only Aricept.
Despite the usefulness of cholinesterase inhibitors, the current
array of AD therapeutics can only delay full-onset AD by
approximately two to three years, after which they are
therapeutically ineffective in inhibiting cognitive decline. It has
been reported that delaying AD onset by five years is sufficient to
reduce the number of AD cases in half and, given the current
shortcomings of cholinesterase inhibitors, further research efforts
are required to meet that goal.
[0004] Neurological imaging of AD has seen the emergence of imaging
tracers that appear to confirm the presence of AD based on plaque
and fibril mediated tracer uptake and, subsequently, are currently
undergoing extensive clinical examination. Many of these tracers
contain chemotypes that derive from fluorescent dyes (Table 1). For
example, increased uptake and binding of the napthylaniline
derivative .sup.18F-FDDNP in living brains correlates well with the
presence of AD when compared to cognitively functional normals of
similar age. [Liu, J., et al., High-Yield, Automated Radiosynthesis
of
2-(1-{6-[.sup.18F]Fluorethyl)(methyl)amino]-2-naphthyl}ethylidene)malonit-
rile ([.sup.18F]FDDNP) Ready for Animal or Human Administration.
Molecular Imaging and Biology, 2007. 9: p. 6-16.] A competing
compound, .sup.11C-PIB, shows enhanced uptake in frontotemporal and
hippocampal brain regions in AD patients when compared to healthy
normals.
[0005] There are several issues, however, that question the
validity of imaging senile plaques and tangles. First, the current
array of AD imaging agents can only confirm the well-established
manifestation of AD and this late stage diagnosis offers little
defense against further disease progression past 36 months.
Secondly, the detection of senile plaques and tangles may not
correlate to development of the early stages of AD. Recent data
suggests that the amyloid cascade model [Hardy, J. and D. Selkoe,
The Amyloid Hypothesis of Alzheimer's Disease: Progress and
Problems on the Road to Therapeutics. Science, 2002. 297: p.
353-356] does not accurately depict the primary factors leading to
cognitive decline in AD patients and that other contributing
factors, such as neuorotoxic soluble oligomers and aggregates may
play a contributory role in neurodegeneration. [Talaga, P.,
Inhibitors of beta-amyloid aggregation: still an issue of structure
and function? Drug Discovery Today: Therapeutic Strategies, 2004.
1: p. 7-12]. To date, FDDNP and PIB are not known to bind to
neurotoxic soluble oligomers and aggregates and thus are not
expected to differentiate accurately between the early stages of AD
from the advanced stages of AD in patients.
[0006] As summarized from a recent discussion group on Dec. 5,
2006, (Biochemical Pharmacology Discussion Group, cosponsored by
the American Chemical Society's New York section), researchers are
now focusing on methods that target AD precursors by blocking
either .beta.-amyloid protein (BAP) production or by controlling
mutant tau protein formation. Clearly, this focused research effort
aims to control the formation of AD precursors that potentially
lead to AD and this new strategy might delay full-onset AD more
effectively that current therapeutics. In parallel, neurological
imaging must mirror the therapeutic trend by identifying AD
precursors in a duel effort to compliment both AD therapeutic
development and, in addition, identify presymptomatic at-risk AD
patients.
[0007] A number of medical diagnostic procedures, including PET and
SPECT utilize radiolabeled compounds, are well known in the art.
PET and SPECT are very sensitive techniques and require small
quantities of radiolabeled compounds, called tracers. The labeled
compounds are transported, accumulated and converted in vivo in
exactly the same way as the corresponding non-radioactively
compound. Tracers, or probes, can be radiolabeled with a
radionuclide useful for PET imaging, such as .sup.11C, .sup.13N,
.sup.15O, .sup.18F, .sup.64Cu and .sup.124I, or with a radionuclide
useful for SPECT imaging, such as .sup.99Tc, .sup.77Br, .sup.61Cu,
.sup.153Gd, .sup.123I, .sup.125I, .sup.131I and .sup.32P.
[0008] PET creates images based on the distribution of molecular
imaging tracers carrying positron-emitting isotopes in the tissue
of the patient. The PET method has the potential to detect
malfunction on a cellular level in the investigated tissues or
organs. PET has been used in clinical oncology, such as for the
imaging of tumors and metastases, and has been used for diagnosis
of certain brain diseases, as well as mapping brain and heart
function. Similarly, SPECT can be used to complement any gamma
imaging study, where a true 3D representation can be helpful, for
example, imaging tumor, infection (leukocyte), thyroid or
bones.
SUMMARY OF THE INVENTION
[0009] In one embodiment, there is provided a radiolabeled compound
of the Formula I to Formula VI:
##STR00001##
wherein:
For Formula I:
[0010] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N
or CR.sup.7; and Q is N or CR.sup.8, provided that no more than two
of A, B, J, K, L, M, P and Q can be N;
[0011] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0012] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0013] provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
[0014] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0015] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0016] provided that the compound of Formula I is not a compound
selected from the group consisting of 2-fluoroethyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
2-fluoropropyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-thiocarboxylate,
9H-pyrido[3,4-b]indole-3-carboxamide,
9H-pyrido[3,4-b]indole-3-carbimidate,
.beta.-carboline-3-carboxylate, .beta.-carboline-3-thiocarboxylate,
.beta.-carboline-3-carboxamide, .beta.-carboline-3-carbimidate;
(S)-4-(3-(3-(2'-18F]-fluoroethylamino)-2-hydroxypropoxy)-carbazol,
R, S, SS and SR-1'-[18F]-fluorocarazolol (FCAR) and [11C]-carazolol
(CAR),
(S)-(-)-4-(2-hydroxy-3-(1'-[18]fluoroisopropyl)-aminopropoxy)carbazole,
7-(2-fluoroethoxy)-1-methyl-9H-.beta.-carboline,
7-(2-fluoropropoxy)-1-methyl-9H-.beta.-carboline,
7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-.beta.-carboline,
7-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}-1-methyl-9H-.beta.-carboline
and carbazolyl-(4)-oxypropanolamine and their derivatives;
[0017] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0018] and pharmaceutically acceptable salts thereof;
For Formula II:
[0019] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0020] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0021] provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
[0022] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0023] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0024] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0025] and pharmaceutically acceptable salts thereof;
For Formula III:
[0026] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0027] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0028] provided that at least one of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is a hydrogen;
[0029] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0030] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0031] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0032] and pharmaceutically acceptable salts thereof;
For Formula IV:
[0033] W is O or N--X--R.sup.9;
[0034] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0035] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5 alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; or Y is
##STR00002##
and R.sup.12 is absent;
[0036] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0037] provided that at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen;
[0038] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.o are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0039] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0040] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0041] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0042] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0043] and pharmaceutically acceptable salts thereof;
For Formula V:
[0044] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0045] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0046] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0047] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0048] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0049] and pharmaceutically acceptable salts thereof;
For Formula VI:
[0050] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0051] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0052] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0053] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0054] each R.sup.10 is independently H or C.sub.1-6alkyl; [0055]
R.sup.11 is a hydrogen or is selected from the group consisting of
halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0056] provided that at least one of R.sup.1 to R.sup.12 comprises
a radiolabel, as defined herein;
[0057] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0058] and pharmaceutically acceptable salts thereof.
[0059] In one variation of the above compound:
For Formula I:
[0060] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N;
and Q is N or CR.sup.8;
[0061] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O-- and --C(S)O--;
and
[0062] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula II:
[0063] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)O-- and --C(S)O--; and
[0064] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.5-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula III:
[0065] Y and Y' are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0066] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula IV:
[0067] W is O or --N--X--R.sup.9;
[0068] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula V:
[0069] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0070] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; and
[0071] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
For Formula VI:
[0072] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0073] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0074] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0075] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0076] R.sup.11 is absent, a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0077] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0078] and pharmaceutically acceptable salts thereof.
[0079] In another embodiment, there is provided a radiolabeled
compound of the formula IIa:
##STR00003##
wherein:
[0080] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2;
[0081] R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
each independently hydrogen or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0082] provided that at least any two of R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 are hydrogens, and at least one of
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8 and R.sup.9
comprises the radiolabel;
[0083] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0084] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0085] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0086] and pharmaceutically acceptable salts thereof.
[0087] In other embodiment, there is provided a radiolabeled
compound of the formula III:
##STR00004##
[0088] wherein:
[0089] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0090] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cyoloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0091] provided that at least one of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is a hydrogen;
[0092] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0093] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0094] provided that at least one of R.sup.5 to R.sup.12 comprises
a radiolabel;
[0095] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131 and
.sup.77Br;
and pharmaceutically acceptable salts thereof.
[0096] In another embodiment, there is provided, a radiolabeled
compound of the formula IV:
##STR00005##
wherein:
[0097] W is O or --N--X--R.sup.9;
[0098] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0099] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.3-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; or Y is
##STR00006##
and R.sup.12 is absent;
[0100] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0101] provided that at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen;
[0102] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.o are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0103] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0104] each R.sup.10 is independently H or C.sub.1-6alkyl; and
[0105] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0106] provided that at least one of R.sup.1 to R.sup.12 comprises
a radiolabel, as defined herein;
[0107] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
and pharmaceutically acceptable salts thereof.
[0108] In another embodiment, there is provided a radiolabel
compound of the formula VI:
##STR00007##
[0109] wherein:
[0110] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0111] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0112] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0113] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0114] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0115] R.sup.11 is a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0116] provided that at least one of R.sup.1 to R.sup.11 comprises
a radiolabel, as defined herein;
[0117] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
and pharmaceutically acceptable salts thereof.
[0118] In another embodiment, there is provided a pharmaceutical
composition for in vivo imaging of amyloid deposits.
[0119] In another embodiment, there is provided a method of
diagnosing Alzheimer's Disease or a predisposition thereto in a
mammal.
[0120] In another embodiment, there is provided a method of
diagnosing Alzheimer's Disease or a predisposition thereto in a
mammal.
[0121] In another embodiment, there is provided a method for
detecting Alzheimer's Disease or a predisposition thereto in a
living brain of a mammal.
[0122] In another embodiment, there is provided a method for
treating a disease or condition, in a mammal in need thereof,
selected from the group consisting of anxiety, depression,
schizophrenia, Alzheimer's Disease, stress-related disease, panic,
a phobia, obsessive compulsive disorder, obesity, post-traumatic
stress syndrome, or epilepsy.
BRIEF DESCRIPTION OF DRAWINGS
[0123] FIG. 1 shows Biacore binding assay results.
[0124] FIG. 2 shows representative scaffolds for compounds found to
bind oligomer, polymers and/or fibrils.
[0125] FIG. 3A shows UV HPLC analysis of AD-CB-001P-WZ-01019
synthesis of AD-CB-002P-WZ01031.
[0126] FIG. 3B shows Gamma HPLC analysis of AD-CB-001P-WZ-01019
synthesis of AD-CB-002P-WZ01031.
[0127] FIG. 4 shows immunostaining of brain sections with
thioflavin T, thioflavin T with tracer and no thioflavin T.
[0128] FIG. 5 shows immunostaining of brain sections with FDDNP,
FDDNP with tracer and no FDDNP.
[0129] FIG. 6 shows coronal slices of a white rat brain using 1 min
framing. After 2 minutes, the tracer concentration reaches a
maximum level in the brain and is completely washed out after 7
minutes.
[0130] FIG. 7 shows amyloid autoradiography staining (ex vivo) of
an AD patient's brain with [18F]-CB-001 shows good amyloid binding
and little/no white matter binding.
[0131] FIG. 8 shows [18F]-CB001 competition studies on AD Brain
slices demonstrate reversible plaque binding and competition with
PiB, and little/no white matter binding.
[0132] FIG. 9 shows the optimal staining and wash protocol
indicating tracer specific.
[0133] FIG. 10 shows [18F]-CB003 clearly distinguishes between
Alzheimer's and normal brains.
[0134] FIG. 11 shows concentration-dependent blocking of [18F]-PiB
tissue binding with PiB and CB003.
[0135] FIG. 12 shows surface plasmon resonance assay results of
CB003 binding to A.beta.42 insoluble aggregates.
[0136] FIG. 13 shows surface plasmon resonance assay results of
CB003 binding to A.beta.42 soluble aggregates.
[0137] FIG. 14 shows surface plasmon resonance assay results of PiB
binding to A.beta.42 insoluble aggregates.
[0138] FIG. 15 shows surface plasmon resonance assay results of PiB
binding to A.beta.42 soluble aggregates.
[0139] FIG. 16 shows surface plasmon resonance assay results of
CB004 binding to A.beta.42 insoluble aggregates.
[0140] FIG. 17 shows surface plasmon resonance assay results of
CB004 binding to A.beta.42 soluble aggregates.
[0141] FIG. 18A shows MicroPET imaging, 2 min p.i., with
[18F]-CB-001 in App and WT mice demonstrates very good brain
uptake.
[0142] FIG. 18B shows MicroPET imaging, 20-30 min p.i., with
[18F]-CB-001 in App and WT mice demonstrates very good brain
uptake.
[0143] FIG. 19 shows MicroPET imaging, 10 min, with [18F]-CB003 in
WT and App mice.
[0144] FIG. 20 left panel shows MicroPET imaging analysis with
[18F]-CB003 in individual WT and App mice. Right panel shows
combined MicroPET imaging analysis with [18F]-CB003 in WT and App
mice.
[0145] FIG. 21 shows percent increase of brain/muscle (B/M) ratio
for MicroPET imaging analysis with [18F]-CB003 in WT and App
mice.
[0146] FIG. 22 shows clearance of [18F]PiB in WT and App mice
brain.
[0147] FIG. 23 shows clearance of [18F]-CB003 in WT and App mice
brain indicates that brain clearance of [18F]-CB003 is much faster
than with [18F]PiB.
DETAILED DESCRIPTION OF THE INVENTION
[0148] The present invention is directed to compounds having the
structural Formula I where the radicals have the meanings given
above.
[0149] "Halogen" or "halo" means F, Cl, Br and I.
[0150] "Alkyl" means a saturated monovalent hydrocarbon radical
having straight or branched moieties. Examples of alkyl groups
include, but are not limited to, methyl, ethyl, n-propyl, isopropyl
and t-butyl.
[0151] "Alkenyl" means an alkyl moieties having at least one
carbon-carbon double bond wherein alkyl is as defined above.
Examples of alkenyl include, but are not limited to, ethenyl and
propenyl,
[0152] "Alkynyl" means alkyl moieties having at least one
carbon-carbon triple bond wherein alkyl is as defined above.
Examples of alkynyl groups include, but are not limited to, ethynyl
and 2-propynyl,
[0153] "Alkylene" or "alkenylenyl" means a saturated, divalent
hydrocarbon radicals i.e., generally present as a bridging or
linking group between two other groups, having straight or branched
moieties. Examples of alkylene groups include --CH.sub.2--
(methylene); --CH.sub.2CH.sub.2-- (ethylene);
--CH.sub.2CH.sub.2CH.sub.2-- (propylene), --CH(CH.sub.3)CH.sub.2--
(isopropylene) etc.
[0154] "Amino" means a nitrogen moiety having two further
substituents where a hydrogen or carbon atom is attached to the
nitrogen. For example, representative amino groups include
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--N(C.sub.2-3-alkyl).sub.2 and the like. Unless indicated
otherwise, the compounds of the invention containing amino moieties
may include protected derivatives thereof. Suitable protecting
groups for amino moieties include acetyl, tert-butoxycarbonyl,
benzyloxycarbonyl and the like.
[0155] "Aryl" means an organic radical derived from an aromatic
hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl,
indenyl, indanyl and fluorenyl. "Aryl" encompasses fused ring
groups wherein at least one ring is aromatic.
[0156] "Cycloalkyl" means non-aromatic saturated cyclic alkyl
moieties consisting of one or more rings, wherein said rings (if
more than one) share at least one carbon atom, wherein alkyl is as
defined above. Examples of cycloalkyl include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclo-[3.1.0]-hexyl, bicyclo-[2.2.1]-hept-1-yl, norbornyl,
spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl
and adamantanyl.
[0157] "HaloC.sub.1-6alkyl" means a C.sub.1-6alkyl group that is
substituted with at least one halogen atom on a carbon atom of the
alkyl group. Non-exclusive, representative examples of such
haloC.sub.1-6alkyl include F--CH.sub.2--, F--CH.sub.2CH.sub.2--,
F--CH.sub.2CH.sub.2CH.sub.2--, CHF.sub.2--, CHF.sub.2CH.sub.2--,
CHF.sub.2CH.sub.2CH.sub.2--, Br--CH.sub.2--,
Br--CH.sub.2CH.sub.2--, Br--CH.sub.2CH.sub.2CH.sub.2--,
CHBr.sub.2--, CHBr.sub.2CH.sub.2--, CHBr.sub.2CH.sub.2CH.sub.2--
and the like.
[0158] "Heterocyclic" or "hetemcycloalkyl" means a non-aromatic
cyclic groups consisting of one or more rings, wherein the rings
(if more than one) share one or two atoms and each ring contains up
to four heteroatoms (i.e. from zero to four heteroatoms, provided
that at least one ring contains at least one heteroatom). The
heterocyclic groups of this invention can also include ring systems
substituted with one or more O, S(O).sub.0-2, and/or N--R.sup.10 as
heteroatoms, wherein R.sup.10 is as defined herein, and wherein the
subscript "0-2" of S(O).sub.0-2 represents an integer of 0, 1 or 2.
Thus, S(O).sub.2 represents the group consisting of S, S(.dbd.O),
and S(O).sub.2. Examples of non-aromatic heterocyclic groups are
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,
piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,
pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl,
1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl and
1,4-dioxaspiro[4.2]heptyl.
[0159] "Heteroaryl" means an aromatic group containing one or more
heteroatoms (O, S, or N), preferably from one to four heteroatoms.
A heteroaryl may be a monocyclic or a polycyclic group. Examples of
heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl,
phthalazinyl, triazinyl, 1,3,5-triazinyl, isoindolyl, purinyl,
oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl,
tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl,
benzofuryl, furopyridinyl, pyrolopyrimidinyl and azaindolyl. In
certain aspects of the present application, the heteroaryl is a
4-substituted-1H-1,2-3-triazol-1-yl.
[0160] As used herein, where a divalent group, such as a linker for
example, is represented by a structure -A-B--, as shown below, it
is intended to also represent a group that may be attached in both
possible permutations, as noted in the two structures below. [0161]
-A-B-- may also be --B-A-
[0162] For example, when a divalent group such as the group
"--N(R.sup.10)C(O)--" is provided, for example, the group is
intended to also include both the divalent group
--N(R.sup.10)C(O)-- and also the divalent group
--C(O)N(R.sup.10)--.
[0163] The substituents or the groups C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkyl,
heteroaryl, heteroaryloxy etc . . . of the variables R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 are also optionally further substituted by
substituents selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SH, --SC.sub.1-6alkyl, --C(O)NH.sub.2,
--C(S)NH.sub.2, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkyl, C.sub.6-14aryl and
heteroaryl.
[0164] For example, in certain aspect of the present application,
the heteroaryl substituent is a
4-substituted-1H-1,2-3-triazol-1-yl. In the radiolabeled compounds
of the present application, a radionuclide may be attached to an
aryl group of the compound of Formulae I to VI, as in a
2-.sup.18F-'carbazole derivative such as the compound represented
as:
##STR00008##
or a 2-(.sup.18F-fluoroethyl)-'carbazole,
2-(.sup.18F-fluoromethyl)-'carbazole, a .sup.11C-methoxy- group,
for example, and/or the radionuclide may be attached to any one or
more of the variables R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.5, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 by way of a
.sup.18F-fluoroethyl- group, a .sup.18F-fluoromethyl- group, a
.sup.11C-methoxy- group,
4-[(.sup.18F-fluoroethyl)-1H-1,2-3-triazol-1-yl]-ethoxy- group,
4-[(.sup.18F-fluoroethyl)-1H-1,2-3-triazol-1-yl]-propyloxy- group,
a .sup.123I, a .sup.124I, a .sup.125I or a .sup.131I, and the group
like. Unless otherwise noted, a compound represented as being
substituted by an atom, such as the generic representation by the
atom fluorine in F--CH.sub.2CH.sub.2-('carbazole) or
F--CH.sub.2CH.sub.2O-('carbazole), for example, is intended to
cover both the naturally occurring element .sup.19F (fluorine-19)
as well as the .sup.18F (fluorine-18) isotope(s) of the element
itself.
[0165] The term "optionally substituted" or "substituted" refers to
the specific substituents or groups wherein one to four hydrogen
atoms in the group may be replaced by one to four substituents, for
example, independently selected from the substituents amino, halo,
cyano, nitro, hydroxyl, --SH, --SC.sub.1-6alkyl, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl, C.sub.3-12cycloalkyl,
C.sub.6-14aryl and heteroaryl, or as specifically disclosed herein.
In addition, the substituents may also include alkyl, aryl,
alkylene-aryl, hydroxy, alkoxy, aryloxy, perhaloalkoxy,
heterocyclyl, azido, amino, guanidino, amidino, halo, alkylthio,
oxo, acylalkyl, carboxy esters, carboxyl, carboxamido, acyloxy,
aminoalkyl, alkylaminoaryl, alkylaminoalkyl, alkoxyaryl, arylamino,
phosphono, sulfonyl, carboxamidoaryl, hydroxyalkyl, haloalkyl,
alkoxyalkyl and perhaloalkyl. In addition, the term "optionally
substituted" or "substituted" in reference to the variables
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9 and R.sup.10, includes groups substituted by one
to four substituents, as identified above, that further comprise a
positron or gamma emitter. Such positron emitters include, but are
not limited to, .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I,
.sup.124I, .sup.125I, .sup.131I and .sup.77Br.
[0166] The term "radiolabeled compound" as used herein refers to
compounds having an atom or group that may provide a radiolabel or
may be converted to a radiolabel, such as from a non-radioactive
atom to a radionuclide that is active, such as for example,
.sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I,
.sup.125I, .sup.131I and .sup.77Br. In addition, for the purpose of
the present application, such "radiolabeled compound" may also
refer to an atom or a group, that comprises a non-active nuclide,
such as a halogen, such as .sup.19F for example, wherein the
compound may be used and administered in a therapeutically
effective amount.
[0167] Compounds of the Formula I to Formula VI may have optical
centers and therefore may occur in different enantiomeric and
diastereomeric configurations. The present invention includes all
enantiomers, diastereomers, and other stereoisomers of such
compounds of the Formula I to Formula VI, as well as racemic
compounds and racemic mixtures and other mixtures of stereoisomers
thereof. Pharmaceutically acceptable salts of the compounds of
Formula I to Formula VI include the acid addition and base salts
thereof. Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include, but are not limited to, the
acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, citrate,
formate, fumarate, gluconate, glucuronate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, lactate, malate, maleate,
malonate, mesylate, methylsulphate, naphthylate, oxalate,
palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate,
pyroglutamate, salicylate, stearate, succinate, sulfonate,
tartrate, tosylate and trifluoroacetate salts. Suitable base salts
are formed from bases which form non-toxic salts. Examples include,
but are not limited to, the aluminum, arginine, benzathine,
calcium, choline, diethylamine, diolamine, glycine, lysine,
magnesium, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example,
hemisulphate and hemicalcium salts. For a review on suitable salts,
see Handbook of Pharmaceutical Salts: Properties, Selection, and
Use by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically
acceptable salts of compounds of Formula I to Formula VI may be
prepared by one or more of three methods: (i) by reacting the
compound of Formula I to Formula VI with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a
suitable precursor of the compound of Formula I to Formula VI; or
(iii) by converting one salt of the compound of Formula I to
Formula VI to another salt by the reaction with an appropriate acid
or base or by means of a suitable ion exchange column.
[0168] In one embodiment, there is provided a radiolabeled compound
of the Formula I to Formula VI:
##STR00009##
wherein:
For Formula I:
[0169] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N
or CR.sup.7; and Q is N or CR.sup.8, provided that no more than two
of A, B, J, K, L, M, P and Q can be N;
[0170] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0171] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.2 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-6alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0172] provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
[0173] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0174] each R.sup.P' is independently H or C.sub.1-6alkyl;
[0175] provided that the compound of Formula I is not a compound
selected from the group consisting of 2-fluoroethyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
2-fluoropropyl
6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-carboxylate,
9H-pyrido[3,4-b]indole-3-thiocarboxylate,
9H-pyrido[3,4-b]indole-3-carboxamide,
9H-pyrido[3,4-b]indole-3-carbimidate,
.beta.-carboline-3-carboxylate, .beta.-carboline-3-thiocarboxylate,
.beta.-carboline-3-carboxamide, .beta.-carboline-3-carbimidate;
(S)-4-(3-(3-(2'-18F]-fluoroethylamino)-2-hydroxypropoxy)-carbazol,
R, S, SS and SR-1'-[18F]-fluorocarazolol (FCAR) and [11C]-carazolol
(CAR),
(S)-(+4-(2-hydroxy-3-(1'-[18]fluoroisopropyl)-aminopropoxy)carbazole,
7-(2-fluoroethoxy)-1-methyl-9H-.beta.-carboline,
7-(2-fluoropropoxy)-1-methyl-9H-.beta.-carboline,
7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-.beta.-carboline,
7-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}-1-methyl-9H-.beta.-carboline
and carbazolyl-(4)-oxypropanolamine and their derivatives;
[0176] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0177] and pharmaceutically acceptable salts thereat
For Formula II:
[0178] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0179] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0180] provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
[0181] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0182] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0183] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0184] and pharmaceutically acceptable salts thereof;
For Formula III:
[0185] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0186] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0187] provided that at least one of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is a hydrogen;
[0188] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0189] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0190] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0191] and pharmaceutically acceptable salts thereof;
For Formula IV:
[0192] W is O or --N--X--R.sup.9;
[0193] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0194] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; or Y is
##STR00010##
and R.sup.12 is absent;
[0195] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0196] provided that at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen;
[0197] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.o are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0198] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0199] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0200] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0201] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0202] and pharmaceutically acceptable salts thereat
For Formula V:
[0203] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0204] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0205] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0206] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0207] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0208] and pharmaceutically acceptable salts thereof;
For Formula VI:
[0209] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--, --C(S)O--,
--N(R.sup.1Q)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0210] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0211] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-5alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5 alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5 alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0212] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--; halo-CH.sub.2
CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0213] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0214] R.sup.11 is a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--; halo-CH.sub.2
CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0215] provided that at least one of R.sup.1 to R.sup.12 comprises
a radiolabel, as defined herein;
[0216] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0217] and pharmaceutically acceptable salts thereof.
[0218] In one variation of the above compound:
For Formula I:
[0219] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N;
and Q is N or CR.sup.8;
[0220] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O-- and --C(S)O--;
and
[0221] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula II:
[0222] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O-- and --C(S)O--;
and
[0223] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.1-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula III:
[0224] Y and Y' are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0225] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula IV:
[0226] W is O or --N--X--R.sup.9;
[0227] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
For Formula V:
[0228] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0229] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3 alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-16alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; and
[0230] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2)
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
For Formula VI:
[0231] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0232] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0233] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0234] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0235] R.sup.11 is absent, a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0236] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and Br;
[0237] and pharmaceutically acceptable salts thereof.
[0238] In another variation of the above compound:
For Formula I:
[0239] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N
or CR.sup.7; and Q is N or CR.sup.8, provided that no more than two
of A, B, J, K, L, M, P and Q can be N;
[0240] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0241] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10), --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula II:
[0242] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0243] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula III:
[0244] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0245] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and C.sub.1-3
alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula IV:
[0246] W is O or --N--X--R.sup.9;
[0247] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0248] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0249] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula V:
[0250] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0251] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula VI:
[0252] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0253] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and
[0254] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
[0255] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0256] and pharmaceutically acceptable salts thereof.
[0257] In another variation of the above compound:
For Formula I:
[0258] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N
or CR.sup.7; and Q is N or CR.sup.8, provided that no more than two
of A, B, J, K, L, M, P and Q can be N;
[0259] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0260] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
For Formula II:
[0261] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0262] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
For Formula III:
[0263] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0264] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
FCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
For Formula IV:
[0265] W is O or --N--X--R.sup.9;
[0266] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0267] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0268] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
For Formula V:
[0269] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0270] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
For Formula VI:
[0271] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0272] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and
[0273] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--;
[0274] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0275] and pharmaceutically acceptable salts thereof.
[0276] In one variation of the above compound:
For Formula I:
[0277] A is N or CR.sup.1; B is N or CR.sup.2; J is N or CR.sup.3;
K is N or CR.sup.4; L is N or CR.sup.5; M is N or CR.sup.6; P is N
or CR.sup.7; and Q is N or CR.sup.8, provided that no more than two
of A, B, J, K, L, M, P and Q can be N;
[0278] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0279] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6R.sup.7
and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula II:
[0280] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0281] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula III:
[0282] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0283] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula IV:
[0284] W is O or --N--X--R.sup.9;
[0285] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0286] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0287] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--, C.sub.1-5
alkylC(O)O--, C.sub.6-10arylC(O)-- and C.sub.6-10arylC(O)O--;
For Formula V:
[0288] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0289] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula VI:
[0290] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2;
[0291] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.2-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and
[0292] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
[0293] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0294] and pharmaceutically acceptable salts thereof.
[0295] In another variation of the above compound:
For Formula I and Formula II:
[0296] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0297] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0298] provided that at least any two of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
[0299] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo(CH.sub.2CH.sub.2).sub.1-6--;
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
haloCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0300] each R.sup.10 is independently H or C.sub.1-6alkyl;
For Formula III:
[0301] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0302] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0303] provided that at least any two of R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are hydrogens;
[0304] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0305] each R.sup.10 is independently H or C.sub.1-6alkyl;
For Formula IV:
[0306] W is O or --N--X--R.sup.9;
[0307] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0308] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR'.degree., --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0309] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0310] provided that at least any two of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are hydrogens;
[0311] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0312] each R.sup.10 is independently H or C.sub.1-6alkyl;
For Formula V:
[0313] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--; and
[0314] R.sup.5 and R.sup.6 are each independently each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0315] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0316] each R.sup.10 is independently H or C.sub.1-6alkyl;
For Formula VI:
[0317] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0318] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and
[0319] R.sup.5 and R.sup.6 are each independently each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-44aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-14arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0320] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0321] each R.sup.10 is independently 11 or C.sub.1-6alkyl;
[0322] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0323] and pharmaceutically acceptable salts thereof.
[0324] In another variation of the above compound:
For Formula I and Formula II:
[0325] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--
and C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula III:
[0326] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--;
For Formula IV:
[0327] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--.
For Formula V and Formula VI:
[0328] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--
and C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--.
[0329] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0330] and pharmaceutically acceptable salts thereof.
[0331] In a particular variation of each of the above compounds,
the halo-moiety of the group selected from halo-C.sub.1-6alkyl,
halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.1-5alkylNR.sup.10C(O)-- is selected from the group
consisting of fluoro, iodo and bromo. In another variation of the
above:
For Formula I and Formula II:
[0332] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of
halo-C.sub.2-5alkoxy, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--;
For Formula III:
[0333] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--;
For Formula IV:
[0334] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--;
For Formula V and Formula VI:
[0335] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
haloC.sub.2-6alkylOC(O)CH(C.sub.1-5alkyl)- and
haloC.sub.2-5alkylNR.sup.10C(O)--;
[0336] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0337] and pharmaceutically acceptable salts thereof.
[0338] In yet another variation:
For Formula I and Formula II:
[0339] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or are each
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula III:
[0340] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula IV:
[0341] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
For Formula V and Formula VI:
[0342] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylNR.sup.10C(O)O--, C.sub.1-5alkylC(O)--,
C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)-- and
C.sub.6-10arylC(O)O--;
[0343] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
[0344] and pharmaceutically acceptable salts thereof.
[0345] In yet another variation:
For Formula I and Formula II:
[0346] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each independently hydrogen or selected
from the group consisting of F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--;
For Formula III:
[0347] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or selected from the group consisting of
F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5 alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--;
[0348] For Formula IV:
[0349] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or selected from the group consisting of
F--C.sub.1-6alkyl, F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--;
[0350] For Formula V and Formula VI:
[0351] R.sup.5 and R.sup.6 are each independently hydrogen or
selected from the group consisting of F--C.sub.1-6alkyl,
F--C.sub.1-5alkoxy,
F--C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
F--CH.sub.2CH.sub.2O--,
F--CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
4-(F--C.sub.1-6alkyl)-1H-1,2,3-triazol-1-yl-(C.sub.2-5alkoxy),
F--C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
F--C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
F--C.sub.1-5alkylNR.sup.10C(O)--;
[0352] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and
.sup.77Br;
and pharmaceutically acceptable salts thereof.
[0353] In another particular variation of the above:
For Formula I and Formula II:
[0354] at least four of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogens;
For Formula III:
[0355] at least two of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogens;
For Formula IV:
[0356] at least two of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
hydrogens;
For Formula V and Formula VI:
[0357] at least one of R.sup.5 or R.sup.6 is a hydrogen;
[0358] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
[0359] In yet another variation of each of the above, the amino
group is selected from the group consisting of NH.sub.2--,
CH.sub.3NH--, (CH.sub.3).sub.2N--, F--C.sub.2-3-alkylNH--,
F--(C.sub.2-3-alkylO).sub.1-4-alkyl-NH--,
(C.sub.1-3-alkyl).sub.2N--, (C.sub.1-6alkyl).sub.2N--,
C.sub.3-6cycloalkylNH--, (C.sub.3-6cycloalkyl).sub.2N--,
C.sub.3-12cycloalkylC.sub.1-5alkylNH--, C.sub.6-14arylNH--,
C.sub.6-10arylC.sub.1-4alkylNH--, heteroarylNH--,
C.sub.6-14aryloxyNH--, C.sub.6-10arylC.sub.1-4alkoxyNH-- and
heteroaryloxyNH--. In a particular variation of the Formula I, II,
V and VI, X is a bond and R.sup.9 is hydrogen.
[0360] In another aspect of each of the above compound, the
compound comprises at least one radionuclide selected from the
group consisting of .sup.11C, .sup.15O, .sup.18F, .sup.123I,
.sup.125I, .sup.131I and .sup.77Br.
[0361] In another aspect, there is provided a radiolabeled compound
wherein the compound is selected from
2-(2-fluoroethoxy)-9H-carbazole;
9-(2-fluoroethyl)-9H-carbazol-2-ol;
N-(2-fluoroethyl)-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-9H-carbazol-3-a-
mine; 7-(2-fluoroethoxy)-N,N-dimethyl-9H-carbazol-2-amine;
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-3-amine;
1-(3,6-diamino-9H-carbazol-9-yl)-3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pr-
opan-1-one;
N-(2-fluoroethyl)-2-hydroxy-11H-benzo[a]carbazole-3-carboxamide;
2-(6-chloro-9H-carbazol-2-yl)-N-(2-fluoroethyl)propanamide;
2-(6-fluoro-9H-carbazol-2-yl)-N,N-dimethylpropanamide;
2-methoxy-9H-carbazole; 6-iodo-2-methoxy-9H-carbazole;
2-(2-fluoroethoxy)-9H-carbazole;
9-(2-fluoroethyl)-9H-carbazol-2-ol;
N-(2-fluoroethyl)-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-9H-carbazol-3-a-
mine; 7-(2-fluoroethoxy)-N,N-dimethyl-9H-carbazol-2-amine;
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-3-amine;
1-(3,6-diamino-9H-carbazol-9-yl)-3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pr-
opan-1-one;
N-(2-fluoroethyl)-2-hydroxy-11H-benzo[a]carbazole-3-carboxamide;
2-(6-chloro-9H-carbazol-2-yl)-N-(2-fluoroethyl)propanamide; and
2-(6-fluoro-9H-carbazol-2-yl)-N,N-dimethylpropanamide.
[0362] In another embodiment, there is provided a radiolabeled
compound of the formula IIa:
##STR00011##
wherein:
[0363] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2;
[0364] R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 are
each independently hydrogen or are each independently selected from
the group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.3-6cycloalkoxy, C.sub.3-12cycloalkylC.sub.1-5alkoxy,
heteroarylC.sub.2-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0365] provided that at least any two of R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 are hydrogens, and at least one of
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8 and R.sup.9
comprises the radiolabel;
[0366] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0367] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0368] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
[0369] In one variation of the above, X is a bond or is selected
from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(O)O-- and --N(R.sup.10)C(O)--;
[0370] R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
each independently hydrogen or are each independently selected from
the group consisting of C.sub.1-3alkylNH--, halo, cyano, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
heteroarylC.sub.2-5alkoxy, C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; and
[0371] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--. In
another variation of the above, X is a bond or is selected from the
group consisting of C.sub.1-6alkylenyl, --C(O)--, --C(O)O-- and
--N(R.sup.10)C(O)--;
[0372] R.sup.2, R.sup.4, R.sup.6 and R.sup.8 are each hydrogen;
[0373] R.sup.3 and R.sup.7 are each independently selected from the
group consisting of C.sub.1-3alkylNH--, (C.sub.1-3alkyl).sub.2N--,
(halo-C.sub.1-6alkyl)N(C.sub.1-3alkyl)-,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6N(C.sub.3-3alkyl)-,
halo, hydroxyl, halo-C.sub.1-6alkyl, C.sub.6-10arylC.sub.1-4alkyl,
4-(halo-C.sub.1-6alkyl)-triazol-1-yl)C.sub.2-5alkoxy,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylC(O)--; and
[0374] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--.
[0375] In another embodiment, there is provided a radiolabeled
compound of the formula III:
##STR00012##
[0376] wherein: Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent;
[0377] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-14arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0378] provided that at least one of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is a hydrogen;
[0379] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0380] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0381] provided that at least one of R.sup.5 to R.sup.12 comprises
a radiolabel;
[0382] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
In one variation of the above, Y and Y' are each independently
selected from the group consisting of amino, halo, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O-- and
halo-CH.sub.2CH.sub.2O-- when R.sup.11 and R.sup.12 are absent;
and
[0383] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.2-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.2-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--.
[0384] In another variation of the above, Y and Y' are each
independently a bond or are each independently selected from the
group consisting of amino, halo, hydroxyl, --C(O)NH.sub.2,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O-- and
halo-CH.sub.2CH.sub.2O-- when R.sup.11 and R.sup.12 are absent;
and
[0385] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
FCH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
haloC.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--.
[0386] In yet another variation of the above, Y and Y' are each
independently a bond or are each independently selected from the
group consisting of amino, halo, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.2-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0387] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen or are each independently selected from the group
consisting of C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--.
[0388] In another embodiment, there is provided a radiolabeled
compound of the formula IV:
##STR00013##
wherein:
[0389] W is O or --N--X--R.sup.9;
[0390] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0391] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; or Y is
##STR00014##
and R.sup.12 is absent;
[0392] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or at least one of R.sup.5 and R.sup.6,
R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0393] provided that at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen;
[0394] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.o are each
independently hydrogen or are each independently selected from the
group consisting of amino, halo, cyano, nitro, hydroxyl,
--SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0395] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0396] each R.sup.10 is independently H or C.sub.1-6alkyl; and
[0397] R.sup.11 and R.sup.12 are each independently absent, a
hydrogen or are each independently selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0398] provided that at least one of R.sup.1 to R.sup.12 comprises
a radiolabel, as defined herein;
[0399] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br
and pharmaceutically acceptable salts thereof.
[0400] In one variation of the above compound, W is O or
--N--X--R.sup.9;
[0401] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--; and
[0402] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, cyano, nitro, hydroxyl, --SR.sup.10,
--C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--.
[0403] In one variation of the above compound, W is O or
--N--X--R.sup.9;
[0404] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O-- and
--N(R.sup.10)C(O)--;
[0405] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.6-14aryloxy,
C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy when R.sup.11 and
R.sup.12 are absent; and
[0406] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, hydroxyl, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, heteroarylC.sub.2-5alkoxy,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O-- and
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--.
[0407] In another variation of the above compound, W is O;
[0408] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
hydroxyl, --SR.sup.10, --C(O)NH.sub.2, halo-C.sub.2-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 and R.sup.12 are absent; and
[0409] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--.
[0410] In yet another variation of the above compound, W is O;
[0411] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(O)O--;
[0412] Y and Y' are each independently a bond or are each
independently selected from the group consisting of amino, halo,
hydroxyl, --C(O)NH.sub.2, --C(S)NH.sub.2, halo-C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O-- and
halo-CH.sub.2CH.sub.2O-- when R.sup.11 and R.sup.12 are absent;
and
[0413] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen or are each independently selected from the group
consisting of amino, halo, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5 alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O-- and
halo-CH.sub.2CH.sub.2O--; or at least one of R.sup.1 and R.sup.2,
R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 together with the carbon
atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0414] provided that at least any two of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are hydrogens;
[0415] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and each
R.sup.10 is independently H or C.sub.1-6alkyl.
[0416] In another embodiment, there is provided a radiolabel
compound of the formula VI:
##STR00015##
[0417] wherein:
[0418] X is a bond or is selected from the group consisting of
C.sub.1-6alkylenyl, --C(O)--, --C(S)--, --C(O)O--, --C(S)O--,
--N(R.sup.10)C(O)--, --N(R.sup.10)C(S)--, --S(O)N(R.sup.10)-- and
--N(R.sup.10)S(O).sub.2--;
[0419] Y is a bond or is selected from the group consisting of
amino, halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and
heteroaryloxy;
[0420] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, cyano, nitro, hydroxyl, --SR.sup.10, --C(O)NH.sub.2,
--C(S)NH.sub.2, haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl, C.sub.1-5alkoxy,
H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--; or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached to, form a substituted or
unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic
ring;
[0421] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0422] each R.sup.10 is independently H or C.sub.1-6alkyl;
[0423] R.sup.11 is a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--;
[0424] provided that at least one of R.sup.1 to R.sup.11 comprises
a radiolabel, as defined herein;
[0425] wherein the radiolabel comprises a radionuclide selected
from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F, .sup.123I, .sup.124I, .sup.125I, .sup.131I and .sup.77Br;
and pharmaceutically acceptable salts thereof.
[0426] In one variation of the above compound, X is a bond or is
selected from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(O)O--;
[0427] Y is a bond or is selected from the group consisting of
amino, halo, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
haloC.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.3-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O-- and
halo-CH.sub.2CH.sub.2O--;
[0428] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of amino,
halo, hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy, heteroaryloxy,
C.sub.1-5alkylNR.sup.10C(O)--,
(C.sub.1-6alkyl).sub.2NC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-5alkylNR.sup.10C(O)--, C.sub.1-5alkylNR.sup.10C(O)O--,
C.sub.1-5alkylC(O)--, C.sub.1-5alkylC(O)O--, C.sub.6-10arylC(O)--
and C.sub.6-10arylC(O)O--;
[0429] R.sup.9 is hydrogen or is selected from the group consisting
of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--; and
[0430] R.sup.11 is absent, a hydrogen or is selected from the group
consisting of halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-12cycloalkylC.sub.1-5alkyl, C.sub.6-14aryl,
C.sub.6-10arylC.sub.1-4alkyl, halo-(CH.sub.2CH.sub.2).sub.1-6--;
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O(CO)-- and
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6(CO)--.
[0431] In another variation of the above, X is a bond or is
selected from the group consisting of C.sub.1-6alkylenyl, --C(O)--,
--C(O)O--;
[0432] Y is a bond or is selected from the group consisting of
amino, halo, hydroxyl, --SR.sup.10, --C(O)NH.sub.2, --C(S)NH.sub.2,
halo-C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.3-12cycloalkylC.sub.1-5alkyl,
C.sub.6-14aryl, C.sub.6-10arylC.sub.1-4alkyl, heteroaryl,
C.sub.1-5alkoxy, H(OCH.sub.2CH.sub.2).sub.1-6O--,
C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--, halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--, C.sub.3-6cycloalkoxy,
C.sub.3-12cycloalkylC.sub.1-5alkoxy, heteroarylC.sub.2-5alkoxy,
C.sub.6-14aryloxy, C.sub.6-10arylC.sub.1-4alkoxy and heteroaryloxy
when R.sup.11 is absent; and
[0433] R.sup.5 and R.sup.6 are each independently hydrogen or are
each independently selected from the group consisting of
halo-C.sub.1-5alkoxy,
halo-C.sub.1-3alkyl(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-CH.sub.2CH.sub.2O--,
halo-CH.sub.2CH.sub.2--(OCH.sub.2CH.sub.2).sub.1-6O--,
halo-C.sub.1-6alkylNR.sup.10C(O)CH(C.sub.1-5alkyl)-,
halo-C.sub.1-6alkylOC(O)CH(C.sub.1-5alkyl)- and
halo-C.sub.1-5alkylNR.sup.10C(O)--.
[0434] In a particular variation of each of the above embodiments,
aspects and variations, all of the variables R.sup.1 to R.sup.12
are not all hydrogens. In a particular variation of each of the
above, the halo group is fluorine. In another variation of each of
the above, the radionuclide is .sup.18F or .sup.11C,
[0435] In another embodiment, there is provided a pharmaceutical
composition for in vivo imaging of amyloid deposits, comprising (a)
a compound of any one of the above, and (b) a pharmaceutically
acceptable carrier. In another embodiment, there is provided a
method of diagnosing Alzheimer's Disease or a predisposition
thereto in a mammal, the method comprising: a) administering to the
mammal a diagnostically effective amount of a radiolabeled
compound, wherein the compound passes the blood-brain barrier and
preferentially binds to a soluble AD oligomers, polymers and
fibrils in a brain tissue and wherein the compound is selected from
the group consisting of radiolabeled flavones, coumarins,
carbazoles, quinolinones, chromenones, imidazoles and triazoles and
their derivatives; b) allowing the compound to distribute into the
brain tissue; and c) imaging the brain tissue, wherein an increase
in binding of the compound to the brain tissue compared to a normal
control level of binding indicates that the mammal is suffering
from or is at risk of developing Alzheimer's Disease. In one
variation of the above method, the compound is a compound of any
one of the above disclosed compounds.
[0436] In another embodiment, there is provided a method of
diagnosing Alzheimer's Disease or a predisposition thereto in a
mammal, the method comprising: a) administering to the mammal a
diagnostically effective amount of a radiolabeled compound or
composition of any one of the above, wherein the compound passes
the blood-brain barrier and preferentially binds to a soluble AD
oligomers, polymers and fibrils in a brain tissue; b) allowing the
compound to distribute into the brain tissue; and c) imaging the
brain tissue, wherein an increase in binding of the compound to the
brain tissue compared to a normal control level of binding
indicates that the mammal is suffering from or is at risk of
developing Alzheimer's Disease. In one variation of the above
method, wherein the radiolabeled compound preferentially binds to
fibrils. In another variation of the above, the brain tissue
comprises a frontotemporal region or the hippocampal region. In a
particular variation of the above method, the increase in binding
is at least 10% greater than said normal control value. In another
variation of each of the above methods, the compound is
administered by intravenous injection.
[0437] In another embodiment, there is provided a method for
detecting Alzheimer's Disease or a predisposition thereto in a
living brain of a mammal, the method comprising: a) administering
the mammal with a diagnostically effective amount of a radiolabeled
compound that passes the blood-brain barrier and preferentially
binds to a soluble AD oligomers, polymers and fibrils in the brain,
wherein the detectably-labeled compound is a compound of any one of
the above; b) allowing the compound to distribute into the brain
tissue; and c) imaging the brain tissue, wherein an increase in
binding of the compound to the brain tissue compared to a normal
control level of binding indicates that the mammal is suffering
from or is at risk of developing Alzheimer's Disease.
[0438] In another embodiment, there is provided a method for
detecting Alzheimer's Disease or a predisposition thereto in a
living brain of a mammal, the method comprising: a) administering
the mammal with a diagnostically effective amount of a radiolabeled
compound of any one of the above, wherein the compound passes the
blood-brain barrier and preferentially binds to a soluble AD
oligomers, polymers and fibrils in the brain; b) allowing the
compound to distribute into the brain tissue; and c) imaging the
brain tissue, wherein an increase in binding of the compound to the
brain tissue compared to a normal control level of binding
indicates that the mammal is suffering from or is at risk of
developing Alzheimer's Disease.
[0439] In another embodiment, there is provided a method of
diagnosing Alzheimer's Disease or a predisposition thereto in a
mammal, the method comprising: a) administering to the mammal a
diagnostically effective amount of a radiolabeled compound, wherein
the compound passes the blood-brain barrier and preferentially
binds to a soluble or insoluble AD oligomers, polymers, fibrils,
hyperphosphorylated tau, neurofibrillary tangles, paired helical
filaments and/or neurotoxic soluble oligomers in a brain, and
wherein the radiolabeled compound is a compound as disclosed
herein; and (b) employing a nuclear imaging technique selected from
the group consisting of positron emission tomography (PET) and
single photon emission computed tomography (SPECT) for monitoring
or visualizing a distribution of the radiolabeled compound within
the brain or within a portion thereof. In one variation of the
above method, the radiolabeled compound or a derivative thereof, is
a compound of any one of the above compounds. In yet another
embodiment, there is provided a method for treating a disease or
condition, in a mammal in need thereof, selected from the group
consisting of anxiety, depression, schizophrenia, Alzheimer's
Disease, stress-related disease, panic, a phobia, obsessive
compulsive disorder, obesity, post-traumatic stress syndrome, or
epilepsy comprising administering to the mammal a therapeutically
effective amount of a compound of any one of the above. In one
variation, the compound is a non-radiolabeled compound of any one
of the above compounds. In another variation, the compound is
administered rectally, topically, orally, sublingually or
parenterally. In one variation, the compound is administered from
about 0.001 to about 100 mg/kg of body weight of the mammal per
day. In another variation, the compound is administered from about
0.1 to about 50 mg/kg of body weight of the mammal per day. In
another variation of each of the above methods, the compound is
selected from the group consisting of flavones, coumarins,
carbazoles, quinolinones, chromenones, imidazoles and triazoles and
their derivatives.
[0440] In one aspect, for the methods of detection that accurately
detect early onset AD prior to clinical symptomology, the focus may
be directed to targeting senile plaque precursors, rather than the
plaques and/or fibrils themselves. Accordingly, a potentially more
effective strategy for detecting and possibly treating AD, would
rely on the detection of biomarkers such as neurotoxic soluble
oligomers, which are linked to AD-related synaptic and neuronal
damage, rather than the late-stage plaque, and fibril biomarkers
associated with fully advanced AD.
TABLE-US-00001 TABLE 1 Known AD positive fluorescent dyes and
imaging agents Binding Name Compound and Reference Target Affinity
Congo Red ##STR00016## A.beta. monomer IC.sub.50: 2-10 uM Anal.
Biochem. 2006, 356, 265-272; J. Biol. Chem. 2005, 280, 5892-5901
Curcumin ##STR00017## A.beta. monomer IC.sub.50: 10-20 uM Anal.
Biochem. 2006, 356, 265-272; J. Biol. Chem. 2005, 280, 5892-5901
ANS ##STR00018## A.beta. monomer IC.sub.50: >100 uM Anal.
Biochem. 2006, 356, 265-272 Thioflavin T ##STR00019## A.beta.
monomer IC.sub.50: >500 uM Anal. Biochem. 2006, 356, 265-272
Iodinated Flavone ##STR00020## A.beta. 40 aggregates Ki = 13 nM
(--NMe2) to 72 nM (--OH) J. Med. Chem. 2005, 48, 7253-7260 Pyridyl
Styrene ##STR00021## A.beta. fibrils Kd = 7.5-9 nM J. Med. Chem.
2007, 50, 2157-2165 Diaryl acetylenes ##STR00022## A.beta. plaques
Kd = ~10 nM Bioorg. Med. Chem. 2007, 17, 3581- 3584 Thiophene
chalcones ##STR00023## A.beta. 1-42 aggregates Ki = 3.9-14 nM
Bioorg. Med. Chem. 2007, 15, 6802- 6809 Aurones ##STR00024##
A.beta. 1-42 aggregates Ki = 1.24 nM Biochem. Biophys. Res. Commun.
2007, 361, 116-121 PIB ##STR00025## A.beta. fibrils Ki = 2.8 nM J.
Med. Chem. 2006, 49, 2725-2730
[0441] An assay was developed using a Biacore instrument that
introduced screening ligands over gold-surface immobilized target
proteins and measured the resultant rates of association and
disassociation in order to screen various compounds that bind to
soluble AD oligomers, polymers and fibrils. In FIG. 1, the left
hand portion of the curve represents the binding of ligands to a
specific substrate. The right portion of the curve represents the
dissociation of the ligand from the substrate. Ligands that
associated quickly and dissociated slowly, relative to a control
ligand, were considered hits.
[0442] Several hundred compounds were screened in a similar fashion
and several common classes of compounds were identified as hits
falling into seven common chemotypes: flavones, coumarins,
carbazoles, quinolinones, chromenones, imidazoles and triazoles
(FIG. 2).
[0443] From the screening library. 38 compounds were identified as
binders to A.beta.42 oligomers/soluble polymers (Table 2). Among
these 38 compounds, 23 compounds bound to A.beta.42 synthetic
fibrils. Several compounds belonging to the flavone and coumarin
architectures, bound very strongly to oligomers, polymers and
fibrils. Chromenes, carbazoles and diaryl triazoles were found to
bind to oligomers and polymers preferentially over fibrils. Several
of these compounds can be prepared as radiolabeled analogs for use
in detecting biomarkers in patients with AD,
TABLE-US-00002 TABLE 2 Compounds identified as binders to
oligomers, polymers and/or fibrils. BINDING LEVELS TO
A.beta..sub.(1-42) Oligomers/Polymers A.beta..sub.(1-42) Fibrils
##STR00026## ++ + ##STR00027## ++ + ##STR00028## + + ##STR00029##
+++ ++ ##STR00030## ++++++ +++++ ##STR00031## + - ##STR00032## ++ +
##STR00033## +++ + ##STR00034## +++++ +++ ##STR00035## + -
##STR00036## + - ##STR00037## + + ##STR00038## ++ + ##STR00039## ++
+ ##STR00040## ++ + ##STR00041## + + ##STR00042## + - ##STR00043##
+ - ##STR00044## + - ##STR00045## ++ - ##STR00046## ++++ ++
##STR00047## + + ##STR00048## +++ + ##STR00049## + - ##STR00050##
++++ ++ ##STR00051## + + ##STR00052## + + ##STR00053## + -
##STR00054## + - ##STR00055## + + ##STR00056## + - ##STR00057## + -
##STR00058## ++++ - ##STR00059## + + ##STR00060## + - ##STR00061##
++ + ##STR00062## ++ ++ ##STR00063## +/- - A "+" sign represents a
hit and the increase in "+" signs relates to increasing binding
affinity. A "-" sign represents no binding.
[0444] Table 3 provides examples of imaging agents derived from the
hit scaffolds, Fluorides are shown in the structures as equivalent
to .sup.18F-fluoride and methyl groups are equivalent to
.sup.11C-carbon methyl groups.
TABLE-US-00003 TABLE 3 Examples of radiolabeled analogs useful for
detecting AD biomarks in vivo. Name Structure 2-(2- fluoroethoxy)-
9H-carbazole ##STR00064## 9-(2- fluoroethyl)-9H- carbazol-2-ol
##STR00065## N-(2- fluoroethyl)-7- (2-(2-(2- methoxyethoxy)
ethoxy)ethoxy)- 9H-carbazol-3- amine ##STR00066## 7-(2-
fluoroethoxy)- N,N-dimethyl- 9H-carbazol-2- amine ##STR00067##
7-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)- N-methyl-9H- carbazol-3-
amine ##STR00068## 1-(3,6-diamino- 9H-carbazol-9- yl)-3-(2-(2-(2-
fluoroethoxy) ethoxy)ethoxy) propan-1-one ##STR00069## N-(2-
fluoroethyl)-2- hydroxy-11H- benzo[a]carbazole- 3-carboxamide
##STR00070## 2-(6-chloro-9H- carbazol-2-yl)- N-(2- fluoroethyl)
propanamide ##STR00071## 2-(6-fluoro-9H- carbazol-2-yl)-
N,N-dimethyl- propanamide ##STR00072## 2-methoxy-9H- carbazole
##STR00073## 6-iodo-2- methoxy-9H- carbazole ##STR00074## 7-(2-
fluoroethoxy)- N,N-dimethyl- 9H-carbazol-2- amine ##STR00075##
tert-butyl 2-(2- (2-(2- fluoroethoxy) ethoxy)ethoxy)-9H-
carbazole-9- carboxylate ##STR00076## 2-(2-(2-(2- fluoroethoxy)
ethoxy)ethoxy)-9- methyl-9H- carbazole ##STR00077## 7-(2-(2-(2-
fluoroethoxy) ethoxy)ethoxy)- N,N-dimethyl- 9H-carbazol-2- amine
##STR00078## N-(7-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-9H-
carbazol-2- yl)acetamide ##STR00079## 7-(2-(2-(2- fluoroethoxy)
ethoxy)ethoxy)-9H- pyrido[2,3- b]indole ##STR00080## 2-(2-(2-(2-
fluoroethoxy) ethoxy)ethoxy)-9H- carbazole ##STR00081## 7-(2-(2-(2-
fluoroethoxy) ethoxy)ethoxy)-N- methyl-9H- carbazol-2-amine
##STR00082## N-(7-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-9H-
carbazol-2- yl)formamide ##STR00083## 6-(2-(2-(2- fluoroethoxy)
ethoxy)ethoxy)-9- (methoxymethyl)- N,N-dimethyl- 9H-carbazol-3-
amine ##STR00084## N-(7-(2- fluoroethoxy)- 9H-carbazol-2-
yl)formamide ##STR00085## N-(7-(2-(2- fluoroethoxy) ethoxy)-9H-
carbazol-2- yl)formamide ##STR00086## N-(2- fluoroethyl)-6-
methoxy-9H- carbazol-3- amine ##STR00087## 7-((4- fluorobutyl)
(methyl)amino)-9H- carbazol-2-ol ##STR00088## 7-((2- fluoroethyl)
(methyl)amino)-9H- carbazol-2-ol ##STR00089## 7-(2-
fluoroethylamino)- 9H-carbazol- 2-ol ##STR00090## 7-((2-(2-(2-
fluoroethoxy) ethoxy)ethyl)(methyl) amino)-9H-carbazol- 2-ol
##STR00091## 7-(2- fluoroethoxy)- N-methyl-9H- carbazol-2- amine
##STR00092## 7-(2- fluoroethoxy)- 9H-carbazol-2- ol ##STR00093##
7-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-9H- carbazol-2-ol
##STR00094## N-(4-(7-amino- 9H-carbazol-2- yloxy)phenyl)-2-
fluoropropanamide ##STR00095## 1-(2-(2-(2-(2- fluoroethoxy)
ethoxy)ethoxy)-9H- carbazol-9- yl)ethanone ##STR00096##
(2-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-9H- carbazol-9-
yl)phenyl) methanone ##STR00097## 2-fluoro-N-(4- (7- (methylamino)-
9H-carbazol-2- yloxy)phenyl) propanamide ##STR00098## N-(7-(4-
fluorobutoxy)- 9H-carbazol-2- yl)formamide ##STR00099## tert-butyl
2-(2- (2-(2- fluoroethoxy) ethoxy)ethoxy)-9H- pyrido[2,3-
b]indol-7- ylcarbamate ##STR00100## 2-(2-(2-(2- fluoroethoxy)
ethoxy)ethoxy)-9H- pyrido[2,3- b]indol-7-amine ##STR00101##
7-(benzyloxy)- N-(2- fluoroethyl)-N- methyl-9H- carbazol-2- amine
##STR00102## 2-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-N- methyl-9H-
pyrido[2,3- b]indol-7-amine ##STR00103## 6-bromo-9H- carbazol-2-ol
##STR00104## 8-(2- fluoroethoxy)-7- hydroxy-4- phenyl-2H-
chromen-2-one ##STR00105## 2-(4-(2- fluoroethoxy)-3-
hydroxyphenyl)- 3,7-dihydroxy- 4H-chromen-4-one ##STR00106## 7-(2-
fluoroethoxy)-8- hydroxy-4- phenyl-2H- chromen-2-one ##STR00107##
4-(4-(2- fluoroethoxy)phenyl)- 7,8-dihydroxy-2H- chromen-2-one
##STR00108## 4-(4-(2- fluoroethylamino) phenyl)-7,8- dihydroxy-2H-
chromen-2-one ##STR00109## 4-(3,4- dihydroxyphenyl)-
7-(2-fluoroethoxy)-8- hydroxy-2H- chromen-2-one ##STR00110##
7-(2-(2-(2- fluoroethoxy) ethoxy)ethoxy)-8- hydroxy-4-(4-
hydroxyphenyl)- 2H-chromen-2- one ##STR00111## 6-(2-
fluoroethoxy)-3- hydroxy-2- phenylquinolin- 4(1H)-one ##STR00112##
1-(2- fluoroethyl)-3,6- dihydroxy-2- phenylquinolin- 4(1H)-one
##STR00113## 2-(3-(2- fluoroethoxy)-4- hydroxyphenyl)- 3,6-
dihydroxyquinolin- 4(1H)-one ##STR00114## 2-(4-(2-(2-(2-
fluoroethoxy) ethoxy)ethoxy)-3- hydroxyphenyl)- 3,6-
dihydroquinolin- 4(1H)-one ##STR00115## 2-(3,4- dihydroxyphenyl)-3-
hydroxy-6- (methylamino) quinolin-4(1H)- one ##STR00116## 1-(2-
fluoroethyl)-3,6- dihydroxy-2-(4- hydroxyphenyl) quinolin-4(1H)-
one ##STR00117## 7-(2-(4-(2- fluoroethyl)-1H- 1,2,3-triazol-1-
yl)ethoxy)-8- hydroxy-4- phenyl-2H- chromen-2-one ##STR00118##
1-(2,4- dimethylphenyl)- 4-(3-fluoro-5- methylphenyl)-
1H-1,2,3-triazole ##STR00119## Chemical Name Formula MW Code
2-(2-fluoroethoxy)- C.sub.14H.sub.12FNO 229.25 CB-001 9H-carbazole
9-(2-fluoroethyl)-9H-carbazol-2-ol C.sub.14H.sub.12FNO 229.25
N-(2-fluoroethyl)-7-(2-(2-(2-methoxyethoxy)
C.sub.21H.sub.27FN.sub.2O.sub.4 390.45
ethoxy)ethoxy)-9H-carbazol-3-amine
7-(2-fluoroethoxy)-N,N-dimethyl-9H- C.sub.17H.sub.18FN.sub.2O
272.32 carbazol-2-amine 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-
C.sub.19H.sub.23FN.sub.2O.sub.3 346.40 CB-008
methyl-9H-carbazol-3-amine
1-(3,6-diamino-9H-carbazol-9-yl)-3-(2-(2-(2-
C.sub.21H.sub.26FN.sub.3O.sub.4 403.45
fluoroethoxy)ethoxy)ethoxy)propan-1-one
N-(2-fluoroethyl)-2-hydroxy-11H-benzo[a]
C.sub.19H.sub.15FN.sub.2O.sub.2 322.33 carbazole-3-carboxamide
2-(6-chloro-9H-carbazol-2-yl)-N-(2- C.sub.17H.sub.16ClFN.sub.2O
318.77 fluoroethyl)propanamide 2-(6-fluoro-9H-carbazol-2-yl)-N,N-
C.sub.17H.sub.17FN.sub.2O 284.33 dimethylpropanamide
2-methoxy-9H-carbazole C.sub.13H.sub.11NO 197.23
6-iodo-2-methoxy-9H-carbazole C.sub.13H.sub.10INO 323.13
7-(2-fluoroethoxy)-N,N-dimethyl-9H- C.sub.16H.sub.17FN.sub.2O
272.32 carbazol-2-amine tert-butyl
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)- C.sub.23H.sub.28FNO.sub.5
417.47 CB-005 9H-carbazole-9-carboxylate
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9- C.sub.19H.sub.22FNO.sub.3
331.38 CB-006 methyl-9H-carbazole
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N,N-
C.sub.20H.sub.25FN.sub.2O.sub.3 360.42 CB-007
dimethyl-9H-carbazol-2-amine
N-(7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.20H.sub.23FN.sub.2O.sub.4 374.41 CB-009
carbazol-2-yl)acetamide 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.17H.sub.19FN.sub.2O.sub.3 318.34 CB-028 pyrido[2,3-b]indole
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.18H.sub.20FNO.sub.3 317.35 CB-003 carbazole
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-
C.sub.19H.sub.23FN.sub.2O.sub.3 346.40 CB-004 9H-carbazol-2-amine
N-(7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.19H.sub.21FN.sub.2O.sub.4 360.38 CB-010 carbazol-2-formamide
6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9-
C.sub.22H.sub.29FN.sub.2O.sub.4 404.48 CB-011
(methoxymethyl)-N,N-dimethyl-9H-carbazol- 3-amine
N-(7-(2-fluoroethoxy)-9H-carbazol-2-yl)
C.sub.15H.sub.13FN.sub.2O.sub.2 272.27 CB-012 formamide
N-(7-(2-(2-fluoroethoxy)ethoxy)-9H-carbazol-
C.sub.17H.sub.17FN.sub.2O.sub.3 316.33 CB-024 2-yl)formamide
N-(2-fluoroethyl)-6-methoxy-9H-carbazol- C.sub.15H.sub.15FN.sub.2O
258.29 CB-013 3-amine 7-((4-fluorobutyl)methyl)amino)-9H-carbazol-
C.sub.17H.sub.19FN.sub.2O 286.34 CB-014 2-ol
7-((2-fluoroethyl)(methyl)amino)-9H-carbazol-2-ol
C.sub.15H.sub.15FN.sub.2O 258.29 CB-015
7-(2-fluoroethylamino)-9H-carbazol-2-ol C.sub.14H.sub.13FN.sub.2O
244.26 CB-016 7-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)(methyl)
C.sub.19H.sub.23FN.sub.2O.sub.3 346.40 CB-019
amino)-9H-carbazol-2-ol
7-(2-fluoroethoxy)-N-methyl-9H-carbazol-2-amine
C.sub.15H.sub.15FN.sub.2O 258.29 CB-020
7-(2-fluoroethoxy)-9H-carbazol-2-ol C.sub.14H.sub.12FNO.sub.2
245.25 CB-025 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.18H.sub.20FNO.sub.4 333.35 CB-026 carbazol-2-ol
N-(4-(7-amino-9H-carbazol-2-yloxy)phenyl)-2-
C.sub.21H.sub.18FN.sub.3O.sub.2 363.38 CB-027 fluoropropanamide
1-(2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.20H.sub.22FNO.sub.4 359.39 CB-017 carbazol-9-yl)ethanone
(2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.25H.sub.24FNO.sub.4 421.46 CB-021
carbazol-9-yl)(phenyl)methanone
2-fluoro-N-(4-(7-(methylamino)-9H-carbazol-2-
C.sub.22H.sub.20FN.sub.3O.sub.2 377.41 CB-029
yloxy)phenyl)propanamide
N-(7-(4-fluorobutoxy)-9H-carbazol-2-yl)
C.sub.17H.sub.17FN.sub.2O.sub.2 300.33 CB-030 formamide tert-butyl
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-
C.sub.22H.sub.28FN.sub.3O.sub.5 433.47 CB-031
9H-pyrido[2,3-b]indol-7-ylcarbamate
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-
C.sub.17H.sub.20FN.sub.3O.sub.3 333.36 CB-032
pyrido[2,3-b]indol-7-amine
7-(benzyloxy)-N-(2-fluoroethyl)-N-methyl-9H-
C.sub.22H.sub.21FN.sub.2O 348.41 CB-033 carbazol-2-amine
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-
C.sub.18H.sub.22FN.sub.3O.sub.3 347.38 CB-034
methyl-9H-pyrido[2,3-b]indol-7-amine 6-bromo-9H-carbazol-2-ol
C.sub.12H.sub.8BrNO 262.10
8-(2-fluoroethoxy)-7-hydroxy-4-phenyl-2H- C.sub.17H.sub.13FO.sub.4
300.28 chromen-2-one 2-(4-(2-fluoroethoxy)-3-hydroxyphenyl)-3,7-
C.sub.17H.sub.13FO.sub.6 332.28 dihydroxy-4H-chromen-4-one
7-(2-fluoroethoxy)-8-hydroxy-4-phenyl-2H- C.sub.17H.sub.13FO.sub.4
300.28 chromen-2-one 4-(4-(2-fluoroethoxy)phenyl)-7,8-dihydroxy-2H-
C.sub.17H.sub.13FO.sub.5 316.28 chromen-2-one
4-(4-(2-fluoroethylamino)phenyl)-7,8-dihydroxy-
C.sub.17H.sub.14FNO.sub.4 315.30 2H-chromen-2-one
4-(3,4-dihydroxyphenyl)-7-(2-fluoroethoxy)-8-
C.sub.17H.sub.13FO.sub.6 332.28 hydroxy-2H-chromen-2-one
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-8-hydroxy-
C.sub.21H.sub.21FO.sub.7 404.39
4-(4-hydroxyphenyl)-2H-chromen-2-one
6-(2-fluoroethoxy)-3-hydroxy-2-phenylquinolin-
C.sub.17H.sub.14FNO.sub.3 299.30 4(1H)-one
1-(2-fluoroethyl)-3,6-dihydroxy-2-phenylquinolin-
C.sub.17H.sub.14FNO.sub.3 299.30 4(1H)-one
2-(3-(2-fluoroethoxy)-4-hydroxyphenyl)- C.sub.17H.sub.14FNO.sub.5
331.30 3,6-dihydroxyquinolin-4(1H)-one
2-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-3-
C.sub.21H.sub.22FNO.sub.7 419.40
hydroxyphenyl)-3,6-dihydroxyquinolin-4(1H)-one
2-(3,4-dihydroxyphenyl)-3-hydroxy-6-(methylamino)
C.sub.16H.sub.14N.sub.2O.sub.4 298.29 quinolin-4(1H)-one
1-(2-fluoroethyl)-3,6-dihydroxy-2-(4-hydroxyphenyl)
C.sub.17H.sub.14FNO.sub.4 315.30 quinolin-4(1H)-one
7-(2-(4-(2-fluoroethyl)-1H-1,2,3-triazol-1-yl)ethoxy)-
C.sub.21H.sub.18FN.sub.3O.sub.4 395.38
8-hydroxy-4-phenyl-2H-chromen-2-one
1-(2,4-dimethylphenyl)-4-(3-fluoro-5-methylphenyl)-
C.sub.17H.sub.16FN.sub.3 281.33 1H-1,2,3-triazole
Synthesis of Ligands and their Labeling Precursors
Halogenation and Radiohalogenation:
[0445] As disclosed herein, for a number of different AD ligands,
such as flavones, coumarins, carbazoles, quinolinones, chromenones,
trisubstituted imidazoles and their derivatives as disclosed
herein, the radiolabeled atom, such as a halogen atom, for example,
may be readily introduced into the ligand using a number of
different methods well known in the art. Accordingly, the
radiolabeled compounds of the Formula I to Formula VI of the
present application may be prepared using standard methods known in
the art for preparing such radiolabeled compounds having a
particular substituent, wherein the compound may be incorporated
with a particular radionuclide selected from the group consisting
of .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I, .sup.125I,
.sup.131I and .sup.77Br.
[0446] In one particular example, the halogen may be introduced by
a method using a tin for halogen exchange process. For example, a
non-radioactive halogen such as iodine, may be replaced by an
organo tin compound via a metal, such as a palladium composition,
to form the radiolabeling tin precursor, as represented below. This
precursor is then subjected to radioactive halogenation via
displacement with Na.sup.125I source, for example, to afford the
radioactive ligand.
##STR00120##
[0447] Alternatively, the radio labeled halogen may be readily
introduced via direct halogenation. For example, for a ligand
comprising an aromatic ring as part of the scaffold, or an aromatic
substituent of a ligand, the aromatic ring may be directly
iodinated using well-established radioiodination procedure. One
such example is represented below using a carbazole ligand.
##STR00121##
[0448] For .sup.11C-labeled compounds, the labeled compound may be
prepared by the alkylation or methylation of a hydroxyl group, such
as with [.sup.11C]CH.sub.3I to provide the corresponding C-11
labeled methoxy derivative. For example, such a process is
represented by the reaction of the flavone derivative shown
below.
##STR00122##
[0449] Other methods of preparing radiolabeled ligands are well
known in the art. Example of such methods are disclosed in, for
example: 1) Jewett, D. M. (1992) A Simple Synthesis of
[.sup.11C]Methyl Triflate Appl. Radiat, Isot. 43, 1383-1385; 2)
Crouzel, C. Langstrom, B., Pike, V. W., and Coenen, H. H. (1987)
Recommendations for a practical production of [.sup.11C]methyl
iodide Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A 38,
601-603; Dannals, R. F., Ravert, H. T.; 3) Wilson, A. A. (1990)
Radiochemistry of Tracers for Neurotransmitter Receptor Studies.
In: Quantitative Imaging: Neuroreceptors, Neurotransmitters, and
Enzymes. (Edited by Frost, J. J. Wagner Jr., H. N. pp. 19-35, Raven
Press, New York; 4) Jewett, D. M., Manger, T. J., and Watkins, G.
L. (1991) Captive Solvent Methods for Fast Simple Carbon-11
Radioalkylations. In: New Trends in Radiopharmaceutical Synthesis,
Quality Assurance and Regulatory Control (Edited by Emran, A. M.)
pp. 387-391, Plenum Press, New York; 5) Marazano, C., Maziere, M.,
Berger, G., and Comar, D. (1977) Synthesis of methyl
iodide-.sup.11C and formaldehyde-.sup.11C Appl. Radiat, Isot. 28,
49 52; 6) Watkins, G., Jewett, D., Mulholland, G., Kitbourn, M.,
and Toorongian, S. (1988) A Captive Solvent Method for Rapid
N-[.sup.11C]Methylation of Secondary Amides: Application to the
Benzodiazepine, 4'-Chlorodiazepam (RO5-4864) Appl. Radiat. Isot.
39, 441-444; and 7) Wilson, A. A., DaSilva, J. N., and Houle, S.
(1996) In vivo evaluation of [.sup.11C] and [.sup.15F]-labelled
cocaine analogues as potential dopamine transporter ligands for
positron emission tomography Nucl. Med. Biol. 23, 141-146. The
subject matter of all references cited herein are incorporated
herein by reference in their entirety.
Synthesis of AD-CB-WZ01013
##STR00123##
[0451] To hydroxycarbazole (73 mg, 0.4 mmol) in 1 mL of NMP was
added Cs.sub.2CO.sub.3 (130 mg, 0.4 mmol) and bromofluoroethane (51
mg, 0.4 mmol). The mixture was stirred at rt for 15 h and diluted
with Et.sub.2O (50 mL). It was washed with 1 M HCl (30 mL) and
water (2.times.40 mL), dried over MgSO.sub.4 and concentrated. The
crude product was purified with silica chromatography (4% EtOAc in
hexane to 25%) to afford the desired product (36 mg) as an
off-white solid.
[0452] .sup.1H NMR (400 MHz, CDCl.sub.3/acetone-d.sub.6) .delta.
9.98 (s, 1H), 7.95 (t, J=8.8 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.28
(t, J=8 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.00 (d, J=2 Hz, 1H), 6.83
(dd, J=8.8, 2.0 Hz, 1H), 4.85 (t, J=4 Hz, 1H), 4.73 (t, J=4 Hz,
1H), 4.35 (t, J=4 Hz, 1H), 4.28 (t, J=4 Hz, 1H); MS (ESI) m/z 230
(M+H.sup.+).
Synthesis of AD-C-WZ01011
##STR00124##
[0454] To hydroxycarbazole (183 mg, 1 mmol) in 4 mL of NMP was
added Cs.sub.2CO.sub.3 (326 mg, 1 mmol) and ethylenedi-tosylate
(370 mg, 1 mmol). The mixture was stirred at rt for 15 h and
diluted with Et.sub.2O (80 mL). It was washed with 1 M HCl (50 mL)
and water (2.times.50 mL), dried over MgSO.sub.4 and concentrated.
The crude product was purified with silica chromatography (50% DCM
in hexane to 100% DCM) to afford the desired product (75 mg) as an
off-white solid.
[0455] .sup.1H NMR (400 MHz, acetone-d.sub.6) .delta. 10.21 (s,
1H), 8.00 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.4
Hz, 2H), 7.45 (m, 3H), 7.30 (t, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz,
1H),); 6.98 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.44 (t, J=4.0 Hz,
2H), 4.30 (t, J=4.0 Hz, 2H), 2.42 (s, 3H); MS (ESI) m/z 382
(M+H.sup.+), 404 (M+Na.sup.+).
Synthesis of 18F-labeled AD-CB-001P-WZ-01019
([.sup.18F]2-(2-Fluoro-ethoxy)-9H-carbazole)
##STR00125##
[0457] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O was delivered to the synthesis module. The
[.sup.18F]fluoride was trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
was added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope was evaporated to dryness. Toluene-4-sulfonic acid
2-(9H-carbazol-2-yloxy)-ethyl ester precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) was added to the reactor and then the
fluorination reaction was heated at 115.degree. C. for 10 min. The
crude reaction mixture was then purified by semi-preparative HPLC
(Column: Phenomenex Luna C-18, 250 mm.times.10 mm; Mobile-Phase
Gradient 95:5 H.sub.20 (+0.05% TFA): MeCN (+0.05% TFA) to 100% MeCN
(+0.05% TFA); Flow rate: 5 mL/min).
[0458] The peak corresponding to
[.sup.18F]2-(2-fluoro-ethoxy)-9H-carbazole was collected and
simultaneously diluted with sterile water (10 mL). The resulting
mixture was passed over a C-18 Sep-Pak so that the product was
trapped and residual acetonitrile was washed away with further
water (10 mL). [.sup.18F]2-(2-Fluoro-ethoxy)-9H-carbazole was then
eluted into the product vial with USP grade ethanol (0.5 mL) and
diluted with sterile water (9.5 mL) to provide a final formulation
(19-34 mCi in 10 mL) suitable for injection (7.5% decay corrected
yield, 100% radiochemical purity).
[0459] Purity was determined by analytical HPLC equipped with a
radioactivity detector and identity was confirmed by comparison
with HPLC data for the corresponding unlabeled reference standard
(FIG. 3A and FIG. 3B).
Synthesis of AD-CB-002P-WZ01031
##STR00126##
[0461] To hydroxycarbazole (92 mg, 0.5 mmol) in 2 mL of NMP was
added Cs.sub.2CO.sub.3 (163 mg, 0.5 mmol) and azido ethyltosylate
(121 mg, 0.5 mmol). The mixture was stirred at rt for 15 h and
diluted with Et.sub.2O (50 mL). It was washed with 0.5 M HCl (50
mL) and water (2.times.50 mL), dried over MgSO.sub.4 and
concentrated. The crude product was purified with silica
chromatography (80% DCM in hexane to 100% DCM) to afford the
desired product (76 mg) as a white solid.
[0462] .sup.1H NMR (400 MHz, CDCl.sub.3/acetone-d.sub.o) .delta.
9.98 (s, 1H), 7.95 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.29 (t, J=8.0
Hz, 1H), 7.14 (t, J=8.0 Hz, 1H),); 7.01 (s, 1H), 6.84 (d, J=8.4 Hz,
1H), 4.28 (t, J=4.8 Hz, 2H), 3.67 (t, J=4.8 Hz, 2H); MS (ESI) iiniz
253 (M+H.sup.4).
Synthesis of AD-CB-002S-WZ01033
##STR00127##
[0464] To azido carbazole (32 mg, 0.127 mmol) in 0.5 mL of DMF was
added CuI (7.6 mg, 0.04 mmol), DIPEA (16.4 mg, 0.127 mmol), and
fluoropentyne (16.4 mg, 0.19 mmol). The reaction mixture was
vigorously stirred for 1 h and diluted with EtOAc (30 mL). It was
washed with water (50 mL), 0.5 M HCl (30 mL), water (2.times.50
mL), dried over MgSO.sub.4 and concentrated. The crude product was
pre-absorbed on silica (3 g) and loaded on a 4 g silica column and
eluted with 30% EtOAc in hexane to 50% to afford the desired
compound (20 mg).
[0465] .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 7.95
(d, J=7.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.40 (d,
J=8.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 6.94
(d, J=2.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 4.83-4.78 (m, 2H),
4.53-4.48 (m, 3H), 4.40 (t, J=6.0 Hz, 1H), 2.85 (t, J=7.6 Hz, 2H),
2.10-1.99 (m, 2H); MS (ESI) m/z 339 (M+H.sup.+).
Synthesis of 18F-Labeled AD-CB-002S-WZ01033
Preparation of [.sup.18F]5-Fluoro-pent-1-yne
##STR00128##
[0467] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O is delivered to the synthesis module. The
[.sup.18F]fluoride is trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
is added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope is evaporated to dryness.
[0468] Toluene-4-sulfonic acid pent-4-ynyl ester (20 mg in 0.8 mL
MeCN) is added to the reactor and the fluorination reaction is
heated at 110.degree. C. for 5 min. Following fluorination, the
crude reaction mixture is purified by distillation and yields
[.sup.18F]5-fluoro-pent-1-yne as a solution in acetonitrile
(trapped at -78.degree. C. due to the volatility of the
product).
Preparation of Triazole
##STR00129##
[0470] A mixture of azide precursor (5 mg), sodium ascorbate (40
mg), tris-(benzyltriazolylmethyl)amine (TBTA, 25 mg) and aqueous
copper sulfate solution (0.1 M, 0.25 mL) in DMF (0.4 mL) and water
(0.1 mL) is added to the cooled pentyne solution described above.
The reaction mixture is then warmed to rt and stirred for 30 min.
After this time, the reaction is purified by semi-preparative HPLC.
The peak corresponding to the product is collected and
simultaneously diluted with sterile water (10 mL). The resulting
mixture is passed over a C-18 Sep-Pak and residual acetonitrile is
washed away with additional water (10 mL). The product is eluted
into the product vial with USP grade ethanol (0.5 mL) and diluted
with sterile water (9.5 mL) providing a final formulation suitable
for injection.
[0471] Purity is determined by analytical HPLC equipped with a
radioactivity detector and identity is confirmed by comparison with
HPLC data for the corresponding unlabeled reference standard.
Synthesis of .sup.18F-Labeled CB-003
##STR00130##
[0473] [.sup.18F]-Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O is delivered to the synthesis module. The
[.sup.18F]-fluoride is trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
is added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope is evaporated to dryness. The precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) is added to the reactor and the fluorination
reaction is heated at 115.degree. C. for 10 min. The mixture was
cooled to 55.degree. C. and most of the acetonitrile was evaporated
under vacuum and a stream of argon as before. To the crude
Boc-protected product was added aqueous hydrochloric acid (1.0 M,
1.0 mL), and the mixture was heated to 105.degree. C. for 3
minutes. After cooling to 35.degree. C., aqueous sodium acetate
(2.0 M, 0.5 mL) was added with stirring. The crude reaction mixture
is then purified by semi-preparative HPLC (Column: Phenomenex Luna
C-18, 250 mm.times.10 mm; Mobile-Phase Gradient 95:5 H.sub.20
(+0.05% TFA): MeCN (+0.05% TFA) to 100% MeCN (+0.05% TFA); Flow
rate: 5 mL/min; time 25 min). The peak corresponding to the final
product is collected and simultaneously diluted with sterile water
(10 mL). The resulting mixture is passed over a C-18 Sep-Pak so
that the product is trapped and residual acetonitrile is washed
away with further water (10 mL). The product is then eluted into
the product vial with USP grade ethanol (0.5 mL) and diluted with
sterile water (9.5 mL) providing a final formulation suitable for
injection (31% decay uncorrected yield, 100% radiochemical purity).
Purity was determined by analytical HPLC equipped with a
radioactivity detector and identity was confirmed by comparison
with HPLC data for the corresponding unlabeled reference
standard.
Synthesis of .sup.18F-Labeled CB-004
##STR00131##
[0475] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O is delivered to the synthesis module. The
[.sup.18F]fluoride is trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
is added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope is evaporated to dryness. The precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) is added to the reactor and the fluorination
reaction is heated at 115.degree. C. for 10 min. The mixture was
cooled to 55.degree. C. and most of the acetonitrile was evaporated
under vacuum and a stream of argon as before. To the crude
Boc-protected product was added aqueous hydrochloric acid (1.0 M,
1.0 mL), and the mixture was heated to 105.degree. C. for 3
minutes. After cooling to 35.degree. C., aqueous sodium acetate
(2.0 M, 0.5 mL) was added with stirring. The crude reaction mixture
is then purified by semi-preparative HPLC (Column: Phenomenex Luna
C-18, 250 mm.times.10 mm; Mobile-Phase Gradient 95:5 H.sub.20
(+0.05% TFA): MeCN (+0.05% TFA) to 100% MeCN (+0.05% TFA); Flow
rate: 5 mL/min; time=25 min). The peak corresponding to the final
product is collected and simultaneously diluted with sterile water
(10 mL). The resulting mixture is passed over a C-18 Sep-Pak so
that the product is trapped and residual acetonitrile is washed
away with further water (10 mL). The product is then eluted into
the product vial with USP grade ethanol (0.5 mL) and diluted with
sterile water (9.5 mL) providing a final formulation suitable for
injection (3% decay uncorrected yield, 100% radiochemical purity).
Purity was determined by analytical HPLC equipped with a
radioactivity detector and identity was confirmed by comparison
with HPLC data for the corresponding unlabeled reference
standard.
Synthesis of .sup.18F-Labeled CB-007
##STR00132##
[0477] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O is delivered to the synthesis module. The
[.sup.18F]fluoride is trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
is added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope is evaporated to dryness. The precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) is added to the reactor and the fluorination
reaction is heated at 115.degree. C. for 10 min. The mixture was
cooled to 55.degree. C. and most of the acetonitrile was evaporated
under vacuum and a stream of argon as before. To the crude
Boc-protected product was added aqueous hydrochloric acid (1.0 M,
1.0 mL), and the mixture was heated to 105.degree. C. for 3
minutes. After cooling to 35.degree. C., aqueous sodium acetate
(2.0 M, 0.5 mL) was added with stirring. The crude reaction mixture
is then purified by semi-preparative HPLC (Column: Phenomenex Luna
C-18, 250 mm.times.10 mm; Mobile-Phase Gradient 95:5 Hhd 20 (+0.05%
TFA): MeCN (+0.05% TFA) to 100% MeCN (+0.05% TFA); Flow rate: 5
mL/min; time=25 min). The peak corresponding to the final product
is collected and simultaneously diluted with sterile water (10 mL).
The resulting mixture is passed over a C-18 Sep-Pak so that the
product is trapped and residual acetonitrile is washed away with
further water (10 mL). The product is then eluted into the product
vial with USP grade ethanol (0.5 mL) and diluted with sterile water
(9.5 mL) providing a final formulation suitable for injection (1.2%
decay uncorrected yield, 100% radiochemical purity). Purity was
determined by analytical HPLC equipped with a radioactivity
detector and identity was confirmed by comparison with HPLC data
for the corresponding unlabeled reference standard.
Synthesis of .sup.18F-Labeled CB-012
##STR00133##
[0479] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O was delivered to the synthesis module. The
[.sup.18F]fluoride was trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
was added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope was evaporated to dryness. Toluene-4-sulfonic acid
2-(9H-carbazol-2-yloxy)-ethyl ester precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) was added to the reactor and then the
fluorination reaction was heated at 115.degree. C. for 10 min. The
crude reaction mixture was then purified by semi-preparative HPLC
(Column: Phenomenex Luna C-18, 250 mm.times.10 mm; Mobile-Phase
Gradient 95:5 H.sub.20 (+0.05% TFA): MeCN (+0.05% TFA) to 100% MeCN
(+0.05% TFA); Flow rate: 5 mL/min). The peak corresponding to the
product was collected and simultaneously diluted with sterile water
(10 mL). The resulting mixture was passed over a C-18 Sep-Pak so
that the product was trapped and residual acetonitrile was washed
away with further water (10 mL).
[.sup.18F]2-(2-Fluoro-ethoxy)-9H-carbazole was then eluted into the
product vial with USP grade ethanol (0.5 mL) and diluted with
sterile water (9.5 mL) to provide a final formulation (19-34 mCi in
10 mL) suitable for injection (2% decay uncorrected yield, 100%
radiochemical purity). Purity was determined by analytical HPLC
equipped with a radioactivity detector and identity was confirmed
by comparison with HPLC data for the corresponding unlabeled
reference standard.
Assays of Carbazole Derivatives:
[0480] From the Biacore assay, two carbazole derivatives displayed
promising binding affinities to oligomers/polymers and fibrils
(Table 4). The beta-carbolise Harmed, a member of the harmala
alkaloids, is the urinary metabolite of harmine. The harmala
alkaloids are MAO inhibitors and are commonly found in Syrian rue,
Peganum harmala, and the South American vine Banisteriopsis caapi,
both of which are purported to possess strong hallucinogenic
effects. The beta-carbolenes have a varied effect on the central
nervous system including binding to the 5-HT.sub.2, 5-HT.sub.1a,
glutamate NMDA and imidazoline receptors; inhibiting MAO-A enzyme
and interfering with dopaminergic transmission. And while
beta-carbolines are thought to be cytotoxic, they also maintain
neuroprotective properties supposedly offering neuroprotection
against dopamine and glutamate and, additionally, by scavenging
reactive oxygen species. A recent report demonstrated that
beta-carboline alkyloids induce a facilitation of short and long
term memory in object recognition tasks in mice, although the means
by which the alkyloids are exerting their effect is unclear. Moura,
D. J., et al., Effects of b-carboline alkaloids in the object
recognition task in mice. Life Sciences, 2006, 79: p.
2099-2104.
[0481] The second active carbazole discovered in the assay is
2-hydroxycarbazole. 2-Hydroxycarbazole has been recently shown to
release Ca.sup.2+ion from skeletal and cardiac muscle through a
distinct pharmacological pathway. The generic carbazole scaffold
exists in several therapeutics including the non-steroidal
anti-inflammatory carprofen, carazolol (a beta-blocker) and
YM-53601 (a squalene synthase inhibitor). Recent work has shown
that carbazole derivatives can act as .gamma.-secretase modulators.
[Narlawar, R., et al., N-Substituted carbazolyloxyacetic acids
modulate Alzheimer associated g-secretas. Bioorganic &
Medicinal Chemistry Letters, 2007, 17: p. 176-182] In another AD
related project, Howlett discovered highly elaborated carbazoles,
such as carvedilol, inhibit fibril formation, albeit the binding
affinities to the fibrils were not determined. [Howlett, D. R., et
al., Common Structural Features Determine the Effectiveness of
Carvedilol, Daunomycin and Rotiletracycline as Inhibitors of
Alzheimer b-Amyloid Fibril Formation. Biochemical Journal, 1999,
343: p. 419-423] Interestingly, an article intending to determine
the practicality of using carbazoles as fibril inhibitors based on
cell permeability suggests that carbazoles are unlikely to cross
the blood brain barrier, as they are PGP substrates, precluding
their use as therapeutics for fibril inhibition. [Saengkhae, C., et
al., Ability of Carbazole Salts, Inhibitors of Alzheimer b-Amyloid
Fibril Formation, to Cross Cellular Membranes. European Journal of
Pharmacology, 2007, 559: p. 124-131]
[0482] By using an appropriate imaging modality, a tracer's
biodistribution pattern becomes instantly visible and accessible.
For example, by using .sup.18F-labeled tracers one can easily
quantify a tracer's uptake into, and washout from, the brain using
positron emission tomography (PET). Tracers with high uptake and
slow washout in normal brains generate low signal to noise ratios.
Tracers with high uptake and fast washout in normal brains have
high signal to noise rations and are considered ideal.
.sup.18F-labeled carbazoles possess ideal brain imaging properties.
For example, an .sup.18F-labeled carbazole was prepared and
administered to a normal, white Sprague-Dawley rat (FIG. 6). Within
minutes, the tracer entered into the brain and washed out over
several minutes.
[0483] The non-radioactive carbazole also successfully competes off
both Thioflavin T and FDDNP in brain tissue sections suggesting
that the tracer binds to similar binding sites (FIGS. 4 and 5).
TABLE-US-00004 TABLE 4 Carbazole-based hits from the Biacore assay.
Binding to oligomers/polymers Binding to fibrils (A.beta.1-42)
(A.beta.1-42) ##STR00134## ++ + ##STR00135## +++ + #73:
7,8-Dihydroxy-4-phenylcoumarin A "+" sign represents a hit and the
increase in "+" signs relates to increasing binding affinity. A "-"
sign represents no binding.
[0484] A list of examples of carbazole-based imaging agents are
shown in Table 5. Many of the compounds are either .sup.18F- or
.sup.11C-labeled.
TABLE-US-00005 TABLE 5 Examples of carbazole-based imaging agents
Mol. Compound Name Structure Formula Weight
2-(2-fluoroethoxy)-9H-carbazole ##STR00136## C.sub.14H.sub.12FNO
229.25 9-(2-fluoroethyl)-9H-carbazol-2-ol ##STR00137##
C.sub.14H.sub.12FNO 229.25 N-(2-fluoroethyl)-7-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)- 9H-carbazol-3-amine ##STR00138##
C.sub.21H.sub.27FN.sub.2O.sub.4 390.45 7-(2-fluoroethoxy)-N,N-
dimethyl-9H-carbazol-2-amine ##STR00139## C.sub.16H.sub.17FN.sub.2O
272.32 7-(2-(2-(2- fluoroethoxy)ethoxy)ethoxy)-N-
methyl-9H-carbazol-3-amine ##STR00140##
C.sub.19H.sub.23FN.sub.2O.sub.3 346.40
1-(3,6-diamino-9H-carbazol-9- yl)-3-(2-(2-(2-
fluoroethoxy)ethoxy)ethoxy)propan- 1-one ##STR00141##
C.sub.21H.sub.26FN.sub.3O.sub.4 403.45 N-(2-fluoroethyl)-2-hydroxy-
11H-benzo[a]carbazole-3-carboxamide ##STR00142##
C.sub.19H.sub.15FN.sub.2O.sub.2 322.33
2-(6-chloro-9H-carbazol-2-yl)- N-(2-fluoroethyl)propanamide
##STR00143## C.sub.17H.sub.16ClFN.sub.2O 318.77
2-(6-fluoro-9H-carbazol-2-yl)- N,N-dimethylpropanamide ##STR00144##
C.sub.17H.sub.17FN.sub.2O 284.33 2-methoxy-9H-carbazole
##STR00145## C.sub.13H.sub.11NO 197.23
6-iodo-2-methoxy-9H-carbazole ##STR00146## C.sub.13H.sub.10INO
323.13
Detailed Biacore Assay Protocol:
[0485] .beta.-Amyloid (A.beta.42) soluble aggregates
(oligomers/soluble polymers). Biotin-LC-A.beta.42 was mixed with
A.beta.42 at a ratio of 3:2. After dissolving in 1% NH.sub.4OH and
dH.sub.2O, the mixture (40 uM concentration) was incubated in
1.times.PBS (pH 7.4) buffer at RT for 6-hours to form
oligomers/soluble polymers. The free monomer of A.beta.42 in the
sample was removed using a Microcon centrifugal filter tube with a
10 KDa of MW cutoff. The Biotin-LC-A.beta.42 oligomers/polymers
were immobilized onto SA chip by streptavidin-biotin capture.
[0486] .beta.-Amyloid (A.beta.42) insoluble aggregates (fibrils).
Fibrils were prepared according to methods published previously
(Agdeppa E D et al. 2001). Briefly, 0.5 mg of A.beta.42
(Biotin-LC-A.beta.42: A.beta.42=1:1) was dissolved in 1 ml of PBS,
pH 7.4, and mixed with a magnetic stir bar for 3 d at 37.degree.
C., resulting in a visibly cloudy solution. The fibril pellet was
collected by centrifugation. The Biotin-LC-A.beta.42 fibrils were
immobilized onto SA chip by streptavidin-biotin capture.
[0487] Screening of amyloid binding compounds with Biacore (Surface
Plasmon Resonance Analysis). A.beta.42 oligomers/soluble polymers
or fibrils were immobilized on Flow Cell 2 (Fc2) or Flow Cell 3
(Fc3) of the Sensor Chip, with Fc1 serving as the control.
Screening compounds at 10 uM concentration was flown through Fc1,
Fc2, and Fc3 for 2 minutes at a flow rate of 30 ul/minute. The Flow
Cells were then washed with running buffer (1.times.PBS) for 2
minute, and regenerated with 50 mM of NaOH for 30 seconds. The real
time interaction between the screening compound and the amyloid
aggregates immobilized on the chip surface was recorded in the
sensorgram.
[0488] Immunostaining of brain sections with Thioflavin T. Brain
samples from donors with Alzheimer disease were paraffin wax
infiltrated after fixation. Paraffin blocks with embedded brain
samples were mounted onto microtome and sectioned. Sections were
then deparaffinized and hydrated, followed by incubation with or
without AD-CB-001S-WZ01013. Staining was carried out with 1 uM
Thioflavin T. Images were obtained with a fluorescence microscope
(FIG. 4).
[0489] Immunostaining of brain sections with FDDNP. Brain samples
from donors with Alzheimer disease were paraffin wax infiltrated
after fixation. Paraffin blocks with embedded brain samples were
mounted onto microtome and sectioned. Sections were then
deparaffinized and hydrated, followed by incubation with or without
AD-CB-001S-WZ01013. Staining was carried out with 1 uM FDDNP.
Images were obtained with a fluorescence microscope (FIG. 5).
[0490] A white Sprague-Dawley rat was injected via tail vein with
.about.850 uCi AD-CB-001, formulated in 10% EtOH:water. A dynamic
scan was conducted for 30 min on a R4 microPET scanner. The data
was reconstructed using 1 min framing. Within minutes, the tracer
entered the rat brain and quickly washed out (FIG. 6).
Preparation of Coumarin Derivatives
##STR00147##
[0492] To coumarin (120 mg, 0.5 mmol) in 2 mL of NMP was added
Cs.sub.2CO.sub.3 (163 mg, 0.5 mmol) and ethylenedi-tosylate (185
mg, 0.5 mmol). The mixture was stirred at rt for 15 h and diluted
with Et.sub.2O (50 mL). It was washed with 1 M HCl (50 mL) and
water (2.times.50 mL), dried over MgSO.sub.4 and concentrated. The
crude product was purified with silica chromatography (DCM 100% and
then 0.3% MeOH in DCM) to afford the desired product (51 mg) as a
clear oil.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (d, J=8.4 Hz,
2H), 7.52 (m, 3H), 7.43 (m, 2H), 7.37 (m, 3H), 6.75 (s, 1H), 6.71
(d, J=9.2 Hz, 1H), 6.23 (s, 1H), 4.41 (t, J=4.4 Hz, 2H), 4.22 (t,
J=4.4 Hz, 2H), 2.46 (s, 3H); MS (ESI) m/z 437 (M+H.sup.+),
Synthesis of AD-C-003S-WZ01041
##STR00148##
[0495] To coumarin (238 mg, 1 mmol) in 4 mL of NMP was added
Cs.sub.2CO.sub.3 (326 mg, 1 mmol) and bromofluoroethane (152 mg,
1.2 mmol). The mixture was stirred at rt for 15 h and diluted with
Et.sub.2O (50 mL). It was washed with 1 M HCl (50 mL) and water
(2.times.50 mL), dried over MgSO.sub.4 and concentrated. The crude
product was purified with silica chromatography (DCM 80% in hexane
to 100%) to afford the desired product (160 mg) as a white
solid.
[0496] .sup.1H NMR (400 MHz, acetone-d6) .delta. 7.60-7.56 (m, 5H),
7.43 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.96 (dd, J=8.8,
2.4 Hz, 1H), 6.18 (s, 1H), 4.91-4.89 (m, 1H), 4.79-4.77 (m, 1H),
4.49-4.47 (m, 1H), 4.42-4.40 (m, 1H); MS (ESI) m/z 285
(M+H.sup.+).
Synthesis of .sup.18F-labeled AD-C-003S-WZ01041
##STR00149##
[0498] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O is delivered to the synthesis module. The
[.sup.18F]fluoride is trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
is added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope is evaporated to dryness. The precursor (4 mg in 0.9 mL
MeCN/0.1 mL DMSO) is added to the reactor and the fluorination
reaction is heated at 115.degree. C. for 10 min. The crude reaction
mixture is then purified by semi-preparative HPLC (Column:
Phenomenex Luna C-18, 250 mm.times.10 mm; Mobile-Phase Gradient
95:5 H.sub.20 (+0.05% TFA) MeCN (+0.05% TFA) to 100% MeCN (+0.05%
TFA); Flow rate: 5 mL/min; time=25 min).
[0499] The peak corresponding to the product is collected and
simultaneously diluted with sterile water (10 mL). The resulting
mixture is passed over a C-18 Sep-Pak so that the product is
trapped and residual acetonitrile is washed away with further water
(10 mL). The product is then eluted into the product vial with USP
grade ethanol (0.5 mL) and diluted with sterile water (9.5 mL)
providing a final formulation suitable for injection.
[0500] Purity is determined by analytical HPLC equipped with a
radioactivity detector and identity is confirmed by comparison with
HPLC data for the corresponding unlabeled reference standard.
Synthesis of AD-C-002P-WZ01029
##STR00150##
[0502] To dihydroxy coumarin (254 mg, 1 mmol) in 4 mL of NMP was
added Cs.sub.2CO.sub.3 (326 mg, 1 mmol) and ethylazido tosylate
(241 mg, 1 mmol). The mixture was stirred at rt for 15 h and
diluted with Et.sub.2O (50 mL). It was washed with 1 M HCl (50 mL)
and water (2.times.50 mL), dried over MgSO.sub.4 and concentrated.
The crude product was purified with silica chromatography (DCM in
hexane from 80% to 100%) to afford the desired mono-alkylated
product (72 mg) as an off-white solid.
[0503] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.53-7.50 (m, 3H),
7.45-7.43 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H),
6.26 (s, 1H), 5.92 (s, 1H), 4.31 (t, J=5.0 Hz, 2H), 3.72 (t, J=5.0
Hz, 2H); MS (ESI) m/z 324 (M+H.sup.+).
Synthesis of AD-C-002S-WZ01035
##STR00151##
[0505] To azidoethyl coumarin (42 mg, 0.13 mmol) in 1 mL of
methanol was added CuSO.sub.4 (21 mg, 0.13 mmol), sodium ascorbate
(28 mg, 0.13 mmol), and fluoropentyne (16.3 mg, 0.19 mmol). The
reaction mixture was vigorously stirred for 1 h and diluted with
EtOAc (30 mL). It was washed with water (2.times.50 mL), dried over
MgSO.sub.4 and concentrated. The crude product was purified with
silica chromatography (eluted with 5% EtOAc in hexane to 60%) to
afford the desired compound (42 mg).
[0506] .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 7.95
(s, 1H), 7.54-7.52 (m, 3H), 7.48-7.44 (m, 2H), 6.94 (d, J=8.8 Hz,
1H), 6.86 (d, J=8.8 Hz, 1H), 4.86 (t, J=4.8 Hz, 2H), 4.55-4.51 (m,
3H), 4.41 (t, J=6.0 Hz, 1H), 2.83 (t, J=7.2 Hz, 2H), 2.14-2.02 (m,
2H); MS (ESI) m/z 410 (M+H.sup.+),
Synthesis of 18F-Labeled AD-C-002S-WZ-01035
Preparation of [.sup.18F] 5-Fluoro-pent-1-yne
##STR00152##
[0508] [.sup.18F]Fluoride (600-900 mCi) as an enriched solution in
H.sub.2.sup.18O was delivered to the synthesis module. The
[.sup.18F]fluoride was trapped on an ion-exchange column and then
eluted into the reaction vessel using aqueous potassium carbonate
(3.0 mg in 0.4 mL H.sub.2O). Kryptofix-2.2.2 phase transfer reagent
was added (20.0 mg in 1.0 mL MeCN) and the water-acetonitrile
azeotrope was evaporated to dryness. Toluene-4-sulfonic acid
pent-4-ynyl ester (20 mg in 0.8 mL MeCN) was added to the reactor
and then the fluorination reaction was heated at 110.degree. C. for
5 min. Following fluorination, the crude reaction mixture was
purified by distillation to yield [.sup.18F] 5-fluoro-pent-1-yne as
a solution in acetonitrile (trapped at -78.degree. C. due to the
volatility of the product).
Preparation of Triazole
##STR00153##
[0510] A mixture of azide precursor (5 mg), sodium ascorbate (40
mg), fris-(benzyltriazolylmethyl)amine (TBTA, 25 mg) and aqueous
copper sulfate solution (0.1 M, 0.25 mL) in DMF (0.4 mL) and water
(0.1 mL) was added to the cooled pentyne solution described above.
The reaction mixture was then warmed to rt and stirred for 30 min.
After this time, the reaction was purified by semi-preparative
HPLC. The peak corresponding to the product was collected and
simultaneously diluted with sterile water (10 mL). The resulting
mixture was passed over a C-18 Sep-Pak so that the product was
trapped and residual acetonitrile was washed away with further
water (10 mL). The product was then eluted into the product vial
with USP grade ethanol (0.5 mL) and diluted with sterile water (9.5
mL) to provide a final formulation (19 mCi in 10 mL) suitable for
injection (10% decay corrected yield, 100% radiochemical
purity).
[0511] Purity was determined by analytical HPLC equipped with a
radioactivity detector and identity was confirmed by comparison
with HPLC data for the corresponding unlabeled reference
standard.
Synthesis of AD-CB-002P-WZ01031
##STR00154##
[0513] To hydroxycarbazole (92 mg, 0.5 mmol) in 2 mL of NMP was
added Cs.sub.2CO.sub.3 (163 mg, 0.5 mmol) and ethylazido tosylate
(121 mg, 0.5 mmol). The mixture was stirred at rt for 15 h and
diluted with Et.sub.2O (50 mL). It was washed with 0.5 M HCl (50
mL) and water (2.times.50 mL), dried over MgSO.sub.4 and
concentrated. The crude product was purified with silica
chromatography (80% DCM in hexane to 100% DCM) to afford the
desired product (76 mg) as a white solid.
[0514] .sup.1H NMR (400 MHz, CDCl.sub.3/acetone-d6) .delta. 9.98
(s, 1H), 7.95 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.29 (t, J=8.0 Hz,
1H), 7.14 (t, J=8.0 Hz, 1H),); 7.01 (s, 1H), 6.84 (d, J=8.4 Hz,
1H), 4.28 (t, J=4.8 Hz, 2H), 3.67 (t, J=4.8 Hz, 2H); MS (ESI) m/z
253 (MAT).
Synthesis of AD-CB-002S-WZ01033
##STR00155##
[0516] To ethylazido carbazole (32 mg, 0.127 mmol) in 0.5 mL of DMF
was added CuI (7.6 mg, 0.04 mmol), DIPEA (16.4 mg, 0.127 mmol), and
fluoropentyne (16.4 mg, 0.19 mmol). The reaction mixture was
vigorously stirred for 1 h and diluted with EtOAc (30 mL). It was
washed with water (50 mL), 0.5 M HCl (30 mL), water (2.times.50
mL), dried over MgSO.sub.4 and concentrated. The crude product was
pre-absorbed on silica (3 g) and loaded on a 4 g silica column and
eluted with 30% EtOAc in hexane to 50% to afford the desired
compound (20 mg).
[0517] .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 7.95
(d, J=7.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.40 (d,
J=8.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H); 6.94
(d, J=2.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 4.83-4.78 (m, 2H),
4.53-4.48 (m, 3H), 4.40 (t, J=6.0 Hz, 1H), 2.85 (t, J=7.6 Hz, 2H),
2.10-1.99 (m, 2H); MS (ESI) m/z 339 (M+H.sup.+).
Synthesis of 18F-labeled AD-CB-002S-WZ01033
Preparation of Triazole
##STR00156##
[0519] A mixture of azide precursor (5 mg), sodium ascorbate (40
mg), iris-(benzyltriazolylmethyl)amine (TBTA, 25 mg) and aqueous
copper sulfate solution (0.1 M, 0.25 mL) in DMF (0.4 mL) and water
(0.1 mL) is added to the cooled pentyne solution described above.
The reaction mixture is then warmed to rt and stirs for 30 min.
After this time, the reaction is purified by semi-preparative HPLC.
The peak corresponding to the product is collected and
simultaneously diluted with sterile water (10 mL). The resulting
mixture is passed over a C-18 Sep-Pak and residual acetonitrile is
washed away with additional water (10 mL). The product is eluted
into the product vial with USP grade ethanol (0.5 mL) and diluted
with sterile water (9.5 mL) providing a final formulation suitable
for injection.
[0520] Purity is determined by analytical HPLC equipped with a
radioactivity detector and identity is confirmed by comparison with
HPLC data for the corresponding unlabeled reference standard.
Synthesis of AD-C-WZ01011
##STR00157##
[0522] To dihydroxy coumarin (100 mg, 0.4 mmol) in 2.5 mL of NMP
was added Cs.sub.2CO.sub.3 (130 mg, 0.4 mmol) and bromofluoroethane
(46 mg, 0.36 mmol). The mixture was stirred at rt for 18 h and
diluted with Et.sub.2O (50 mL). It was washed with 1 M HCl (50 mL)
and water (2.times.50 mL) and dried over MgSO.sub.4 and
concentrated. The crude product was purified with silica
chromatography (MeOH in DCM from 0% to 1%) to afford the desired
mono-alkylated product (25 mg) as a white solid.
[0523] .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
7.55-7.48 (m, 5H), 6.96 (q, J=7.6 Hz, 2H), 6.19 (s, 1H), 4.86 (m,
1H), 4.75 (m, 1H), 4.43 (m, 1H), 4.37 (m, 1H); MS (ESI) m/z 301
(M+H.sup.+),
General Procedure for Carbazole N-Boc Protection
[0524] To a round bottomed flask equipped with a magnetic stir bar,
rubber septum, and argon inlet containing THF (40 vol) was placed
carbazole (1.0 equiv). To this solution was added NaH (60%
dispersion in oil, 3 equiv) at 0.degree. C. and the reaction was
allowed to stir at 0.degree. C. for 30 min. To this reaction was
added (Boc).sub.2O (1.2 equiv) at 0.degree. C. and the reaction was
allowed to stir for 1 h. After the reaction was complete by LCMS,
poured into water (25 vol) and extracted into EtOAc (3.times.20
vol). The combined organic extracts were washed with water
(2.times.25 vol), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The residue was purified over silica gel using Hexanes:EtOAc
as an eluent to afford the final product.
General Procedure for Carbazole N-Methylation:
[0525] To a round bottomed flask equipped with a magnetic stir bar,
rubber septum, and argon inlet containing THF (50 vol) was placed
carbazole (1.0 equiv). To this solution was added NaH (60%
dispersion in oil, 3 equiv) at 0.degree. C. and the reaction was
allowed to stir at 0.degree. C. for 30 min. To this reaction was
added MeOTf (1.0 equiv) at 0.degree. C. and the reaction was
allowed to stir for 1 h. After the reaction was complete by LCMS,
poured into water (25 vol) and extracted into EtOAc (3.times.20
vol). The combined organic extracts were washed with water
(2.times.25 vol), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The residue was purified over silica gel using Hexanes:EtOAc
as an eluent to afford the final product.
General Experimental Procedure for Phenolic Alkylation:
[0526] To a round bottomed flask equipped with a magnetic stir bar
containing DMF (20 vol) was placed phenol (1 equiv). To this
solution was added alkylating agent (1.0 equiv), Cs.sub.2CO.sub.3
(1.2 equiv) and the reaction was allowed to stir at 60.degree. C.
for 16 h. The reaction was then poured into water (25 vol) and
extracted into EtOAc (3.times.20 vol). The combined organic
extracts were washed with water (2.times.25 vol), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified over silica gel using Hexanes:EtOAc as an eluent to afford
the final product.
General Experimental Procedure for Suzuki Coupling Reaction:
[0527] To a round bottomed flask equipped with a magnetic stir bar
rubber septum, and argon inlet containing toluene:H.sub.2O (1:1, 40
vol) was placed chloro compound (1 equiv). To this solution was
added boronic acid (1.5 equiv), Pd(PPh.sub.3).sub.4 (0.02 equiv),
K.sub.2CO.sub.3 and the reaction was allowed to stir at 110.degree.
C. for 16 h. The reaction was then poured into water (25 vol) and
extracted into EtOAc (3.times.20 vol). The combined organic
extracts were washed with water (2.times.25 vol), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified over silica gel using Hexanes:EtOAc as an eluent to afford
the final product.
General Experimental Procedure for Carbazole Formation Using
P(OEt).sub.3:
[0528] To a round bottomed flask equipped with a magnetic stir bar
containing P(OEt).sub.3 (25 vol) was placed biaryl (1 equiv). The
reaction was allowed to stir at 150.degree. C. for 16 h. After the
reaction was complete, P(OEt).sub.3 was removed in vacuo. The
residue was purified over silica gel using Hexanes:EtOAc as the
eluent to afford the final compound.
Synthesis of CB1-Nosylate Precursor
##STR00158##
[0529] Preparation of ethane-1,2-diyl bis(2-nitrobenzenesulfonate)
(DHK-4-14)
[0530] To a 50 mL round bottomed flask equipped with a magnetic
stir bar containing DCM (10 mL) was placed 1,2-ethanediol (0.25 g,
4.0 mmol). To this solution was added nosyl chloride (1.9 g, 8.5
mmol) and Et.sub.3N (0.90 g, 8.9 mmol) at 0.degree. C. and the
reaction was allowed to stir at room temperature for 16 h. After
the reaction was complete, the white solid was filtered, washed
with DCM (100 mL) and dried in vacuo to afford DHK-4-14 (1.3 g,
75%) as a colorless solid.
[0531] MS: [M+Na].sup.+: 455.0
Preparation of 2-(9H-carbazol-2-yloxy)ethyl 2-nitrobenzenesulfonate
(DHK-4-15)
[0532] To a 25 mL round bottomed flask equipped with a magnetic
stir bar containing DMF (5 vol) was placed carbazole (0.2 g, 1.1
mmol). To this solution was added the DHK-4-14 (0.52 g, 1.2 mmol),
Cs.sub.2CO.sub.3 (0.43 g, 1.3 mmol) and the reaction was allowed to
stir at room temperature for 16 h. The reaction was then poured
into water (25 mL) and extracted into EtOAc (4.times.50 mL). The
combined organic extracts were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The crude residue was purified by flash
chromatography using Hexanes:EtOAc (50:50) on a Combiflash
purification system to yield DHK-4-15 as a white solid (0.28 g,
62%). MS: [M+Na].sup.+: 435.0
Synthesis of CB-5
##STR00159##
[0533] Preparation of tert-butyl
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazole-9-carboxylate:
CB-5: DHK-4-27
[0534] General experimental procedure for carbazole N-Boc
protection was followed. Reaction was performed on a 0.03 g scale.
Product eluted out in 30-35% EtOAc:Hexanes mixture in a gradient
elution on a Combiflash purification system. Isolated 0.03 g (74%)
of CB-5 as a colorless oil. MS: [M+H].sup.+: 418.0
Synthesis of CB-6: DHK-4-28
##STR00160##
[0535] Preparation of
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9-methyl-9H-carbazole:
CB-6
[0536] General experimental procedure for carbazole N-methylation
was followed. Reaction was performed on a 0.05 g scale. Product
eluted out in 40-45% EtOAc:Hexanes mixture in a gradient elution on
a Combiflash purification system. Isolated 0.04 g (78%) of CB-6 as
a white solid. MS: [M+H].sup.+: 332.1.
Synthesis of N-Boc-Protected CB-3 Precursor
##STR00161##
[0537] Preparation of tert-butyl
2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)-9H-carbazole-9-carboxylate:
DHK-4-32
[0538] General experimental procedure for carbazole N-Boc
protection was followed. Reaction was performed on a 0.07 g scale.
Product eluted out in 40% EtOAc:Hexanes mixture in a gradient
elution on a Combiflash purification system. Isolated 0.07 g (82%)
of DHK-4-32 as white solid.
[0539] MS: [M+Na].sup.+: 592.
Synthesis of N-methyl CB-3 Precursor
##STR00162##
[0540] Preparation of
2-(2-(2-(9-methyl-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl
4-methylbenzenesulfonate: DHK-4-30
[0541] General experimental procedure for carbazole N-methylation
was followed. Reaction was performed on a 0.075 g scale. Product
eluted out in 40% EtOAc:Hexanes mixture in a gradient elution on a
Combiflash purification system. Isolated 0.07 g (91%) of DHK-4-30
as a white solid. MS: [M+H].sup.+: 484.2
Synthesis of CB-7 Std
##STR00163##
[0542] Preparation of
1-chloro-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2-nitrobenzene:
DHK-4-51
[0543] General experimental procedure for phenolic alkylation was
followed. Reaction was performed on a 0.25 g scale. Product eluted
out in 20-30% EtOAc:Hexanes mixture in a gradient elution on a
Combiflash purification system. Isolated 0.44 g (99%) of DHK-4-51
as yellow oil. MS: [M+H].sup.+: 308.0.
Preparation of
4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N,N-dimethyl-2'-nitrobiphenyl-4-a-
mine: DHK-4-26
[0544] General experimental procedure for Suzuki coupling reaction
was followed. Reaction was performed on a 0.11 g scale. Product
eluted out in 50-60% EtOAc:Hexanes mixture in a gradient elution on
a Combiflash purification system. Isolated 0.06 g (43%) of DHK-4-26
as yellow oil. MS: [M+H].sup.+: 393.1
Preparation of
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N,N-dimethyl-9H-carbazol-2-amine
DHK-4-29: CB-7
[0545] General experimental procedure for carbazole formation using
P(OEt).sub.3 was followed. Reaction was performed on a 0.06 g
scale. Product eluted out in 70-80% EtOAc:Hexanes mixture in a
gradient elution on a Combiflash purification system. Isolated 0.03
g (49%) of DHK-4-29 CB-7 as white solid. MS: [M+H].sup.+:
361.1.
Synthesis of CB-9 Std
##STR00164##
[0546] Preparation of
1-chloro-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2-nitrobenzene:
DHK-4-51
[0547] General experimental procedure for phenolic alkylation was
followed. Reaction was performed on a 0.25 g scale. Product eluted
out in 20-30% EtOAc:Hexanes mixture in a gradient elution on a
Combiflash purification system. Isolated 0.44 g (99%) of DHK-4-51
as yellow oil. MS: [M+H].sup.+: 308.0.
Preparation of
N-(4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2'-nitrobiphenyl-4-yl)acetamid-
e: DHK-4-31
[0548] General experimental procedure for Suzuki coupling reaction
was followed. Reaction was performed on a 0.11 g scale. Product
eluted out in 80-90% EtOAc:Hexanes mixture in a gradient elution on
a Combiflash purification system. Isolated 0.14 g (100%) of
DHK-4-31 as yellow oil. MS: [M+H].sup.+: 407.0.
Preparation of
N-(7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-yl)acetamide:
DHK-4-33: CB-9
[0549] General experimental procedure for carbazole formation using
P(OEt).sub.3 was followed. Reaction was performed on a 0.15 g
scale. Product eluted out in 90% EtOAc:Hexanes mixture in a
gradient elution on a Combiflash purification system. Isolated 0.03
g (49%) of CB-9 as white solid. MS: [M+H].sup.+: 375.1.
Synthesis of CB-28 Std
##STR00165##
[0550] Preparation of
1-chloro-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2-nitrobenzene:
DHK-4-51
[0551] General experimental procedure for phenolic alkylation was
followed. Reaction was performed on a 0.25 g scale. Product eluted
out in 20-30% EtOAc:Hexanes mixture in a gradient elution on a
Combiflash purification system. Isolated 0.44 g (99%) of DHK-4-51
as yellow oil.
[0552] MS: [M+H].sup.+: 308.0.
Preparation of
3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2-nitrophenyl)pyridine:
DHK-4-56
[0553] General experimental procedure for Suzuki coupling reaction
was followed. Reaction was performed on a 0.095 g scale. Product
eluted out in 40-50% EtOAc:Hexanes mixture in a gradient elution on
a Combiflash purification system. Isolated 0.01 g (9%) of DHK-4-56
as yellow oil. MS: [M+H].sup.+: 351.1.
Preparation of
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-pyrido[2,3-b]indole
DHK-4-58: CB-28
[0554] General experimental procedure for carbazole formation using
P(OEt).sub.3 was followed. Reaction was performed on a 0.01 g
scale. Product eluted out in 50% EtOAc:Hexanes mixture in a
gradient elution on a Combiflash purification system. Isolated
0.002 g (22%) of CB-28 as white solid, MS: [M+H].sup.+: 319
Synthesis of CB-7-Precursor
##STR00166##
[0555] Preparation of 4-(benzyloxy)-1-chloro-2-nitrobenzene:
DHK-4-63
[0556] General experimental procedure for phenolic alkylation was
followed. Reaction was performed on a 1 g scale. K.sub.2CO.sub.3
was used as a base and acetone was used as the solvent. Reaction
time was 4 h. Product eluted out in 20-30% EtOAc:Hexanes mixture in
a gradient elution on a Combiflash purification system. Isolated
1.45 g (95%) of DHK-4-63 as white crystalline solid. MS:
[M+H].sup.+: 264.0
Preparation of
4'-(benzyloxy)-N,N-dimethyl-2'-nitrobiphenyl-4-amine: DHK-4-66
[0557] General experimental procedure for Suzuki coupling reaction
was followed. Reaction was performed on a 0.47 g scale. Product
eluted out in 20-30% EtOAc:Hexanes mixture in a gradient elution on
a Combiflash purification system. Isolated 0.21 g (34%) of DHK-4-66
as orange solid. MS: [M+H].sup.+: 349.1
Preparation of 7-(benzyloxy)-N,N-dimethyl-9H-carbazol-2-amine
DHK-4-68
[0558] General experimental procedure for carbazole formation using
P(OEt).sub.3 was followed. Reaction was performed on a 0.21 g
scale. Product eluted out in 20-30% EtOAc:Hexanes mixture in a
gradient elution on a Combiflash purification system. Isolated 0.13
g (68%) of DHK-4-68 as white solid. MS: [M+H].sup.+: 317.1
Preparation of tert-butyl
2-(benzyloxy)-7-(dimethylamino)-9H-carbazole-9-carboxylate:
DHK-4-69
[0559] General experimental procedure for carbazole N-Boc
protection was followed. Reaction was performed on a 0.13 g scale.
Reaction temperature was carried at room temperature for 16 h,
Product eluted out in 10% EtOAc:Hexanes mixture in a gradient
elution on a Combiflash purification system. Isolated 0.12 g (70%)
of DHK-4-69 as white solid. MS: [M+H].sup.+: 417.2.
Preparation of tert-butyl
2-(dimethylamino)-7-hydroxy-9H-carbazole-9-carboxylate:
DHK-4-71
[0560] To a 50 mL round bottomed flask equipped with a magnetic
stir bar containing EtOAc (50 mL) was placed DHK-4-69 (0.11 g, 0.19
mmol). To this solution was added Pd/C (10%, 20 mg) and the
reaction was allowed to stir under H.sub.2 (1 atm) at RT for 16 h.
After the reaction was complete, the reaction mixture was filtered
through celite and the volatiles were removed in vacuo to afford
DHK-4-71 (0.09 g, 100%) as white solid.
Preparation of tert-butyl
2-(dimethylamino)-7-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)-9H-carbazole-
-9-carboxylate: DHK-4-72: CB-7 precursor
[0561] General experimental procedure for phenolic alkylation was
followed. Reaction was performed on a 0.09 g scale. Product eluted
out in 45% EtOAc:Hexanes mixture in a gradient elution on a
Combiflash purification system. Isolated 0.07 g (41%) of CB-7
precursor as white solid. MS: [M+H].sup.+: 613.2.
Synthesis of AD-CB-003S-WZ0129
##STR00167##
[0563] To
2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbe-
nzenesulfonate) (8.7 g, 19 mmol) was added TBAF (22.8 mL, 1.0 M THF
solution, 22.8 mmol). The mixture was heated to reflux for 1 h
under Ar atmosphere and cooled to rt and concentrated under reduced
pressure. The crude material was purified with silica
chromatography (5% to 40% THF in hexane) to afford
2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as a
clear oil (2.5 g, 43%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.80 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.61 (m, 1H), 4.49
(m, 1H), 4.16 (m, 2H), 3.75 (m, 1H), 3.71-3.67 (m, 3H), 3.62 (m,
4H); MS (ESI) m/z 307 (M+H.sup.+).
[0564] To 2-hydroxycarbazole (45 mg, 0.25 mmol) and
2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (82 mg,
0.27 mmol) in 0.5 mL NMP was added Cs.sub.2CO.sub.3 (82 mg, 0.25
mmol). The mixture was stirred at rt for 15 h under Ar atmosphere
and diluted with Et.sub.2O (50 mL). It was washed with water
(3.times.50 mL) and dried over MgSO.sub.4. Solvent was removed
under reduced pressure and the crude product was purified with
silica chromatography (5% to 50% EtOAc in hexane) to afford the
desired product as white solid (37 mg, 47%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.02 (s, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.91 (d,
J=8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.20 (m, 1H), 6.91 (d, J=2.4 Hz,
1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 4.63 (m, 1H), 4.51 (m, 1H), 4.21
(m, 2H), 3.90 (m, 2H), 3.80-3.76 (m, 3H), 3.74-3.71 (m, 3H); MS
(ESI) m/z 318 (M+H.sup.+).
Synthesis of AD-CB-003P-WZ0141
##STR00168##
[0566] To 2-hydroxycarbazole (183 mg, 1 mmol) and
2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (687 mg,
1.5 mmol) in 5 mL NMP was added Cs.sub.2CO.sub.3 (326 mg, 1 mmol).
The mixture was stirred at rt for 15 h under Ar atmosphere and
diluted with Et.sub.2O (100 mL). It was washed with water
(3.times.100 mL) and dried over MgSO.sub.4. Solvent was removed
under reduced pressure and the crude product was purified with
silica chromatography (5% to 60% EtOAc in hexane) to afford the
desired product as white solid (165 mg, 35%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.21 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.91 (d,
J=8.4 Hz, 1H), 7.77-7.75 (m, 2H), 7.37-7.30 (m, 2H), 7.28 (s, 1H),
7.25 (m, 1H), (td, J=7.6, 1.2 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.83
(dd, J=8.8, 2.4 Hz, 1H), 4.15 (m, 4H), 3.84 (m, 2H), 3.69-3.65 (m,
4H), 3.62-3.59 (m, 2H), 2.38 (s, 3H); MS (ESI) m/z 470 (M+H.sup.+),
492 (M+Na.sup.+).
AD-CB-004S-WZ01165
##STR00169##
[0568] To 4-chloro-3-nitrophenol (1.74 g, 10 mmol) and benzyl
bromide (2.05 g, 12 mmol) in 25 mL of acetone was added
K.sub.2CO.sub.3 (2.76 g, 20 mmol). The mixture was heated at
60.degree. C. for 4 h under Ar atmosphere and cooled to rt. It was
filtered and the solid was washed with ether (80 mL) and the
combined filtrate was concentrated and chromatographed (EtOAc in
hexane, 3% to 30% gradient) to afford
4-(benzyloxy)-1-chloro-2-nitrobenzene as a light-yellow solid (2.5
g, 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46 (d, J=2.8
Hz, 1H), 7.42-7.34 (m, 5H), 7.11 (dd, J=8.8, 2.8 Hz, 1H), 5.08 (s,
2H); MS (ESI) m/z 264 (M+H.sup.+).
[0569] To 4-(benzyloxy)-1-chloro-2-nitrobenzene (526 mg, 2 mmol)
and tent-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (670
mg, 2.1 mmol) in 12 mL dioxane was added 4 mL of a 1 M
Na.sub.2CO.sub.3 (aq) solution and
Tetrakis(triphenylphosphine)palladium (69 mg, 0.06 (nmol). The
suspension was heated at reflux for 15 h under Ar atmosphere and
cooled to rt. It was added EtOAc (100 mL) and washed with brine (80
mL), water (80 mL), and dried over MgSO.sub.4. After solvent
removal, the residue was chromatographed (hexane/EtOAc) to afford
tert-butyl 4'-(benzyloxy)-2'-nitrobiphenyl-4-ylcarbamate as a
yellow solid (740 mg, 88%). NMR (400 MHz, CDCl.sub.3) .delta.
7.44-7.34 (m, 8H), (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 3H), 6.50 (s,
1H), 5.12 (s, 2H), 1.51 (s, 9H); MS (ESI) m/z 443 (M+Na.sup.+).
[0570] A suspension of tert-butyl
4'-(benzyloxy)-2'-nitrobiphenyl-4-ylcarbamate (740 mg, 1.67 mmol)
in 2 mL of triethyl phosphite was heated at 145.degree. C. for 15 h
under Ar atmosphere and cooled to rt. It was added 10 mL of hexane
and let sit for 10 min. Solid was collected via filtration and
washed with ether/hexane (v:v 1/1, 10 mL) and dried under high
vacuum to afford tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate
as a off-white solid (480 mg, 74%). .sup.1H NMR (400 MHz, CDCl3)
.delta. 7.89 (s, 1H), 7.83-7.78 (m, 3H), 7.46 (d, J=7.2 Hz, 2H),
7.38 (m, 2H), 7.32 (d, J=7.2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.88
(dd, J=8.8, 2.4 Hz, 1H), 6.83 (dd, J=8.4, 2.0 Hz, 1H), 6.60 (s,
1H), 5.15 (s, 2H), 1.52 (s, 9H); MS (ESI) m/z 389 (M+H.sup.+).
[0571] To tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate (220
mg, 0.56 mmol) in 50 mL MeOH was added Palladium on activated
carbon (80 mg). The mixture was stirred at rt under H2 atmosphere
for 3 h. Solid was filtered off and the filtrate was concentrated
to afford tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate as a brown
solid (165 mg, 100%). This material was used directly for the next
reaction without purification. MS (ESI) m/z 619 (2M+Na.sup.+).
[0572] To tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate (165 mg,
0.55 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl
4-methylbenzenesulfonate (202 mg, 0.66 mmol) in 2 mL of NMP was
added Cs.sub.2CO.sub.3 (179 mg, 0.55 mmol). The mixture was stirred
at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL).
It was washed with water (3.times.50 mL) and dried over MgSO.sub.4.
After solvent removal, the residue was chromatographed
(hexane/EtOAc) to afford tert-butyl
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate as
a white solid (130 mg, 55%).
[0573] .sup.1H NMR (400 MHz, CDCl3) .delta. 7.94 (s, 1H), 7.83-7.79
(m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.86 (dd, J=8.4, 2.0 Hz, 1H), 6.83
(dd, J=8.8, 2.4 Hz, 1H), 6.63 (s, 1H), 4.64 (m, 1H), 4.51 (m, 1H),
4.21 (m, 2H), 3.91 (m, 2H), 3.81-3.71 (m, 6H), 1.55 (s, 9H); MS
(ESI) m/z 433 (M+H.sup.+).
[0574] To tert-butyl
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate
(130 mg, 0.3 mmol) was added 10 mL of a 4 M HCl in dioxane
solution. The mixture was stirred at rt for 5 h and concentrated
under reduced pressure. The residue was washed with ether (15 mL)
and suspended in EtOAc (50 mL). To this suspension was added 10 mL
of a NaHCO.sub.3 (sat.) and the mixture was stirred for 5 min. The
organic layer was dried over MgSO.sub.4 and concentrated to afford
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-amine as a
brown solid (95 mg, 95%). MS (ESI) m/z 333 (M+H.sup.+).
[0575] A mixture of
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-amine (95 mg,
0.28 mmol), paraformaldehyde (43 mg, 1.43 mmol), and NaOMe (492 mg,
25% MeOH solution, 2.3 mmol) in 8 mL of MeOH was heated at reflux
for 1.5 h under Ar atmosphere and cooled to rt. To this mixture was
added NaBH.sub.4 (54 mg, 1.43 mmol) and the mixture was heated at
reflux for 2 h. After cooling to rt, the mixture was quenched onto
ice. It was extracted with ether (3.times.30 mL) and the combined
organic phase was dried over MgSO.sub.4 and concentrated. The crude
product was purified with chromatography (hexane/EtOAc) to afford
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-2-amine
(AD-CB-003P-WZ0141) as a light-brown solid (55 mg, 56%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.76 (s, 1H), 7.77 (t, J=8.8 Hz,
2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (s, 1H), 6.53 (dd, J=8.4,
2.0 Hz, 1H), 6.46 (s, 1H), 4.62 9m, 1H), 4.50 (m, 1H), 4.13 (t,
J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H), 3.83 (s, 1H), 3.79-3.67 (m,
6H), 2.87 (s, 3H); MS (ESI) m/z 347 (M+H.sup.+).
AD-CB-004 Pa-WZ01179
##STR00170##
[0577] To tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate (200
mg, 0.51 mmol) was added 10 mL of a 4 M HCl in dioxane solution.
The mixture was stirred at rt for 4 h and concentrated under
reduced pressure. The residue was washed with ether (15 mL) and
suspended in EtOAc (50 mL). To this suspension was added 10 mL of a
NaHCO.sub.3 (sat.) and the mixture was stirred for 5 min. The
organic layer was dried over MgSO.sub.4 and concentrated to afford
7-(benzyloxy)-9H-carbazol-2-amine as a brown solid (150 mg, 100%).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.33 (s, 1H), 7.99 (d,
J=8.4 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.42 (d, J=6.8 Hz, 2H),
7.34-7.21 (m, 3H), 7.27-7.23 (m, 1H), 7.00-6.97 (m, 2H), 6.81 (dd,
J=8.8, 2.4 Hz, 1H), 5.12 (s, 2H); MS (ESI) m/z 289 (M+H.sup.+).
[0578] A mixture of 7-(benzyloxy)-9H-carbazol-2-amine (150 mg, 0.52
mmol), paraformaldehyde (78 mg, 2.6 mmol), and NaOMe (900 mg, 25%
MeOH solution, 4.16 mmol) in 15 mL of MeOH was heated at reflux for
2 h under Ar atmosphere and cooled to rt. To this mixture was added
NaBH.sub.4 (98 mg, 2.6 mmol) and the mixture was heated at reflux
for 2 h. After cooling to rt, the mixture was quenched onto ice (30
g). It was extracted with EtOAc (3.times.50 mL) and the combined
organic phase was dried over MgSO.sub.4 and concentrated. The crude
product was purified with chromatography (hexane/EtOAc) to afford
7-(benzyloxy)-N-methyl-9H-carbazol-2-amine as a light-brown solid
(130 mg, 82%). .sup.1H NMR (400 MHz, acetone-d6) .delta. 9.78 (s,
1H), 7.72 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.2
Hz, 2H), 7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.98 (d, J=2.4 Hz, 1H),
6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.49 (dd,
J=8.4, 2.4 Hz, 1H), 5.13 (s, 2H), 4.96 (s, 1H), 2.82 (s, 3H); MS
(ESI) m/z 303 (M+H.sup.+).
[0579] To 7-(benzyloxy)-N-methyl-9H-carbazol-2-amine (120 mg, 0.4
mmol), formic acid (55 mg, 1.2 mmol) and DMAP (5 mg, 0.04 mmol) in
3 mL of pyridine was added portionwise EDC (230 mg, 1.2 mmol). The
mixture was stirred at rt for 3 h under Ar atmosphere and
concentrated under reduced pressure. The residue was diluted with
EtOAc (50 mL) and washed with water (2.times.50 mL), 0.5 M HCl
(2.times.50 mL), and brine (50 mL), and dried over MgSO.sub.4.
After solvent removal, the crude product was purified with
chromatography (hexane/EtOAc) to afford
N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide as a white
solid (110 mg, 83%). .sup.1H NMR (400 MHz, acetone-d6) .delta.
10.34 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.8
Hz, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.39 (m, 2H), 7.34-7.28 (m, 1H),
7.13 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 6.91 (dd,
J=8.4, 2.4 Hz, 1H), 5.19 (s, 2H), 3.31 (s, 3H); MS (ESI) m/z 331
(M+H.sup.+).
[0580] To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (110
mg, 0.33 mmol) in 50 mL MeOH was added Palladium on activated
carbon (50 mg). The mixture was stirred at it under H2 atmosphere
for 15 h. Solid was filtered off and the filtrate was concentrated
to afford N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide as a
brown solid (75 mg, 94%). This material was used directly for the
next reaction without purification. MS (ESI) m/z 241
(M+H.sup.+).
[0581] To N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide (45 mg,
0.187 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl
4-methylbenzenesulfonate (172 mg, 0.38 mmol) in 0.5 mL NMP was
added Cs.sub.2CO.sub.3 (65 mg, 0.2 mmol). The mixture was stirred
at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL).
It was washed with water (2.times.50 mL), 0.5 M HCl (50 mL) and
brine (50 mL), and dried over MgSO.sub.4. Solvent was removed under
reduced pressure and the crude product was purified with silica
chromatography (hexane/EtOAc) to afford
2-(2-(2-(7-(N-methylformamido)-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl
4-methylbenzenesulfonate (AD-CB-004 Pa-WZ01179) as a light-brown
oil (48 mg, 48%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.52
(s, 1H), 8.45 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.8 Hz,
1H), 7.80-7.77 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.4 Hz,
1H), 7.02 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.89
(dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 4.17 (m, 2H), 3.88 (m, 2H),
3.72-3.68 (m, 4H), 3.66-3.61 (m, 2H), 3.39 (s, 3H), 2.41 (s, 3H);
MS (ESI) m/z 527 (M+H.sup.+).
AD-CB-004Pb-WZ01191
##STR00171##
[0583] To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (140
mg, 0.42 mmol) in 5 mL dry THF at 0.degree. C. under Ar atmosphere
was added NaH (50 mg, 60% in oil, 1.26 mmol) in 4 portions. The
mixture was then stirred at rt for 20 min followed by the addition
of tert-butyl phenyl carbonate (244 mg, 1.26 mmol) with a syringe.
The reaction was allowed to stir at rt for 3 h and quenched onto
ice (30 g). The mixture was extracted with EtOAc (2.times.40 mL)
and the combined organic phase was dried over MgSO.sub.4. After
solvent removal, the residue was chromatographed to afford
tert-butyl
2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a
white solid (120 mg, 66%). .sup.1H NMR (400 MHz, CDCl3) .delta.
8.56 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.4 Hz, 1H),
7.83 (d, J=8.4 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.39 (in., 2H),
7.37-7.32 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.8,
2.4 Hz, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 1.75 (s, 9H); MS (ESI) m/z
431 (M+H.sup.+).
[0584] To tert-butyl
2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate (120
mg, 0.28 mmol) in 50 mL MeOH was added Palladium on activated
carbon (50 mg). The mixture was stirred at rt under H2 atmosphere
for 3 h. Solid was filtered off and the filtrate was concentrated
to afford tert-butyl
2-hydroxy-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a
brown solid (95 mg, 100%). This material was used directly for the
next reaction without purification. MS (ESI) m/z 341
(M+H.sup.+).
[0585] To tert-butyl
2-hydroxy-7-(N-methylformamido)-9H-carbazole-9-carboxylate (65 mg,
0.19 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl
4-methylbenzenesulfonate (174 mg, 0.38 mmol) in 0.5 mL NMP was
added Cs.sub.2CO.sub.3 (68 mg, 0.21 mmol). The mixture was stirred
at rt for 15 h under Ar atmosphere and diluted with EtOAc (80 mL).
It was washed with water (3.times.50 mL), and dried over
MgSO.sub.4. Solvent was removed under reduced pressure and the
crude product was purified with silica chromatography
(hexane/EtOAc) to afford tert-butyl
2-(N-methylformamido)-7-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)-9H-carba-
zole-9-carboxylate (AD-CS-004Pb-WZ01191) as a clear oil (75 mg,
63%). .sup.1H NMR (400 MHz, CDCl3) .delta. 8.56 (s, 1H), 8.14 (s,
1H), 7.89 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H),
7.79 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.15 (dd, J=8.4, 2.0 Hz, 1H),
7.00 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 3.89 (m, 2H), 3.88 (m,
2H), 3.73-3.68 (m, 4H), 3.66-3.63 (m, 2H), 3.41 (s, 3H), 2.42 (s,
3H), 1.76 (s, 9H); MS (ESI) m/z 527 (M+H.sup.+).
AD-CB-010S-WZ01183
##STR00172##
[0587] To 4-(benzyloxy)-1-chloro-2-nitrobenzene (394 mg, 1.5 mmol)
N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)formamide
(370 mg, 1.5 mmol) in 6 mL dioxane was added 3 mL of a 1 M
Na.sub.2CO.sub.3 (aq) solution and
Tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol). The
suspension was heated at reflux for 15 h under Ar atmosphere and
cooled to rt. It was added EtOAc (80 mL) and washed with brine (50
mL), water (2.times.80 mL), and dried over MgSO.sub.4. After
solvent removal, the residue was chromatographed (hexane/EtOAc) to
afford N-(4'-(benzyloxy)-2'-nitrobiphenyl-4-yl)formamide as a
yellow solid (395 mg, 75%). MS (ESI) m/z 349 (M+H.sup.+).
[0588] A suspension of
N-(4'-(benzyloxy)-2'-nitrobiphenyl-4-yl)formamide (350 mg, 1 mmol)
in 2 mL of triethyl phosphite was heated at 145 C for 15 h under Ar
atmosphere and cooled to rt. It was added 10 mL of hexane and let
sit for 10 min, Solid was collected via filtration and washed with
ether/hexane (v:v 1/1, 10 mL) and dried under high vacuum to
N-(7-(benzyloxy)-9H-carbazol-2-yl)formamide as a light-brown solid
(280 mg, 88%). MS (ESI) m/z 317 (M+H.sup.4).
[0589] To N-(7-(benzyloxy)-9H-carbazol-2-yl)formamide (250 mg, 0.79
mmol) in 50 mL MeOH was added Palladium on activated carbon (60
mg). The mixture was stirred at rt under H2 atmosphere for 15 h.
The mixture was concentrated under reduced pressure and dried under
high vacuum to afford N-(7-hydroxy-9H-carbazol-2-yl)formamide mixed
with the catalyst as a black solid (240 mg). This material was used
directly for the next reaction without purification. MS (ESI) m/z
227 (M+H.sup.+).
[0590] To N-(7-hydroxy-9H-carbazol-2-yl)formamide (30 mg) and
2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (48 mg,
0.156 mmol) in 0.3 mL of NMP was added Cs.sub.2CO.sub.3 (42 mg,
0.13 mmol). The mixture was stirred at rt for 15 h under Ar
atmosphere and diluted with EtOAc (30 mL). It was washed with water
(3.times.30 mL) and dried over MgSO.sub.4. After solvent removal,
the residue was chromatographed (hexane/EtOAc) to
N-(7-(2-fluoroethoxy)-9H-carbazol-2-yl)formamide
(AD-CB-010S-WZ01183) as a white solid (17 mg, 36%). For the major
rotomer: .sup.1H NMR (400 MHz, acetone-d6) .delta. 10.10 (s, 1H),
9.28 (s, 1H), 8.39 (d, J=1.6 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.91
(s, 1H), 7.87 (d, J=8.4, Hz, 2H), 7.17 (dd, J=8.4, 2.0 Hz, 1H),
7.01 (d, J=2.0 Hz, 1H), 6.80 (dd, J=8.4, 2.0 Hz, 1H), 4.58 (m, 1H),
4.46 (m, 1H), 4.21 (m, 2H), 3.88 (m, 2H), 3.77 (m, 1H), 3.73-3.66
(m, 5H); MS (ESI) m/z 361 (M+H.sup.+).
AD-CB-012S-WZ01185
##STR00173##
[0592] Compound AD-CB-012S-WZ01185 was prepared using the same
procedure for the preparation of AD-CB-010S-WZ01183. For the major
rotomer: .sup.1H NMR (400 MHz, acetone-d6) .delta. 10.08 (s, 1H),
9.19 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H),
7.84-7.77 (m, 3H), 7.07 (dd, J=8.4, 2.0 Hz, 1H), 6.93 (d, J=2.0 Hz,
1H), 6.69 (dd, J=8.4, 2.0 Hz, 1H), 4.73 (m, 1H), 4.61 (m, 1H), 4.24
(m, 1H), 4.17 (m, 1H); MS (ESI) Ink 273 (M+H.sup.+).
AD-CB-024S-WZ02033
##STR00174##
[0594] Compound AD-CB-024S-WZ02033 was prepared using the same
procedure for the preparation of AD-CB-010S-WZ01183. For the major
rotomer: .sup.1H NMR (400 MHz, acetone-d6) .delta. 10.19 (s, 1H),
9.31 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.88
(d, J=8.2 Hz, 2H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=2.0 Hz,
1H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 4.62 (m, 1H), 4.50 (m, 1H), 4.20
(m, 2H), 3.88 (m, 2H), 3.83 (m, 1H), 3.75 (m, 1H); MS (ESI) m/z 317
(M+H.sup.+).
AD-CB-013S-WZ-02001
##STR00175##
[0596] A mixture of palladium acetate (37 mg, 0.165 mmol) and BINAP
(154 mg, 0.248 mmol) in 5 mL dioxane was stiffed for 10 min under
Ar atmosphere. To this mixture was added 1-bromo-4-nitrobenzene
(1.11 g, 5.5 mmol), 4-methoxyaniline (745 mg, 6.07 mmol),
CsCO.sub.3 (2.5 g, 7.73 mmol), and 10 mL of dioxane. The mixture
was heated at reflux for 15 h and cooled and diluted with ether (80
mL). The solid was removed through filtration and the filtrate was
concentrated. The residue was chromatographed (hexane/EtOAc) to
afford 4-methoxy-N-(4-nitrophenyl)aniline as a yellow solid (786
mg, 58%). MS (ESI) m/z 245 (M+H.sup.+).
[0597] To 4-methoxy-N-(4-nitrophenyl)aniline (785 mg, 3.2 mmol) in
5 mL of AcOH was added Pd(OAc).sub.2 (1.43 g, 6.4 mmol). The
mixture was heated at 100.degree. C. for 15 h under air atmosphere
and cooled to rt and concentrated under reduced pressure. The
residue was taken up in EtOAc (100 mL) and washed with NaHCO.sub.3
(2.times.100 mL) and water (100 mL). After solvent removal, the
crude was purified with chromatography (hexane/EtOAc) to afford
3-methoxy-6-nitro-9H-carbazole as a orange solid (495 mg, 64%).
.sup.1H NMR (400 MHz, acetone-d6) .delta. 10.90 (s, 1H), 9.09 (d,
J=2.4 Hz, 1H), 8.27 (dd, J=9.2, 2.4 Hz, 1H), 7.96 (d, J=2.4 Hz,
1H), 7.62 (d, J=9.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.14 (dd,
J=8.8, 2.8 Hz, 1H), 392 (s, 3H); MS (ESI) m/z 243 (MAT).
[0598] To 3-methoxy-6-nitro-9H-carbazole (100 mg, 0.41 mmol) in 40
mL MeOH was added Palladium on activated carbon (50 mg). The
mixture was stirred at rt under H2 atmosphere for 5 h. Solid was
filtered off and the filtrate was concentrated to afford
6-methoxy-9H-carbazol-3amine as a brown solid (80 mg, 92%). This
material was used directly for the next reaction without
purification. MS (ESI) m/z 213 (M+H.sup.+).
[0599] To 6-methoxy-9H-carbazol-3-amine (16 mg, 0.075 mmol) and
1-bromo-2-fluoroethane (48 mg, 0.375 mmol) in 0.3 mL of NMP was
added Cs.sub.2CO.sub.3 (30 mg, 0.09 mmol). The mixture was stirred
at rt for 72 h under Ar atmosphere and diluted with EtOAc (30 mL).
It was washed with water (3.times.30 mL) and dried over MgSO.sub.4.
After solvent removal, the residue was purified by reversed-phase
HPLC (buffer A: 0.05% aqueous TFA; buffer B: 0.05% TFA in MeCN) to
afford a light-brown wax (5 mg, 26%). .sup.1H NMR (400 MHz,
acetone-d6) .delta. 7.75 (s, 1H), 7.67 (s, 1H), 7.52 (d, J=2.4 Hz,
1H), 7.35 (t, J=9.6 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.00 (dd,
J=8.8, 2.4 Hz, 1H), 4.81 (t, J=5.2 Hz, 1H), 4.69 (t, J=4.8 Hz, 1H),
3.89 (s, 3H); MS (ESI) m/z 259 (M+H.sup.+).
AD-C-004S-WZ01055
##STR00176##
[0601] To 7,8-dihydroxy-4-phenyl-2H-chromen-2-one (500 mg, 2 mmol)
and 3,4-dihydro-2H-pyran in 4 mL THF and 4 mL DCM was added
pyridinium paratoluene sulfonate (PPTS, 8 mg). The mixture was
stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc
(50 mL). It was washed with NaHCO.sub.3 (sat. 30 mL) and water (50
mL) and dried over MgSO.sub.4 and concentrated under reduced
pressure. The residue was chromatographed (hexane/EtOAc) to afford
8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one
as a yellow solid (180 mg, 26%). MS (ESI) m/z 339 (M+H.sup.+).
[0602] To
8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2--
one (40 mg, 0.12 mmol) and 1-bromo-2-fluoroethane (22 mg, 0.17
mmol) in 0.4 mL NMP was added Cs.sub.2CO.sub.3 (46 mg, 0.14 mmol).
The mixture was stirred at rt for 5 h under Ar atmosphere and
diluted with ether (40 mL). It was washed with water (3.times.30
mL) and dried over MgSO.sub.4 and concentrated. The crude product
was purified with chromatography (hexane/EtOAc) to afford
842-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-21.sup.-1-chro-
men-2-one as a white solid (34 mg, 73%). MS (ESI) m/z 385
(M+H.sup.+).
[0603] To
8-(2-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-c-
hromen-2-one was added 1.5 mL of a 4 M HCl dioxane solution. The
mixture was stirred at rt for 30 min under Ar atmosphere and
concentrated. The crude product was purified with chromatography
(hexane/EtOAc) to afford
8-(2-fluoroethoxy)-7-hydroxy-4-phenyl-2H-chromen-2-one
(AD-C-004S-WZ01055) as a white solid (24 mg, 90%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 7.57-7.54 (m, 3H), 7.52-7.49
(m, 2H), 7.08 (dd, J=8.8, 1.2 Hz, 1H), 6.87 (dd, J=8.8, 1.2 Hz,
1H), 6.11 (d, J=1.2 Hz, 1H), 4.86 (m, 1H), 4.74 (m, 1H), 4.50 (m,
1H), 4.43 (m, 1H); MS (ESI) m/z 301 (M+H.sup.+), 323
(M+H.sup.+).
AD-C-004P-WZ01051
##STR00177##
[0605] To
8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2--
one (115 mg, 0.34 mmol) and ethane-1,2-diyl
bis(4-methylbenzenesulfonate) (188 mg, 0.51 mmol) in 1 mL NMP was
added Cs.sub.2CO.sub.3 (133 mg, 0.41 mmol). The mixture was stirred
at rt for 15 h under Ar atmosphere and diluted with ether (50 mL).
It was washed with water (3.times.50 mL) and dried over MgSO.sub.4
and concentrated. The crude product was purified with
chromatography (hexane/EtOAc) to
2-(2-oxo-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-8-yloxy)ethy-
l 4-methylbenzenesulfonate as a white wax (97 mg, 53%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.83 (d, J=8.4 Hz, 1H), 7.53-7.50 (m,
3H), 7.43-7.41 (m, 2 h), 7.36 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.8 Hz,
1H), 7.06 (d, J=9.2 Hz, 1H), 6.22 (s, 1H), 5.56 (t, J=2.8 Hz, 1H),
4.41 (m, 4H), 3.86 (td, J=10.8, 2.8 Hz, 1H), 3.61 (m, 1H),
2.08-1.86 (m, 3H), 1.76-1.63 (m, 3H); MS (ESI) m/z 537
(M+H.sup.+).
AD-F-001S-WZ01067
##STR00178##
[0607] To 1-(2,4-dihydroxyphenyl)ethanone (1.52 g, 10 mmol) in 12
mL acetone was added K2CO3 (1.38 g, 10 mmol) followed by slow
addition of chloro(methoxy)methane (885 mg, 11 mmol) with stirring
under Ar atmosphere at rt. The reaction mixture was stirred at rt
for 4 h and filtered. Solid was washed with EtOAc (80 mL) and the
combined filtrate was washed with NaH.sub.2PO.sub.4 (sat. 50 mL)
and water (80 mL) and dried over MgSO.sub.4 and concentrated. The
crude product was purified with silica chromatography
(hexane/EtOAc) to afford
1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanoate as a off-white
solid (1.2 g, 61%). MS (ESI) m/z 197 (M+H.sup.+).
[0608] A mixture of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol),
benzyl bromide (1.71 g, 10 mmol), and K.sub.2CO.sub.3 (1.24 g, 9
mmol) in 20 mL acetone was stirred at rt for 15 h under Ar
atmosphere. Solid was filtered off and the filtrated was diluted
with EtOAc (100 mL) and washed with NaH.sub.2PO.sub.4 (sat. 100
mL), and dried over MgSO.sub.4 and concentrated. The residue was
chromatographed (hexane/EtOAc) to afford
4-(benzyloxy)-3-hydroxybenzaldehyde as a white solid (1.15 g, 50%).
.sup.1H NMR (400 MHz, CDCl3) .delta. 9.84 (s, 1H), 7.46 (d, J=2.0
Hz, 1H), 7.44-7.40 (m, 6H), 7.04 (d, J=8.0 Hz, 1H), 5.80 (s, 1H),
5.21 (s, 2H); MS (ESI) m/z 229 (M+H.sup.+).
[0609] A mixture of 4-(benzyloxy)-3-hydroxybenzaldehyde (912 mg, 4
mmol), chloro(methoxy)methane (480 mg, 6 mmol), and DIPEA (1.03 g,
8 mmol) in 20 mL DCM was stirred at rt under Ar atmosphere for 15
h. It was diluted with ether (100 mL) and washed with 0.5 M HCl
(2.times.50 mL) and water (2.times.80 mL), dried over MgSO.sub.4
and concentrated. The crude product was purified with silica
chromatography (hexane/EtOAc) to afford
4-(benzyloxy)-3-(methoxymethoxy)benzaldehyde as a clear oil (960
mg, 88%). MS (ESI) m/z 273 (M+H.sup.+).
[0610] To 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone (618 mg,
3.15 mmol) and 4-(benzyloxy)-3-(methoxymethoxy)benzaldehyde (816
mg, 3 mmol) in a 25-mL round-bottom flask under Ar atmosphere was
added 2.5 mL of a freshly made 5% KOH in EtOH solution. The mixture
was vigorously stirred at rt until it solidified and kept at rt for
6 days. It was taken up in ether (100 mL) and added 0.5 M HCl to
pH=5, and stirred for 3 min. The mixture was washed with water
(2.times.100 mL) and dried over MgSO4 and concentrated. The residue
was chromatographed (hexane/EtOAc) to afford
(E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(methoxymet-
hoxy)phenyl)prop-2-en-1-one as a clear oil (780 mg, 58%). MS (ESI)
m/z 451 (M+H.sup.+).
[0611] To
(E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(m-
ethoxymethoxy)phenyl)prop-2-en-1-one (450 mg, 1 mmol) in 1.5 mL
MeOH was added 4 mL of a 15% NaOH solution, followed by hydrogen
peroxide (113 mg, 30% solution). The mixture was stirred at rt for
2 h and additional 226 mg of hydrogen peroxide was added. The
reaction was stirred for 15 and quenched onto NaH.sub.2PO.sub.4
(sat. 50 mL). It was extracted with EtOAc (3.times.50 mL) and the
combined organic phase was dried over MgSO.sub.4 and concentrated.
The residue was chromatographed (hexane/EtOAc) to afford
2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymet-
hoxy)-4H-chromen-4-one as a off-white solid (55 mg, 12%). MS (ESI)
m/z 465 (M+H.sup.+).
[0612] To
2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxym-
ethoxy)-4H-chromen-4-one (55 mg, 0.12 mmol) in 2 mL of DCM was
added DIPEA (31 mg, 0.24 mmol), followed by slow addition of
chloro(methoxy)methane (15 mg, 0.18 mmol). The reaction mixture was
stirred at rt under Ar atmosphere for 3 h and diluted with ether
(30 mL). It was washed with water (3.times.30 mL) and dried over
MgSO.sub.4 and concentrated. The crude product was purified with
silica chromatography (hexane/EtOAc) to afford
2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-
-4H-chromen-4-one as a white solid (55 mg, 90%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.14 (d, J=8.8 hz, 1H), 7.91 (d, J=2.0 Hz,
1H), 7.71 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.46-7.44 (m, 2H), 7.39 (m,
2H), 7.34-7.31 (m, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8,
2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H),
5.24 (s, 2H), 5.21 (s, 2H), 3.55 (s, 3H), 3.51 (s, 3H), 3.18 (s,
3H); MS (ESI) m/z 509 (M+H.sup.+).
[0613] To
2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethox-
y)-4H-chromen-4-one (55 mg, 0.108 mmol) in 10 mL MeOH was added
Palladium on activated carbon (20 mg). The mixture was stirred at
rt under H.sub.2 atmosphere for 2 h. Solid was filtered off and the
filtrate was concentrated to afford
2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-
-4-one as a yellow solid (45 mg, 99%). This material was used
directly for the next reaction without purification. MS (ESI) m/z
419 (M+H.sup.+).
[0614] To
2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4-
H-chromen-4-one (20 mg, 0.048 mmol) and 1-bromo-2-fluoroethane (18
mg, 0.14 mmol) in 0.3 mL NMP was added Cs.sub.2CO.sub.3 (39 mg,
0.12 mmol). The mixture was stirred at rt for 15 h under Ar
atmosphere and diluted with ether (30 mL). It was washed with
NaH.sub.2PO.sub.4 (sat. 30 mL) and water (2.times.30 mL) and dried
over MgSO.sub.4 and concentrated. The crude product was purified
with chromatography (hexane/EtOAc) to afford
2-(4-(2-fluoroethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4-
H-chromen-4-one as a white solid (19 mg, 85%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.15 (d, J=8.8 Hz, 1H), 7.91 (d, J=2.0 Hz,
1H), 7.76 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.05
(dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.29 (s, 4H), 5.22
(s, 2H), 4.89 (m, 1H), 4.78 (m, 1H), 4.40 (m. 1H), 4.32 (m, 1H),
3.56 (s, 3H), 3.51 (s, 3H) 3.20 (s, 3H); MS (ESI) raiz 465
(M+H.sup.+).
[0615] To
2-(4-(2-fluoroethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxym-
ethoxy)-4H-chromen-4-one (19 mg, 0.041 mmol) was added 1 mL of 4 M
HCl solution in dioxane. The mixture was stirred at rt for 3 h.
Volatiles were removed under reduced pressure and the residue was
washed with ether (2.times.1 mL) and dried under high vacuum to
afford
2-(4-(2-fluoroethoxy)-3-hydroxyphenyl)-3,7-dihydroxy-4H-chromen-4-one
(AD-F-001S-WZ01067) as a yellow solid (11 mg, 81%). .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.73 (s, 1H), 9.39 (s, 1H), 9.17 (s,
1H), 7.89 (d, J=9.6 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.59 (dd,
J=8.4 Hz, 2.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.87 (m, 2H), 4.80
(m, 1H), 4.68 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H); MS (ESI) m/z 333
(M+H.sup.+), 355 (M+Na.sup.+).
AD-C-001P-WZ01079
##STR00179##
[0617] To
2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4-
H-chromen-4-one (19 mg, 0.045 mmol) and 2-bromoethanol (44 mg, 0.36
mmol) in 0.2 mL NMP was added Cs.sub.2CO.sub.3 (29 mg, 0.09 mmol).
The mixture was stirred at rt for 15 h under Ar atmosphere and
diluted with ether (30 mL). It was washed with NaH.sub.2PO.sub.4
(sat. 30 mL) and water (2.times.30 mL) and dried over MgSO.sub.4
and concentrated. The crude product was purified with
chromatography (hexane/EtOAc) to
2-(4-(2-hydroxyethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)--
4H-chromen-4-one (18 mg, 86%). MS (ESI) m/z 463 (M+H.sup.+).
[0618] To
2-(4-(2-hydroxyethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxy-
methoxy)-4H-chromen-4-one (18 mg, 0.039 mmol) and DIPEA (15 mg,
0.11 mmol) was added 4-methylbenzene-1-sulfonyl chloride (11 mg,
0.058 mmol). The mixture was stirred at rt for 15 h under Ar
atmosphere and diluted with ether (30 mL). It was washed with 0.5 M
HCl (2.times.30 mL) and water (50 mL), and dried over MgSO.sub.4
and concentrated. The crude product was chromatographed to afford
2-(4-(3,7-bis(methoxymethoxy)-4-oxo-4H-chromen-2-yl)-2-(methoxymethoxy)ph-
enoxy)ethyl 4-methylbenzenesulfonate (AD-C-001P-WZ01079) as a
yellow wax (20 mg, 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.15 (dd, J=8.8, 2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.76 (dd,
J=8.4 Hz, 2.0 Hz, 2H), 7.73 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=6.8
Hz, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.05 (dd,
J=8.8, 2.0 Hz, 1H), 6.94 (dd, J=8.8, 2.0 Hz, 1H), 5.29 (d, J=1.6
Hz, 2H), 5.22 (d, J=2.0 Hz, 4H), 4.42 (t, J=3.0 Hz, 2H), 4.32 (t,
J=3.0 Hz, 2H), 3.53 (d, J=2.4 Hz, 3H), 3.52 (d, J=2.0 Hz, 3H), 3.20
(d, J=2.4 Hz, 3H), 2.46 (s, 3H); MS (ESI) m/z 617 (M+H.sup.+).
Synthetic Scheme of CB 14-16, 19 and 20
##STR00180## ##STR00181##
[0619] 7((4-fluorobutyl)(methyl)amino)-9H-carbazol-2-ol (CB-14)
##STR00182##
[0621] To a round bottom flask containing Compound 6 (21 mg, 0.073
mmol) in DMF (1 ml), were added cesium carbonate (28.5 mg, 0.087
mmol) and 1-bromo-4-fluorobutane (56.4 mg, 0.364 mmol). The
reaction was stirred at rt for 30 min. The reaction was work-up
with EtOAc (15 mL.times.3) and water (10 mL). The organic layers
were washed with brine (10 mL), dried and concentrated in vacuo.
The residue was dissolved in MeOH (10 ml). To the reaction mixture,
was added Pd/C (22 mg). The mixture was stirred at rt overnight
under hydrogen (1 atm). The reaction was filtered through a celite
plug, concentrated in vacuo and purified on HPLC to afford CB-14
(11 mg, 0.029 mmol, 40.3% yield). .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta.: 8.74 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.53 (s,
1H), 7.25 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 6.73 (d, J=8.4 Hz, 1H),
4.44 (m, 1H), 4.32 (m, 1H), 3.70 (m, 2H), 3.35 (s, 3H), 1.74-1.67
(m, 4H); LRMS for C.sub.19H.sub.19F.sub.4N.sub.2O.sub.2+H.sup.+,
calc'd: 384.1, found: 287.2 (M+H.sup.+-TFA).
7((2-fluoroethyl)(methyl)amino)-9H-carbazol-2-ol (CB-15)
##STR00183##
[0623] To a round bottom flask containing Compound 6 (37 mg, 0.122
mmol) in DMF (0.5 ml), were added cesium carbonate (47.8 mg, 0.147
mmol) and 1-bromo-2-fluoroethane (78 mg, 0.612 mmol). The reaction
was stirred at rt for 30 min. The reaction was work-up with EtOAc
(15 mL.times.3) and water (10 mL). The organic layers were washed
with brine (10 mL), dried and concentrated in vacuo. The residue
was dissolved in MeOH (10 ml). To the reaction mixture, was added
Pd/C (22 mg). The mixture was stirred at rt overnight under
hydrogen (1 atm). The reaction was filtered through a celite plug,
concentrated in vacuo and purified on HPLC to afford CB-15 (5 mg,
0.019 mmol, 7.3% yield). .sup.1H-NMR (400 MHz, CD.sub.3CN) .delta.:
7.96 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.31 (d, J=2.0 Hz,
1H), 7.05 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.76
(dd, J=8.0 Hz, 2.0 Hz, 1H), 4.86 (m, 1H), 4.74 (m, 1H), 4.60-4.52
(m, 2H), 3.28 (br, 1H), 3.03 (s, 3H); LRMS for
C.sub.17H.sub.15F.sub.4N.sub.2O.sub.2+H.sup.+, calc'd: 356.1,
found: 259.2 (M+H.sup.+-TFA).
7-(2-fluoroethylamino)-9H-carbazol-2-ol (CB-16)
##STR00184##
[0625] To a round bottom flask containing Compound 5 (21 mg, 0.073
mmol) in DMF (1 ml), were added cesium carbonate (28.5 mg, 0.087
mmol) and 1-bromo-2-fluoroethane (46 mg, 0.36 mmol). The reaction
was stirred at rt for 72 hours. The reaction was work-up with EtOAc
(15 mL.times.3) and water (10 mL). The organic layers were washed
with brine (10 mL), dried and concentrated in vacuo. The residue
was dissolved in MeOH (10 ml). To the reaction mixture, was added
Pd/C (20 mg). The mixture was stirred at rt overnight under
hydrogen (1 atm). The reaction was filtered through a celite plug,
concentrated in vacuo and purified on HPLC to afford CB-16 (5 mg,
0.015 mmol, 20% yield). .sup.1H-NMR (400 MHz, CD.sub.3CN) .delta.:
9.00 (br, 1H), 7.77-7.73 (m, 2H), 6.82 (s, 1H), 6.81 (s, 1H),
6.72-6.65 (m, 2H), 4.71 (m, 1H), 4.60 (m, 1H), 3.60-3.50 (m, 2H);
LRMS for C.sub.16H.sub.13F.sub.4N.sub.2O.sub.2+H.sup.+, calc'd:
342.3, found: 245.1 (M+H.sup.+-TFA).
7-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)(methyl)amino)-9H-carbazol-2-ol
(CB-19)
##STR00185##
[0627] To a round bottom flask containing Compound 6 (41 mg, 0.14
mmol) in DMF (0.5 ml), were added cesium carbonate (53 mg, 0.16
mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl
4-methylbenzenesulfonate (125 mg, 0.407 mmol). The reaction was
stirred at rt for 4 weeks. The reaction was work-up with EtOAc (15
mL.times.3) and water (10 mL). The organic layers were washed with
brine (10 mL), dried and concentrated in vacuo. The residue was
dissolved in MeOH (10 ml). To the reaction mixture, was added Pd/C
(20 mg). The mixture was stirred at 11 overnight under hydrogen
atmosphere (1 atm). The reaction was filtered through a celite
plug, concentrated in vacuo and purified on HPLC to afford CB-19 (7
mg, 0.020 mmol, 14% yield. .sup.1H-NMR (400 MHz, CD.sub.3CN)
.delta.: 9.43 (br, 1H), 8.07 ((d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz,
1H), 7.58 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.93
(d, J=2.0 Hz, 1H), 6.77 (dd, J=8.0 Hz, 2.0 Hz, 1H), 4.59 (m, 1H),
4.52 (m, 1H), 3.74-3.50 (m, 10H), 3.28 (s, 3H); LRMS for
C.sub.21H.sub.23F.sub.4N.sub.2O.sub.4+Na.sup.+, calc'd: 444.2,
found: 347.2 (M+H.sup.+-TFA).
7-(2-fluoroethoxy)-N-methyl-9H-carbazol-2-amine (CB-20)
##STR00186##
[0629] To a round bottom flask containing Compound 6 (90 mg, 0.29
mmol) in MeOH (10 ml), were added Pd/C (20 mg). The reaction was
purged with hydrogen and stirred at rt for 2 h under hydrogen
atmosphere (1 atm). The reaction was filtered through a celite plug
concentrated in vacuo to afford a dark solid (60 mg, 0.28 mmol, 95%
yield). To a round bottom flask containing the above dark solid (15
mg, 0.071 mmol) in DMF (0.5 mL), was added cesium carbonate (21 mg,
0.65 mmol) and 2-bromo-1-fluoroethane (8.1 mg, 0.065 mmol). The
reaction was stirred at rt overnight. The reaction was concentrated
in vacuo via MeCN co-evaporation. The residue was purified on HPLC
to afford CB-20 (7.0 mg, 0.027 mmol, 38% yield). .sup.1H NMR (400
MHz, CD.sub.3CN) .delta.: 9.52 (br, 1H), 7.91-7.86 (m, 2H), 7.13
(s, 1H), 7.02 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.82 (dd, J=7.6 Hz,
J=2.4 Hz 1H), 4.85 (m, 1H), 4.72 (m, 1H), 4.34-4.25 (m, 2H), 2.96
(s, 3H); LRMS for C.sub.17H.sub.15N.sub.2O.sub.2+H.sup.+, calc'd:
356.1, found: 259.1 (M+H.sup.+-TFA).
Synthetic Scheme of CB 25, 26
##STR00187##
[0630] 4'-(benzyloxy)-2'-nitrobiphenyl-4-ol (Compound 7)
##STR00188##
[0632] A round bottom flask charged with Compound 2 (1.96 g, 7.44
mmol), 4-Hydroxyphenylboronic acid pinacol ester (1.56 g, 7.09
mmol), terakis(triphenylphosphine) palladium (0.410 g, 0.354 mmol),
were purged with Argon. To the mixture, was added DME (10 ml) and
potassium carbonate (1.96 g, 14.2 mmol) in Water (2 ml). The
mixture was heated for 60 hours. The reaction was diluted with HCl
(1N, 10 mL) and brine (40 mL), then extracted with EtOAc (50
mL.times.3). The combined organic layer were washed with Brine (50
mL), dried (MgSO4) and concentrated in vacuo. The residue was
purified on a silica gel column (EtOAc:Hexanes=1:4) to afford
Compound 7 as a yellow solid (2 g, 6.22 mmol, 88% yield).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.45-7.33 (m, 7H),
7.37-7.15 (m, 3H), 6.88-6.85 (m, 2H), 5.14 (s, 2H), 5.03 (s, 1H);
LRMS for C.sub.19H.sub.15NO.sub.4+H.sup.+, calc'd: 322.1, found:
322.1 (M+H.sup.+).
7-(benzyloxy)-9H-carbazol-2-ol (Compound 8)
##STR00189##
[0634] To a pressure resistant vial, was added Compound 7 (2.00 g,
6.22 mmol and Triethyl phosphite (6.53 ml, 37.3 mmol. The mixture
was heated to 160.degree. C. overnight. The reaction mixture was
concentrated in vacuo. The residue was suspended in chloroform (20
mL), solid precipitate formed and was filtered and washed with
ether (10 mL.times.2) to afford Compound 8 (900 mg, 3.11 mmol,
50.0% yield). .sup.1H-NMR (400 MHz, DMSO) .delta.: 10.81 (br, 1H),
9.25 (br, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H),
7.50-7.33 (m, 5H), 6.95 (s, 1H), 6-78-6.76 (m, 2H), 6.56 (dd,
J=8.4, 2.0 Hz 1H), 5.16 (s, 2H); LRMS for
C.sub.19H.sub.15NO.sub.2+H.sup.+, calcd: 290.1, found: 290.1
(M+H.sup.+).
7-(2-fluoroethoxy)-9H-carbazol-2-ol (CB-25)
##STR00190##
[0636] To a round bottom flask containing Compound 8 (50 mg, 0.17
mmol) in DMF (1 ml), was added cesium carbonate (62 mg, 0.19 mmol)
and 1-bromo-2-fluoroethane (33 mg, 0.26 mmol). The reaction was
stirred at rt for 15 h and then diluted with water (15 mL). White
precipitate (50 mg) was collected via filtration and dried in
vacuo. The solid was dissolved in MeOH (10 mL). To the reaction,
was added Pd/C (30 mg) and acetic acid (5 drops). The mixture was
stirred under hydrogen (1 atm) atmosphere for 20 h and then
filtered through a celite plug, concentrated in vacuo. The residue
was purified on HPLC to afford CB-25 (18 mg, 0.053 mmol, 31%
yield). .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.: 8.99 (br, 1H),
7.72 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.0 Hz,
1H), 6.76 (d, J=2.0 Hz, 1H), 6.67 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.58
(dd, J=8.0 Hz, 2.0 Hz, 1H), 4.75-4.74 (m, 1H), 4.63-4.61 (m, 1H),
4.23-4.13 (m, 2H); LRMS for
C.sub.16H.sub.12F.sub.4NO.sub.3+H.sup.+, calc'd: 343.1, found:
246.0 (M+H.sup.+-TFA).
7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ol (CB-26)
##STR00191##
[0638] To a round bottom flask containing Compound 8 (50 mg, 0.17
mmol) in DMF (1 ml), was added cesium carbonate (56 mg, 0.17 mmol)
and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (53
mg, 0.17 mmol). The reaction was stirred at rt for 15 h and then
diluted with water (15 mL). White precipitate (72 mg) was collected
via filtration and dried in vacuo. The solid was dissolved in MeOH
(10 mL). To the reaction, was added Pd/C (20 mg) and acetic acid (5
drops). The mixture was stirred under hydrogen (1 atm) atmosphere
for 20 h and then filtered through a celite plug and concentrated
in vacuo. The residue was purified on HPLC to afford CB-26 (20 mg,
0.046 mmol, 27% yield). .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.:
9.03 (br, 1H), 7.81-7.75 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 6.84 (d,
J=2.4 Hz, 1H), 6.76 (dd, J=7.6 Hz, 2.0 Hz, 1H), 6.67 (dd, J=7.6 Hz,
2.0 Hz, 1H), 4.59-4.57 (m, 1H), 4.47-4.45 (m, 1H), 4.17-4.15 (m,
2H), 3.83-3.63 (m, 8H); LRMS for C.sub.20H.sub.20NO.sub.5+H.sup.+,
calc'd: 431.1, found: 334.1 (M+H.sup.+-TFA).
Synthetic Scheme of CB 27
##STR00192##
[0639] tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate (Compound
9)
##STR00193##
[0641] To a round bottom flask containing Compound 4 (1.0 g, 2.6
mmol) in MeOH (150 mL), was added palladium on charcoal (400 mg).
The flask was purged with hydrogen gas and stirred under hydrogen
atmosphere overnight. The reaction mixture was filtered through a
celite plug and concentrated to afford Compound 9 as a grey solid
(700 mg, 2.34 mmol, 90% yield), .sup.1H NMR (400 MHz,
(CD.sub.3).sub.2CO) .delta.: 9.99 (br, 1H), 8.41 (br, 1H), 8.24 (s,
1H), 7.86 (s, 1H), 7.81-7.78 (m, 2H), 7.18 (dd, J=8.4 Hz, 2.0 Hz,
1H), 6.90 (d, J=2.0 Hz, 1H), 6.70 (dd, J=8.4 Hz, 2.0 Hz, 1H), 1.51
(s, 9H).
tert-butyl 7-(4-nitrophenoxy)-9H-carbazol-2-ylcarbamate (Compound
10)
##STR00194##
[0643] To a round bottom flask containing Compound 9 (80 mg, 0.268
mmol) in DMF (2 mL) was added potassium carbonate (74.1 mg, 0.536
mmol) and 4-fluoro-nitrobenzene (41.6 mg, 0.295 mmol). The reaction
mixture was heated for 20 min at 140.degree. C. After cooling down
to rt, the mixture was diluted with water (20 mL) and extracted
with EtOAc (20 mL.times.3). The organic layers were dried,
concentrated. The residue was purified on a silica gel column
(EtOAc:Hexanes=3:7) to afford Compound 10 as a yellow solid (50 mg,
0.12 mmol, 44% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
8.22 (d, J=9.2 Hz, 2H), 8.10 (br, 1H), 8.00-7.90 (m, 3H), 7.12 (s,
1H), 7.06-6.90 (m, 4H), 6.70 (br, 1H), 1.56 (s, 9H); LRMS for
C.sub.23H.sub.21N.sub.3O.sub.5+H.sup.+, calc'd: 420.2, found: 420.2
(M+H.sup.+).
tert-butyl 7-(4-nitrophenoxy)-9H-carbazol-2-ylcarbamate (CB-27)
##STR00195##
[0645] To a round bottom flask containing Compound 10 (35 mg, 0.083
mmol) in MeOH (5 mL), was added palladium on charcoal (10 mg). The
flask was purged with hydrogen gas and stirred under hydrogen
atmosphere overnight. The reaction mixture was filtered through a
silica gel plug and concentrated to afford the amine intermediate
(23 mg). To a vial containing 2-fluoropropanoic acid (10.87 mg,
0.118 mmol) in DCM (1 mL), was added EDC (22.64 mg, 0.118 mmol) and
DMAP (1 mg). The mixture was stirred at rt for 5 min. The above
amine intermediate was dissolved in DCM (1 ml) and added into the
reaction vial dropwise. The reaction mixture was stirred at rt from
3 hour. The reaction mixture was then washed with water (3 mL) and
concentrated. The residue was redissolved in HCl (4.0 M in dioxane,
5 mL) and stirred overnight. The mixture was concentrated and
purified on HPLC to afford CB-27 (12 mg, 0.026 mmol, 31% yield).
.sup.1H NMR (400 MHz, CD.sub.3CN) .delta.: 9.42 (br, 1H), 8.69 (br,
1H), 7.92 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.60 (m, 2H),
7.04-7.01 (m, 4H), 6.86 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),
5.11 (dt, J=49.2, 6.8 Hz, 1H), 1.58 (dd, J=24.8, 6.8 Hz, 3H); LRMS
for C.sub.23H.sub.18F.sub.4N.sub.3O.sub.3+H.sup.+, calc'd: 460.1,
found: 364.1 (M+HtTFA).
Experimental Section for the Preparation of Carbazole
Derivatives
##STR00196##
[0647] 4-(Benzyloxy)-N-(4-nitrophenyl)aniline 1: To a oven dried
flask was charged with Pd(OAc).sub.2 (81 mg, 0.36 mmol) and
(S)-(-)-BINAP (336 mg, 0.54 mmol), followed by toluene (10 mL). The
mixture was stirred under Ar at room temperature for 5 min. To this
mixture was added 4-nitroiodobenzene (3.0 g, 12 mmol),
4-benzyloxyaniline hydrochloride (3.39 g, 14.4 mmol),
Cs.sub.2CO.sub.3 (9.8 g, 30 mmol) and toluene (40 mL). The
resulting mixture was heated under Ar at 100.degree. C. for 16 hrs,
and then cooled to room temperature and poured into H.sub.2O (100
mL). The layers were separated. The aqueous layer was extracted
with EtOAc (3.times.20 mL). The combined organic layers were washed
with brine (2.times.20 mL), dried (MgSO.sub.4) and filtered. The
filtrate was concentrated. The residue was purified via column
chromatography (silica gel, 5-40% EtOAc/hexane) to give the desired
product as an orange solid (1.2 g, 31%). .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta.: 8.09 (d, J=9.2 Hz, 2H), 7.30-7.49 (m, 5H), 7.15
(d, J=9.2 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H),
6.10 (br s, 1H), 5.09 (s, 2H). MS: m/z=321 (M+H.sup.+).sup.+.
[0648] 3-(Benzyloxy)-9-nitro-9H-carbazole 2: A mixture of
4-(benzyloxy)-N-(4-nitrophenyl)aniline 1 (0.5 g, 1.56 mmol) and
Pd(OAc).sub.2 (0.8 g, 3.56 mmol) in acetic acid (20 mL) was
refluxed and monitored by TLC. After refluxing for 2 hrs, TLC
showed that no starting material was present. It was concentrated
in vacuo to remove acetic acid. The residue was diluted with EtOAc
(30 mL), washed with H.sub.2O (20 mL), sat. NaHCO.sub.3 solution
(2.times.20 mL), brine (20 mL), and then dried (MgSO.sub.4) and
filtered. The filtrate was concentrated in vacuo. The residue was
purified via column chromatography (silica gel, 5-40% EtOAc/hexane)
to give the desired product 2 as a dark yellow solid (100 mg, 20%).
.sup.1H NMR (acetone-d.sub.6, 400 MHz) .delta.: 10.92 (br s, 1H),
9.08 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.8, 2.4 Hz, 1H), 8.07 (d,
J=2.4 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 3H), 7.40
(t, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz,
1H), 5.26 (s, 2H). MS: m/z=319 (M+H.sup.+).sup.+.
[0649] 3-Amino-6-(benzyloxy)-9H-carbazole 3: To a suspension of
3-(benzyloxy)-9-nitro-9H-carbazole 2 (100 mg, 0.31 mmol) and
Cu(OAc).sub.2 (57 mg, 0.31 mmol) in EtOH (20 mL) was added
NaBH.sub.4 (240 mg, 6.3 mmol). The resulting mixture was stirred at
room temperature for 3 hrs, and then concentrated in vacuo. The
residue was dissolved in H.sub.2O (30 mL), extracted with EtOAc
(2.times.30 mL). The combined organic layers were dried
(MgSO.sub.4), filtered and concentrated in vacuo to give a solid
(90 mg). It was used directly in the next step without any further
purification. .sup.1H NMR (acetone-d.sub.6, 400 MHz) .delta.: 9.67
(br s, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.52 (d, J=6.8 Hz, 2H), 7.39
(t, J=6.8 Hz, 2H), 7.26-7.33 (m, 3H), 7.19 (d, J=8.8 Hz, 1H), 7.03
(dd, J=8.8, 2.4 Hz, 1H), 6.81 (dd, J=8.8, 2.4 Hz, 1H), 5.17 (s,
2H), 4.24 (br s, 2H). MS: m/z=289 (M+H.sup.+).sup.+.
[0650] 6-(Benzyloxy)-N-methyl-9H-carbazol-3-amine 4: To a
suspension of 3-amino-6-(benzyloxy)-9H-carbazole 3 (90 mg, 0.31
mmol) and paraformaldehyde (47 mg, 1.57 mmol) in MeOH (20 mL) was
added a solution of NaOMe in MeOH (0.32 mL, 1.56 mmol). The
resulting mixture was heated at 80.degree. C. for 1 h, then
NaBH.sub.4 (59 mg, 1.55 mmol) was added. The resulting mixture was
heated at 80.degree. C. for 2 hrs, and then cooled to room
temperature. To this solution was added NaOH (1 N, 30 mL). The
mixture was then extracted with CH.sub.2Cl.sub.2 (3.times.20 mL).
The combined organic layers were dried (MgSO.sub.4), filtered. The
filtrate was concentrated in vacuo to give a brown solid (93 mg,
100%). It was used directly in the next step without any further
purification. .sup.1H NMR (acetone-d.sub.6, 400 MHz) .delta.: 9.68
(br s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.53 (d, J=7.6 Hz, 2H),
7.20-7.42 (m, 6H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 6.79 (dd, J=8.4,
2.4 Hz, 1H), 5.17 (s, 2H), 2.85 (s, 3H). MS: m/z=303
(M+H.sup.+).sup.+,
[0651] 6-(Methylamino)-9H-carbazol-3-ol 5: A mixture of
6-(benzyloxy)-N-methyl-9H-carbazol-3-amine 4(93 mg, 0.31 primal),
Pd/C (10 mg) and acetic acid (10 drops) in MeOH (10 mL) was
hydrogenated at room temperature for 1.5 hrs. It was passed through
a short Celite pad. The filtrate was concentrated in vacuo to give
the desired product 5 (66 mg). It was used directly in the next
step without any further purification. MS: m/z=213
(M+H.sup.+).sup.+.
[0652] [3-(Benzyloxy)-6-(dimethylamino)-9H-carbazol-9-yl]methanol
7: To a solution of 6-(benzyloxy)-N-methyl-9H-carbazol-3-amine 4
(110 mg, 0.38 mmol) and aqueous formaldehyde solution (37%, 1.0 mL)
in acetonitrile (30 mL) was added NaB(OAc).sub.3 (323 mg, 1.52
mmol). The resulting mixture was stirred at room temperature for 6
hrs, and then concentrated. The residue was dissolved in H.sub.2O
(30 mL), extracted with CH.sub.2Cl.sub.2 (2.times.30 mL). The
combined organic layers were dried (MgSO.sub.4), filtered. The
filtrate was concentrated in vacuo to give the desired product
(0.12 g). It was used directly in the next step without any further
purification. MS: m/z=347 (M+H.sup.+).sup.+.
[0653] 6-(Dimethylamino)-9-(methoxymethyl)-9H-carbazol-3-ol 8: A
mixture of
[3-(benzyloxy)-6-(dimethylamino)-9H-carbazol-9-yl]methanol 7 (120
mg,), Pd/C (100 mg) and acetic acid (cat, amount) in MeOH (15 mL)
was hydrogenated at room temperature for 4 hrs. It was filtered
through a short Celite pad. The filtrate was concentrated in vacuo
to give the desired product (94 mg, 100%). .sup.1H NMR
(acetone-d.sub.6, 400 MHz) .delta.: 7.38-7.50 (m, 4H), 7.05 (dd,
J=8.8, 2.4 Hz, 1H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 5.62 (s, 2H),
3.20 (s, 3H), 2.94 (s, 6H). MS: m/z=271 (M+H.sup.+).sup.+.
##STR00197##
[0654] General procedures for the preparation of O-alkylated
carbazole derivatives: To a solution of carbazol-3-ol derivatives
(1 eq.) and Cs.sub.2CO.sub.3 (1.5 eq.) in DMF (10 mL) was added a
solution of
2-(2-(2-fluoroethoxy)ethoxy)ethyl-4-methylbenzenesulfonate (1.2
eq.) in DMF (1.0 mL). The resulting mixture was stirred at room
temperature overnight, and then concentrated in vacuo. The residue
was purified via column chromatography (silica gel, 5-50%
EtOAc/hexane) to provide the desired products.
[0655]
6-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-3-amine
6: (3 mg, 5%). .sup.1H NMR (acetone-d.sub.6, 400 MHz) .delta.: 7.59
(d, J=2.4 Hz, 1H), 7.28-7.33 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 6.97
(dd, J=8.8, 2.4 Hz, 1H), 6.85 (dd, J=8.8, 2.0 Hz, 1H), 4.51 (dt,
J=48, 4.0 Hz, 2H), 4.19 (t, J=4.4 Hz, 2H), 3.61-3.88 (m, 8H), 3.87
(s, 3H). MS: m/z=347 (M+H.sup.+).sup.+.
[0656]
6-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-9-(methoxymethyl)-N,N-dimeth-
yl-9H-carbazol-3-amine 9: (50 mg, 36%). .sup.1H NMR
(acetone-d.sub.6, 400 MHz) .delta.: 7.68 (d, J=2.4 Hz, 1H),
7.46-7.52 (m, 3H), 7.04-7.08 (m, 2H), 5.66 (s, 2H), 4.52 (dt,
J=48.4, 4.4 Hz, 2H), 4.21 (t, J=4.8 Hz, 2H), 3.63-3.87 (m, 8H). MS:
ink=405 (M+H.sup.+).sup.+.
##STR00198##
[0657] General procedures for the preparation of acylated carbazole
derivatives: To a solution of
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazole (1.0 eq.) in
DMF (3.0 mL) was added NaH (excess). After stirring at room
temperature for 5 min, an acyl halide (excess) was added. The
resulting mixture was stirred at room temperature overnight, and
then concentrated in vacuo. The residue was purified via column
chromatography (silica gel, 0-40% EtOAc/hexane) to give the desired
product.
##STR00199##
[0658]
1-(2-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-9-yl)ethanone-
: (4 mg, 36%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 8.21 (d,
J=8.0 Hz, 1H), 7.99-8.25 (m, 2H), 7.94 (d, J=2.4 Hz, 1H), 7.36-7.46
(m, 2H), 7.06 (dd, J=8.4, 2.4 Hz, 1H), 4.52 (dt, J=48, 4.4 Hz, 2H),
4.27 (t, 4.4 Hz, 2H), 3.89 (t, 5=8.8 Hz, 2H), 3.64-3.78 (m, 6H),
2.91 (s, 3H). MS: m/z=360 (M+H.sup.+).sup.+.
##STR00200##
[0659]
1-(2-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-9-yl)phenylme-
thanone: (51 mg, 78%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.:
7.84-7.92 (m, 2H), 7.62-7.74 (m, 3H), 7.53 (t, J=8.0 Hz, 2H),
7.27-7.33 (m, 2H), 7.17-7.23 (m, 1H), 6.99 (dd, J=8.4, 2.4 Hz, 1H),
4.57 (dt, J=47.6, 4.4 Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 3.70-3.87
(m, 8H). MS: iii/z=422 (M+H.sup.4).sup.+.
Preparation of 2-(7-formamido-9H-carbazol-2-yloxy)ethyl
4-methylbenzenesulfonate: AD-CB-012P-WZ02039
##STR00201##
[0661] Compound 2-(7-formamido-9H-carbazol-2-yloxy)ethyl
4-methylbenzenesulfonate (AD-CB-012P-WZ02039) was prepared using
the same procedure for the preparation of AD-CB-012S-WZ01185) from
N-(7-hydroxy-9H-carbazol-2-yl)formamide (100 mg) and
ethane-1,2-diyl bis(4-methylbenzenesulfonate) (325 mg). (white
solid, 22 mg, 12%). For the major rotomer: .sup.1H NMR (400 MHz,
acetone-d6) .delta. 10.19 (s, 1H), 9.31 (s, 1H), 8.38 (d, J=1.6 Hz,
1H), 8.11 (d, J=2.0 Hz, 1H), 7.90-7.81 (m, 4H), 7.45 (d, J=8.4 Hz,
2H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.69
(dd, J=8.4, 2.0 Hz, 1H), 4.43-4.41 (m, 2H), 4.29-4.27 (m, 2H); MS
(ESI) ink 425 (M+H.sup.+).
Preparation of N-(7-(4-fluorobutoxy)-9H-carbazol-2-yl)formamide:
AD-CB-30S-WZ02055
##STR00202##
[0663] Compound N-(7-(4-fluorobutoxy)-9H-carbazol-2-yl)formamide
(AD-CB-30S-WZ02055) was prepared using the same procedure for the
preparation of AD-CB-012S-WZ01185) from
N-(7-hydroxy-9H-carbazol-2-yl)formamide (20 mg) and
1-bromo-4-fluorobutane (27 mg). (white solid, 11 mg, 42%). .sup.1H
NMR (400 MHz, acetone-d6) .delta. 10.18 (s, 1H), 9.31 (s, 1H), 8.39
(d, J=2.0 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.95 (d, J=1.6 Hz, 2H),
7.88 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d,
J=2.4 Hz, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 4.61 (m, 1H), 4.49 (m,
1H), 4.11 (m, 2H), 1.97-1.88 (m, 4H); MS (ESI) m/z 301
(M+H.sup.+).
Preparation of
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-pyrido[2,3-b]indol-7-amine
hydrochloride
##STR00203##
[0664] Preparation of WZ02045
[0665] To 4-chloro-3-nitroaniline (2.5 g, 14.5 mmol) in 40 mL DCM
was added TEA (2.9 g, 29 mmol), DMAP (177 mg, 1.45 mmol), and
di-tert-butyl dicarbonate (4.7 g, 21.7 mmol). The mixture was
stirred at rt for 24 h and concentrated. The residue was diluted
with Et2O (100 mL), washed with brine (100 mL), water (100 mL), 0.5
M HCl (2.times.100 mL), and brine (100 mL), dried over MgSO.sub.4
and concentrated. The crude product was purified by silica
chromatography (EtOAc/hexane) to afford tert-butyl
4-chloro-3-nitrophenylcarbamate (WZ02045) as a yellow solid (1.5 g,
38%). MS (ESI) m/z 295 (M+Na.sup.+).
Preparation of WZ02049
[0666] A mixture of tert-butyl 4-chloro-3-nitrophenylcarbamate (818
mg, 3 mmol),
2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-
ine (933 mg, 3 mmol), tetrakis(triphenylphosphine)palladium (104
mg, 0.09 mmol), 10 mL of dioxane, and 6 mL of 1 M Na.sub.2CO.sub.3
was heated at reflux for 15 h. It was diluted with 50 mL Et.sub.2O
and washed with brine (2.times.50 mL) and dried over MgSO.sub.4 and
concentrated. The crude product was purified by silica
chromatography (EtOAc/hexane) to afford tert-butyl
4-(6-(benzyloxy)pyridin-3-yl)-3-nitrophenylcarbamate (WZ02049) as a
yellow wax (1.2 g, 95%). MS (ESI) ink 444 (M+Na.sup.+).
Preparation of WZ02057
[0667] A suspension of above compound (800 mg, 1.9 mmol) in 2 mL of
triethyl phosphite was heated at 148.degree. C. for 15 h. After
cooling, it was concentrated under reduced pressure to remove
volatiles. The crude product was purified by silica chromatography
(EtOAc/hexane) to afford tert-butyl
2-(benzyloxy)-9H-pyrido[2,3-b]indol-7-ylcarbamate (WZ02057) as a
off-white solid (400 mg, 54%). MS (ESI) m/z 390 (M+W).
Preparation of WZ02061
[0668] To above compound (220 mg, 0.56 mmol) dissolved in 80 mL
MeOH was added Palladium on activated carbon (80 mg). The mixture
was stirred at rt under H.sub.2 atmosphere for 15 h. Solid was
filtered off and the filtrate was concentrated to afford tert-butyl
2-hydroxy-9H-pyrido[2,3-b]indol-7-ylcarbamate (WZ02061) as a white
solid (105 mg, 100%). This material was used directly for the next
reaction without purification. MS (ESI) m/z 300 (M+H.sup.+).
Preparation of WZ02063
[0669] To above compound (50 mg, 0.167 mmol) in 1 nL of NMP was
added 24242-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (76
mg, 0.25 mmol), and Cs.sub.2CO.sub.3 (65 mg, 0.2 mmol). The mixture
was stirred at rt for 15 h and diluted with Et2O (40 mL), washed
with water (3.times.30 mL), and dried over MgSO.sub.4 and
concentrated. The crude product was purified by silica
chromatography (EtOAc/hexane) to afford tert-butyl
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-pyrido[2,3-b]indol-7-ylcarbamat-
e (WZ02063) as a clear wax (45 mg, 62%). MS (ESI) m/z 434
(M+H.sup.+).
Preparation of AD-CB-032S-WZ02067
[0670] The above compound (45 mg, 0.1 mmol) was treated with 2 mL
of a 4 M HCl in dioxane solution at rt for 5 h and concentrated
under reduced pressure. The residue was washed with ether (5 mL)
and dried under high vacuum to afford
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-pyrido[2,3-b]indol-7-amine
hydrochloride (AD-CB-032S-WZ02067) as a light-yellow solid (23 mg,
62%). .sup.1H NMR (400 MHz, methanol-d4) .delta. 8.42 (d, J=8.4 Hz,
1H), 8.12 (d, J=8.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.21 (dd,
J=8.4, 2.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.58-4.54 (m 3H), 4.43
(m, 1H), 3.91 (m, 2H), 3.76-3.72 (m, 3H), 3.70-3.66 (m, 3H); MS
(ESI) m/z 334 (M+H.sup.+).
Preparation of
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-pyrido[2,3-b]indol-7-A-
D-CB-034S-WZ02069
[0671] Compound AD-CB-034S-WZ02069 was prepared using the same
procedure for the preparation of AD-CB-004S from
2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-pyrido[2,3-b]indol-7-amine
hydrochloride (AD-CB-032S-WZ02067, 20 mg) (10 mg, 53%). .sup.1H NMR
(400 MHz, methanol-d4) .delta. 8.06 (d, J=8.0 Hz, 1H), 7.66 (d,
J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.58 (dd, J=8.4, 2.0 Hz,
1H), 6.53 (d, J=8.0 Hz, 1H), 4.58 (m 1H), 4.53-4.45 (m, 3H), 3.88
(m, 2H), 3.76 (m, 1H), 3.73-3.67 (m, 5H), 3.03 (s, 3H); MS (ESI)
m/z 348 (M+H.sup.+).
Preparation of 6-bromo-9H-carbazol-2-ol: W138
##STR00204##
[0672] Preparation of WZ02013
[0673] To 9H-carbazol-2-ol (915 mg, 5 mmol) in 10 mL DMF and 20 mL
DCM was added TEA (1.0 g, 10 mmol), followed by acetyl chloride
(589 mg, 7.5 mmol) at 0.degree. C. The reaction mixture was then
stirred at rt for 1 h and poured onto ice (50 g). The mixture was
extracted with EtOAc (2.times.60 mL) and combined organic phase was
dried over MgSO.sub.4 and concentrated. The crude product was
purified by silica chromatography to afford 9H-carbazol-2-yl
acetate (WZ02013) as an off-white solid (800 mg, 71%). MS (ESI) m/z
348 (M+H.sup.+).
Preparation of WZ02025
[0674] To a solution of 9H-carbazol-2-yl acetate (500 mg, 2.2 mmol)
in DCM (40 mL) was added a solution of NBS in 25 mL of DCM dropwise
at rt. The reaction mixture was stirred in the dark for 5 h. It was
washed with water (3.times.50 mL) and dried over MgSO.sub.4 and
concentrated. The crude product was purified by silica
chromatography (EtOAc/hexane) to afford 6-bromo-9H-carbazol-2-yl
acetate (WZ02025) as an off-white solid (250 mg, containing 17%
dibrominated product). MS (ESI) m/z 305 (M+H.sup.+).
Preparation of W138
[0675] A suspension of 6-bromo-9H-carbazol-2-yl acetate (200 mg,
0.65 mmol) in 30 mL MeOH and 4 mL of 1.0 M aqueous LiOH was stirred
for 5 h. It was neutralized with 1 M HCl and concentrated. The
crude product was purified by silica chromatography (EtOAc/hexane)
to afford 6-bromo-9H-carbazol-2-ol (W138) as an off-white solid
(125 mg, containing 15% dibrominated product). .sup.1H NMR (400
MHz, acetone-d6) .delta. 8.58 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 1H),
7.92 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.4, 2.0 Hz, 1H), 7.35 (s, 1H),
7.13 (d, J=8.4 Hz, 1H), 6.92 (d, 5-2.0 Hz, 1H), 6.76 (dd, J=8.8,
2.0 Hz, 1H); MS (ESI) m/z 263 (M+H.sup.+).
Ex Vivo Competition Assay Using Amyloid (AD patient's brain slice)
Autoradiography Staining
[0676] The carbazole series of AD imaging agents display
surprisingly good qualities when compared to previously established
results performed by others. Data from prior art suggests that
compounds with higher Log P values have higher amyloid affinities,
yet these same compounds can also suffer from high non-specific
binding, i.e poor brain washout (J. Molecular Neuroscience 2003,
20, 255-260). For the disclosed studies in this application, c Log
P values were used in place of Log P values.
[0677] A study was conducted to examine the grey to white matter
binding ratios for 4 different tracers: CB-001, CB-003, FDDNP and
F-PiB (FIG. 7 and FIG. 8). A known carbazole containing imaging
agent, 18F-fluorocarazolol, was not examined in this study because
of its relatively low c Log P value (2.77) compared to FDDNP and
PiB, and its competing specific uptake into the beta-adrenoceptors.
In addition, there is no prior art data suggesting that
18F-fluorocarazolol binds to AD plaques. After the human brain
slices from AD patients were incubated with a given tracer for 30
min, the slices were washed with various EtOH:water solutions in an
attempt to optimize the grey-to white matter ratios (FIG. 9). The
results were surprising and unexpected in view of previous work
performed by other researchers. CB-001 has a slightly higher c Log
P than FDDNP (3.8 vs 3.4) and would be expected to have poorer
washout than FDDNP based on these values. However, despite the
difference in c Log P values, CB-001 has a lower non-specific
binding propensity and displays a much better grey to white matter
ratio compared to FDDNP (see section above, "original wash"). More
specifically, the white matter binding of FDDNP is several shades
darker than CB-001's white matter binding, indicating low
non-specific binding of CB-001. In contrast, F-PiB, which has a c
Log P value of 3.99, also displays reasonable, binding ratios
similar to CB-001, albeit displaying a very weak overall signal.
The washing data suggests that the carbazoles are a viable and
novel target for imaging AD-related targets due to their unique
binding and washout properties.
[0678] To expand on these results, CB-003, a tracer with a c Log P
value similar to FDDNP, was prepared and tested. Using washing
conditions that were far milder than the harsh washing conditions
(FIG. 9), CB-003 displayed excellent grey to white matter binding
ratios that are far superior to the results taken from FDDNP, PiB
and CB-001. These favorable and unique results suggest that CB-003
would have a more favorable brain washout in living systems,
leading to more specific uptake and lowered non-specific binding,
leading to a clear advantage over FDDNP and PiB imaging.
Summary of Washing Results:
TABLE-US-00006 [0679] Grey/white matter Grey/white binding ratio
matter binding using harsh ratio using mild FDDNP wash wash Name
Structure cLogP conditions* conditions** CB-001 ##STR00205## 3.789
Excellent Poor CB-003 ##STR00206## 3.4032 N/A Excellent FDDNP
##STR00207## 3.422 Fair Poor PiB ##STR00208## 3.9907 Poor (signal
is washed away) Poor *published FDDNP wash conditions: 30 min
incubation of CB-1 or CB-3 tracer, PBS wash (5 min), 70% EtOH:water
(1 min), 90% EtOH:water (1 min), 70% EtOH:water (1 min), PBS (5
min). The brain slices were 20 um thick. **mild was conditions: 30
min incubation of CB-1 or CB-3 tracer, PBS wash (5 min), 30%
EtOH:water (2 min), 40% EtOH:water (2 min), 20% EtOH:water (2 min),
PBS (5 min). The brain slices were 20 um thick.
[0680] The results demonstrate that 1) PiB blocks [18F]-CB001
staining with increasing concentrations, suggesting the two
compounds to compete for the same amyloid binding pockets; 2) PiB
appears to block tracer binding with the same strength as cold
CB001, suggesting both to have similar binding affinities; 3) FDDNP
is much less capable of blocking [18F]-CB001 staining, due to its
lower amyloid binding affinity.
[0681] This data suggests the following order of (non-specific)
white matter binding:
FDDNP>CB001>[18F]-PiB>CB003
[0682] IC50 Determination with [18F]-PiB by Ex Vivo Competition
Assay Using Autoradiography Staining
TABLE-US-00007 Compound IC50 Average Code 1 2 3 4 5 6 7 8 9 10 11
12 13 IC50 SD SD % F-PiB 43 43 40 50 55 41 45 6 13 PiB 80 40 40 48
60 43 50 280 52 14 28 CB7 260 170 200 290 300 244 57 23 CB4 260 350
300 300 400 322 54 17 CB12 610 300 450 390 438 130 30 CB24 540 540
CB1 1000 480 740 368 50 CB10 900 900 CB3 1100 900 920 973 110
11
[0683] To further demonstrate the efficiency of employing these
CB-related tracers as AD imaging agents, CB-003 was used to clearly
differentiate between a healthy brain and an AD brain (FIG. 10).
More specifically, by using the mild wash protocol, the amyloid
deposits were clearly visible in the grey matter with little white
matter uptake. The results were corroborated by both antibody IHC
and thioflaving T amyloid staining, confirming the specificity of
uptake. These surprising results demonstrate that this tracer
possess the unique quality of rapid washout from white matter and
significant high uptake in grey matter that is specific for AD
plaques.
[0684] The carbazoles compete directly against 18F-PiB for the same
binding sites in human AD brains (FIG. 11). This surprising result
could not have been predicted given their dissimilar structures and
CB-003's lack of a phenolic OH and terminal NH-Me group, which are
deemed essential for binding to AD plaques. Despite CB-003 lacking
both of these functional groups, it still competes with 18F-PiB for
binding sites in human AD brains. Because of the simplicity of its
structure, the labeling yields of CB-001 and CB-003 are
exceptionally high and better than the labeling yields of
18F-PiB.
Surface Plasmon Resonance (SPR) Assay
[0685] An assay was developed using a Biacore instrument that
introduced the ligands over gold-surface immobilized target
proteins and measured the resultant rates of association and
disassociation in order to test various compounds that bind to
soluble AD oligomers, polymers and fibrils (FIGS. 12 to 17).
[0686] The carbazole series also demonstrated a unique and
surprising ability to bind favorably and preferentially to
insoluble aggregates (9 nM) over soluble aggregates (262 nM) (FIG.
12 and FIG. 13). PiB also binds well to insoluble aggregates (16
nM) but also binds essentially equally as well to soluble
aggregates (48 nM) (FIG. 14 and FIG. 15). For imaging applications
where it is favorable to distinguish between a tracer's binding to
insoluble versus soluble aggregates, CB-003 provides a larger
binding ratio of 29:1, whereas PiB only provides a ratio 3:1. Thus,
CB-003 may provide more selective binding information relative to
PiB. The results indicate that 1) for soluble aggregate binding,
PIB>CB3>CB4; and 2) for insoluble aggregate binding,
PIB=CB3/CB4.
[0687] The results demonstrate that 1) WT and App mice show
statistically significant differences in tracer retention in the
brain (FIG. 18A, FIG. 18B and FIG. 19); 2) App mice show up to 25%
larger brain/muscle ratios compared to WT mice (FIG. 20 and FIG.
21). The carbazoles display both a surprising high uptake in mice
brains (both WT and APP) and sufficiently slow washout such that
one can distinguish WT from APP mice (FIG. 22 and FIG. 23). Without
being bound by any theory proposed herein, we speculate that the
reason behind these results may be that CB-003 possesses a faster
washout rate than 18F-PiB, which is consistent with consistent with
the staining data: 18F-PiB requires harsher wash conditions in
order to give reasonable grey to white matter ratios. The rapid
washout of CB-003 is presumably a major factor for its low
non-specific binding, yet the washout is slow enough to distinguish
WT from APP. This suggests that the carbazoles display a unique
combination of excellent washout and retention properties in human
AD brains that are not obvious from prior art data. CB-003, being a
neutral compound, would also potentially possess greater uptake
values versus zwitterionic-based imaging agents such as methylene
blue.
* * * * *