Novel Imaging Agents for Detecting Neurological Dysfunction
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
1 . A radiolabeled compound of the Formula I to Formula VI:
wherein:
For Formula I:
A is N or CR 1 ; B is N or CR 2 ; J is N or CR 3 ; K is N or CR 4 ; L is N or CR 5 ; M is N or CR 6 ; P is N or CR 7 ; and Q is N or CR 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogens;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
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, β-carboline-3-carboxylate, β-carboline-3-thiocarboxylate, β-carboline-3-carboxamide, β-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-β-carboline, 7-(2-fluoropropoxy)-1-methyl-9H-β-carboline, 7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline, 7-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}-1-methyl-9H-β-carboline and carbazolyl-(4)-oxypropanolamine and their derivatives;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof;
For Formula II:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogens;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 , halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
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 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent;
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O —; or at least one of R 5 and R 6 , R 6 and R 7 or R 7 and R 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 5 , R 6 , R 7 and R 8 is a hydrogen;
each R 10 is independently 1-1 or C 1-6 alkyl;
R 11 and R 12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof;
For Formula IV:
W is O or —N—X—R 9 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; or Y is
and R 12 is absent;
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 5 and R 6 , R 6 and R 7 or R 7 and R 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 1 , R 2 , R 3 and R 4 is a hydrogen;
R 5 , R 6 , R 7 , R 8 and R o are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
R 11 and R 12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof;
For Formula V:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 2-6 alkyl, perhaloC 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or R 5 and R 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 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy;
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or R 5 and R 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 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
R 11 is a hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
provided that at least one of R 1 to R 12 comprises a radiolabel, as defined herein;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
2 . The radiolabeled compound of claim 1 , wherein:
For Formula I:
A is N or CR 1 ; B is N or CR 2 ; J is N or CR 3 ; K is N or CR 4 ; L is N or CR 5 ; M is N or CR 6 ; P is N; and Q is N or CR 8 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O— and —C(S)O—; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O— and —C(S)O—; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-6 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent;
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 2-5 alkoxy, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O —; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 9 ;
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 or R 3 and R 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; and
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy;
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 ; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
R 11 is absent, a hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
3 . The compound of claim 2 , wherein:
For Formula I:
A is N or CR 1 ; B is N or CR 2 ; J is N or CR 3 ; K is N or CR 4 ; L is N or CR 5 ; M is N or CR 6 ; P is N or CR 7 ; and Q is N or CR 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and—N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
For Formula II:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 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 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroaryl C 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
For Formula IV:
W is O or —N—X—R 9 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
For Formula V:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 is absent; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
4 . The compound of claim 1 , wherein:
For Formula I:
A is N or CR 1 ; B is N or CR 2 ; J is N or CR 3 ; K is N or CR 4 ; L is N or CR 5 ; M is N or CR 6 ; P is N or CR 7 ; and Q is N or CR 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —X(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(O)—;
For Formula II:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of halo-C 2-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(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 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, FCH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, haloC 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(O)—;
For Formula IV:
W is O or —N—X—R 9 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 2-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(O)—;
For Formula V:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(O)—;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 is absent; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and halo-C 1-5 alkylNR 10 C(O)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
5 . The compound of claim 1 , wherein:
For Formula I:
A is N or CR 1 ; B is N or CR 2 ; J is N or CR 3 ; K is N or CR 4 ; L is N or CR 5 ; M is N or CR 6 ; P is N or CR 7 ; and Q is N or CR 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 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula II:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(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 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 2-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula IV:
W is O or —N—X—R 9 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 2-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula V:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 2-6 alkyl, perhaloC 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 is absent; and
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
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 1-6 alkylenyl, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogens;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo(CH 2 CH 2 ) 1-6 —; haloCH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, haloCH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and haloCH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
each R 10 is independently H or C 1-6 alkyl;
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 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, haloC 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , or R 7 and R 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 5 , R 6 , R 7 and R 8 are hydrogens;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
each R 10 is independently H or C 1-6 alkyl;
For Formula IV:
W is O or —N—X—R 9 ;
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 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 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 and R 12 are absent; and
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 aryl C 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, haloC 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 1-6 alkylOC(O)CH(C 1-5 alkyl)-, haloC 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or at least one of R 1 and R 2 , R 2 and R 3 or R 3 and R 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 1 , R 2 , R 3 and R 4 are hydrogens;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
each R 10 is independently H or C 1-6 alkyl;
For Formula V:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —; and
R 5 and R 6 are each independently each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
—R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
each R 10 is independently H or C 1-6 alkyl;
For Formula VI:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 2-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy and heteroaryloxy when R 11 is absent; and
R 5 and R 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 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
—R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—; and
each R 10 is independently H or C 1-6 alkyl;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
7 . The compound of claim 6 , wherein:
For Formula I and Formula II:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(0 CH 2 CH 2 ) 1-6 O—;
For Formula III:
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—;
For Formula IV:
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—.
For Formula V and Formula VI:
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O— and C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—.
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
8 . The compound of claim 1 , wherein the halo-moiety of the group selected from halo-C 1-6 alkyl, halo-C 2-5 alkoxy, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-CH 2 CH 2 —(OCH 2 CH 2 ) t-6 O—, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)—, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—, halo-C 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 2-6 alkylOC(O)CH(C 1-5 alkyl)- and haloC 1-5 alkylNR 10 C(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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of halo-C 2-5 alkoxy, haloC 1-6 alkyl, perhaloC 1-6 alkyl, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, haloC 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 2-6 alkylOC(O)CH(C 1-5 alkyl)- and haloC 2-5 alkylNR 10 C(O)—;
For Formula III:
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, haloC 1-6 alkyl, perhaloC 1-6 alkyl, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, haloC 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 2-6 alkylOC(O)CH(C 1-5 alkyl)- and haloC 2-5 alkylNR 10 C(O)—;
For Formula IV:
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, haloC 1-6 alkyl, perhaloC 1-6 alkyl, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, haloC 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 2-6 alkylOC(O)CH(C 1-5 alkyl)- and haloC 2-5 alkylNR 10 C(O)—;
For Formula V and Formula VI:
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of halo-C 1-5 alkoxy, haloC 1-6 alkyl, perhaloC 1-6 alkyl, halo-C 2-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, haloC 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, haloC 2-6 alkylOC(O)CH(C 1-5 alkyl)- and haloC 2-5 alkylNR 10 C(O)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
10 . The compound of claim 6 , wherein:
For Formula I and Formula II:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula III:
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula IV:
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
For Formula V and Formula VI:
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, heteroarylC 2-5 alkoxy, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 -arylC(O)O—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
11 . The compound of claim 6 , wherein:
For Formula I and Formula II:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or selected from the group consisting of F—C 1-6 alkyl, F—C 1-5 alkoxy, F—C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, 4-(F—C 1-6 alkyl)-1H-1,2,3-triazol-1-yl-(C 2-5 alkoxy), F—C 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, F—C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and F—C 1-5 alkylNR 10 C(O)—;
For Formula III:
R 5 , R 6 , R 7 and R 8 are each independently hydrogen or selected from the group consisting of F—C 1-6 alkyl, F—C 1-5 alkoxy, F—C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, 4-(F—C 1-6 alkyl)-1H-1,2,3-triazol-1-yl-(C 2-5 alkoxy), F—C 2-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, F—C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and F—C 1-5 alkylNR 10 C(O)—;
For Formula IV:
R 1 , R 2 , R 3 and R 4 are each independently hydrogen or selected from the group consisting of F—C 1-6 alkyl, F—C 1-5 alkoxy, F—C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, 4-(F—C 1-6 alkyl)-1H-1,2,3-triazol-1-yl-(C 2-5 alkoxy), F—C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, F—C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and F—C 1-5 alkylNR 10 C(O)—;
For Formula V and Formula VI:
R 5 and R 6 are each independently hydrogen or selected from the group consisting of F—C 1-6 alkyl, F—C 1-5 alkoxy, F—C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, F—CH 2 CH 2 O—, F—CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, 4-(F—C 1-6 alkyl)-1H-1,2,3-triazol-1-yl-(C 2-5 alkoxy), F—C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, F—C 1-6 alkylOC(O)CH(C 1-5 alkyl)- and F—C 1-5 alkylNR 10 C(O)—;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
12 . The compound of claim 6 , wherein:
For Formula I and Formula II:
at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogens;
For Formula III:
at least two of R 5 , R 6 , R 7 and R 8 are hydrogens;
For Formula IV:
at least two of R 1 , R 2 , R 3 and R 4 are hydrogens;
For Formula V and Formula VI:
at least one of R 5 or R 6 is a hydrogen;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
13 . The compound of claim 1 , wherein the amino group is selected from the group consisting of NH 2 —, CH 3 NH—, (CH 3 ) 2 N—, C 1-3 -alkylNH—, F—C 2-3 -alkylNH—, F—(C 2-3 -alkylO) 1-4 -alkyl-NH—, (C 1-3 -alkyl) 2 N—, C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 3-6 cycloalkylNH—, (C 3-6 cycloalkyl) 2 N—, C 3-12 cycloalkylC 1-5 alkylNH—, C 6-14 arylNH—, C 6-10 arylC 1-4 alkylNH—, heteroarylNH—, C 6-14 aryloxyNH—, C 6-10 arylC 1-4 alkoxyNH— and heteroaryloxyNH—.
14 . The compound of claim 1 of the Formula I, II, V and VI, wherein X is a bond and R 9 is hydrogen.
15 . (canceled)
16 . (canceled)
17 . A radiolabeled compound of the formula IIa:
wherein:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 ;
R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—;
provided that at least any two of R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogens, and at least one of R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 comprises the radiolabel;
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 ; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 , -halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
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 1-6 alkylenyl, —C(O)O— and —N(R 10 )C(O)—;
R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are each independently hydrogen or are each independently selected from the group consisting of C 1-3 alkylNH—, halo, cyano, hydroxyl, —SR 10 , —C(O)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, heteroaryloxy, heteroarylC 2-5 alkoxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; and
R 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—.
19 . The compound of claim 17 , wherein:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(O)O— and —N(R 10 )C(O)—;
R 2 , R 4 , R 6 and R 8 are each hydrogen;
R 3 and R 7 are each independently selected from the group consisting of C 1-3 alkylNH—, (C 1-3 alkyl) 2 N—, (halo-C 1-6 alkyl)N(C 1-3 alkyl)-, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 N(C 1-3 alkyl)-, halo, hydroxyl, halo-C 1-6 alkyl, C 6-10 arylC 1-4 alkyl, 4-(halo-C 1-6 alkyl)-triazol-1-yl)C 2-5 alkoxy, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylC(O)—; and
R 9 is hydrogen or is selected from the group consisting of halo, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—.
20 .- 28 . (canceled)
29 . A radiolabel compound of the formula VI:
wherein:
X is a bond or is selected from the group consisting of C 1-6 alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R 10 )C(O)—, —N(R 10 )C(S)—, —S(O)N(R 10 )— and —N(R 10 )S(O) 2 —;
Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , halo-C 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy) C 6-10 arylC 1-4 alkoxy and heteroaryloxy;
R 5 and R 6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR 10 , —C(O)NH 2 , —C(S)NH 2 , haloC 1-6 alkyl, perhaloC 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, C 1-5 alkoxy, H(OCH 2 CH 2 ) 1-6 O—, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O—, halo-CH 2 CH 2 O—, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy), C 6-10 arylC 1-4 alkoxy, heteroaryloxy, C 1-5 alkylNR 10 C(O)—, (C 1-6 alkyl) 2 NC(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylNR 10 C(O)CH(C 1-5 alkyl)-, halo-C 1-6 alkylOC(O)CH(C 1-5 alkyl)-, halo-C 1-5 alkylNR 10 C(O)—, C 1-5 alkylNR 10 C(O)O—, C 1-5 alkylC(O)—, C 1-5 alkylC(O)O—, C 6-10 arylC(O)— and C 6-10 arylC(O)O—; or R 5 and R 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 9 is hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 (CO)—;
each R 10 is independently H or C 1-6 alkyl;
R 11 is a hydrogen or is selected from the group consisting of halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, halo-(CH 2 CH 2 ) 1-6 —; halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 —, halo-CH 2 CH 2 —(OCH 2 CH 2 ) 1-6 O(CO)— and halo-CH 2 CH 2 -(0 CH 2 CH 2 ) 1-6 (CO)—;
provided that at least one of R 1 to R 11 comprises a radiolabel, as defined herein;
wherein the radiolabel comprises a radionuclide selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I and 77 Br;
and pharmaceutically acceptable salts thereof.
30 .- 48 . (canceled)