IDO inhibitors

Abstract

Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunosuppression associated with an infectious disease, e.g., HIV-I infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.

Claims

1. A solid pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier and a compound selected from the group consisting of: O-((4,4-dichlorobiphenyl-2-yl)methyl)hydroxylamine; O-(5-chloro-2-(thiophen-3-yl)benzyl)hydroxylamine; O-((4-chlorobiphenyl-2-yl)methyl)hydroxylamine; O-(5-chloro-2-(thiophen-2-yl)benzyl)hydroxylamine; methyl 4-(aminooxy)-4-phenylbutanoate; O-((4-chlorobiphenyl-3-yl)methyl)hydroxylamine; O-((3,4,4-trichlorobiphenyl-2-yl)methyl)hydroxylamine; O-(5-chloro-2-(pyrimidin-5-yl)benzyl)hydroxylamine; O-(5-chloro-2-(1H-indol-5-yl)benzyl)hydroxylamine; (S)-2-(aminooxy)-N-methyl-2-phenylacetamide; methyl 2-(aminooxy)-2-phenylacetate; O-(1,3-diphenylpropyl)hydroxylamine; 3-(aminooxymethyl)-N-phenylaniline; O-((4,5-dichlorobiphenyl-3-yl)methyl)hydroxylamine; 2-(aminooxymethyl)-N-benzylaniline; O-(3-cyclohexyl-1-phenylpropyl)hydroxylamine; 2-(aminooxymethyl)-N-phenylaniline; O-(cyclohexyl(phenyl)methyl)hydroxylamine; 2-(aminooxy)-N-methyl-2-phenylacetamide; O-(1,2-diphenylethyl)hydroxylamine; O-(1,2,3,4-tetrahydronaphthalen-1-yl)hydroxylamine; 3-(aminooxymethyl)-N-benzylaniline; O-(2-(pyridin-4-yl)benzyl)hydroxylamine; O-(3-(pyridin-4-yl)benzyl)hydroxylamine; O-(2-cyclohexyl-1-phenylethyl)hydroxylamine; 4-(aminooxy)-N-methyl-4-phenylbutanamide; 2-(aminooxy)-2-phenylethanamine; 3-(aminooxy)-3-phenylpropan-1-amine; O-(2-morpholino-1-phenylethyl)hydroxylamine; 3-(aminooxymethyl)-N-benzylaniline; 2-(aminooxy)-N-methyl-2-phenylethanamine; 4-(aminooxy)-N-cyclohexyl-4-phenylbutanamide; tert-butyl 2-(aminooxy)-2-phenylethylcarbamate; (R)-2-(aminooxy)-N-methyl-2-phenylacetamide; 3-(aminooxy)-N-methyl-3-phenylpropan-1-amine; N-(2-(aminooxy)-2-phenylethyl)acetamide; O-(3-morpholino-1-phenylpropyl)hydroxylamine; and (S)-3-(aminooxy)-3-phenylpropan-1-ol; or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In one aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (I); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (I); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (I); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (I); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (I); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (I),

(2) ##STR00002##

(3) or a pharmaceutically acceptable salt thereof, wherein

(4) n is 0, 1, 2, 3 or 4;

(5) Z is N, N.sup.+(R.sup.1), N(R.sup.10), O, or S, provided that when Z is N.sup.+(R.sup.1), then a pharmaceutically acceptable anion is present;

(6) bonds a and b are independently a single or double bond provided that (i) when bond a is a double bond, then Z is N and R.sup.2a is absent; and (ii) when bond b is a double bond, then Z is N(R.sup.1), O, or S and R.sup.2a and R.sup.3a are absent;

(7) R.sup.1 is R.sup.N, C.sub.3-C.sub.8cycloalkyl, aryl, heteroaryl, arylC.sub.1-C.sub.6alkyl, heteroarylC.sub.1-C.sub.6alkyl, or -G.sup.1;

(8) R.sup.10 is R.sup.1 or OR;

(9) R.sup.2 and R.sup.3 are each independently R.sup.1, halogen, cyano, nitro, OR, OOH, N(R.sup.N).sub.2, N(H)(OH), ONH.sub.2, ON(R.sup.N)C(O)OR;

(10) or R.sup.2 and R.sup.3 taken together with the atoms to which they are attached form a fused 5 or 6 membered aryl or a 5 or 6 membered heteroaryl group, wherein the aryl and heteroaryl groups are optionally substituted with one or more R.sup.4 groups;

(11) R.sup.2a and R.sup.3a are independently hydrogen, C.sub.1-C.sub.6alkyl, hydroxyC.sub.1-C.sub.6alkyl, cyano, OOH, OH, or G.sup.1;

(12) or R.sup.2 and R.sup.2a taken together form R.sup.D; or R.sup.3 and R.sup.3a taken together form R.sup.D;

(13) each R.sup.4 is independently hydrogen, halogen, cyano, nitro, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, CH.sub.2COOR, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl;

(14) each G.sup.1 is independently C(O)NH(R.sup.70), CH.sub.2R.sup.500, -L.sup.1-R.sup.5, or -L.sup.10-R.sup.50, wherein

(15) R.sup.70 is (i) phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH; or (ii) a 5 or 6 membered heteroaryl, optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH;

(16) L.sup.1 is C.sub.2-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(17) R.sup.5 is cyano, nitro, NH.sub.2, NH(C.sub.1-C.sub.6alkyl), NH(OH), OH, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, OC(O)NH.sub.2, N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, C(O)S(OR), C(O)S(N(R).sub.2), N(H)SC(O)CH.sub.3, OSC(O)R, P(O)(OR).sub.2, C(O)CH.sub.2P(O)(OR).sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)R.sup.70, NHC(S)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, or N(H)C(S)SR.sup.8, wherein

(18) R.sup.8 is C.sub.1-C.sub.6 alkyl-G.sup.4, wherein

(19) G.sup.4 is (i) aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(20) or (ii) saturated or unsaturated heterocyclyl, each optionally substituted with one or more groups which are each independently R.sup.D, halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(21) or (iii) hydrogen, cyano, N(R.sup.N).sub.2, NR.sup.N(OH), OR, ONH.sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)NH.sub.2, or P(O)(OR).sub.2;

(22) L.sup.10 is a bond or C.sub.1-C.sub.6alkyl-,

(23) R.sup.50 is a group of the formula,

(24) ##STR00003##

(25) wherein q is 0 or 1; r is 0, 1, or 2;

(26) bonds d and e are independently a single or double bond;

(27) each R.sup.6 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, or phenyl;

(28) each X is independently O or S;

(29) X.sup.1 and X.sup.2 are both hydrogen or X.sup.1 and X.sup.2 taken together form R.sup.D; and

(30) each Y is independently O, S, or N(R.sup.N);

(31) R.sup.500 is C(O)OR, C(O)NH.sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, NHC(O)R.sup.70, NHC(S)R.sup.70, N(H)C(O)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, C(O)N(H)OH, N(OH)C(O)R, N(H)C(S)SR.sup.8, or R.sup.50;

(32) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(33) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(34) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(35) provided that

(36) (a) one and only one G.sup.1 is present;

(37) (b) when bond b is a double bond, Z is N(H), O, or S, R.sup.3 is (CH.sub.2).sub.1-3N(H)C(S)SR.sup.8, then R.sup.8 is not CH.sub.2-G.sup.4;

(38) (c) the compound is not -(3-benzofuranyl)alanine, -(3-benzo[b]thienyl)alanine, 1-methyltryptophan, 1-ethyltryptophan, hexyl (1H-indol-3-yl)methylcarbamodithioate and 2-amino-(3-indolin-3-yl)propanoic acid; and

(39) (d) when bond b is a double bond, Z is N(H), N(CH.sub.3), or N(CH.sub.2CH.sub.3), R.sup.3 is -G.sup.1, and G.sup.1 is CH.sub.2CH(NH(R.sup.N))COOR, CH.sub.2C(CH.sub.3)(NH.sub.2)COOR, CH(CH.sub.3)CH(NH.sub.2)COOH, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2COOH, CH.sub.2CH(OH)COOH, or CHCHCOOR, then either n is not 0 or R.sup.2 is not hydrogen and R.sup.2 or R.sup.4 are not C.sub.1-C.sub.2alkyl, aryl, halogen, OH, OCH.sub.3, OCH.sub.2Ph, COOH, or nitro.

(40) In an embodiment of the first aspect, the compound is of one of formulae (Ia)-(In),

(41) ##STR00004## ##STR00005##

(42) and the remaining variables are as defined for formula (I).

(43) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C(O)NH(R.sup.70), wherein R.sup.70 is a phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(44) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C(O)NH(R.sup.70), wherein R.sup.70 is a 5-membered heteroaryl optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(45) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C(O)NH(R.sup.70), wherein R.sup.70 is a thiazolyloptionally substituted with one to three groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(46) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.2-C.sub.6alkyl- wherein the alkyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and R.sup.5 is cyano, nitro, NH.sub.2, NH(C.sub.1-C.sub.6alkyl), NH(OH), OH, C(O)OR, C(O)NH.sub.2, C(NH)NH.sub.2, C(O)N(H)OH, OC(O)NH.sub.2, N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, C(O)CF.sub.3, N(H)S(O)R, N(H)S(O).sub.2R, N(H)SC(O)CH.sub.3, P(O)(OR).sub.2, C(O)N(H)R.sup.70, NHC(S)R.sup.70, NHC(S)NHR.sup.70, or N(H)C(S)SR.sup.8.

(47) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-C(O)NH(R.sup.70).

(48) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-C(O)NH(R.sup.70), wherein R.sup.70 is a phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(49) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-C(O)NH(R.sup.70), wherein R.sup.70 is a phenyl substituted with one or two groups which are each independently NH.sub.2, SH, or OH.

(50) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-C(O)NH(R.sup.70), wherein R.sup.70 is thiazolyl optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(51) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-C(O)NH(R.sup.70), wherein R.sup.70 is thiazolyl.

(52) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-NHC(S)R.sup.70.

(53) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-NHC(S)R.sup.70, wherein R.sup.70 is a phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(54) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-NHC(S)R.sup.70, wherein R.sup.70 is a phenyl substituted with one or two groups which are each independently NH.sub.2, SH, or OH.

(55) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-NHC(S)R.sup.70, wherein R.sup.70 is thiazolyl optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(56) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-NHC(S)R.sup.70, wherein R.sup.70 is thiazolyl.

(57) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-N(H)C(S)SR.sup.8.

(58) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8.

(59) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is C.sub.2-C.sub.6alkyl-N(H)C(S)SR.sup.8, wherein R.sup.8 is C.sub.1-C.sub.6 alkyl-G.sup.4, wherein G.sup.4 is aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(60) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is C.sub.1-C.sub.6 alkyl-G.sup.4, wherein G.sup.4 is aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(61) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is C.sub.1-C.sub.6 alkyl-G.sup.4, wherein G.sup.4 is phenyl optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(62) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is C.sub.1-C.sub.6 alkyl-G.sup.4, wherein G.sup.4 is phenyl substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(63) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is CH.sub.2CH.sub.2G.sup.4, wherein G.sup.4 is aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(64) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is CH.sub.2CH.sub.2G.sup.4, wherein G.sup.4 is phenyl optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(65) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2CH.sub.2N(H)C(S)SR.sup.8, wherein R.sup.8 is CH.sub.2CH.sub.2G.sup.4, wherein G.sup.4 is phenyl substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(66) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is -L.sup.10-R.sup.50.

(67) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is -L.sup.10-R.sup.50, herein L.sup.10 is a bond, and R.sup.50 is a group of the formula,

(68) ##STR00006##

(69) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is C.sub.1-C.sub.6alkyl-, and R.sup.50 is a group of the formula,

(70) ##STR00007##

(71) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is C.sub.1-C.sub.6alkyl-, and R.sup.50 is a group of the formula,

(72) ##STR00008##

(73) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2R.sup.500, wherein R.sup.500 is C(O)OR, C(O)NH.sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, NHC(O)R.sup.70, NHC(S)R.sup.70, N(H)C(O)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, C(O)N(H)OH, N(OH)C(O)R, or R.sup.50.

(74) In a an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2R.sup.500, wherein R.sup.500 is C(O)OR.

(75) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2R.sup.500, wherein R.sup.500 is C(O)NH.sub.2.

(76) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2R.sup.50.

(77) In an embodiment of the first aspect, the compound is of one of formulae (I) and (Ia)-(In), and G.sup.1 is CH.sub.2C(O)CF.sub.3.

(78) In a second aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (II); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (II); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (II); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (II); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (II); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (II),

(79) ##STR00009##

(80) or a pharmaceutically acceptable salt thereof, wherein

(81) bonds a and b are each a single or double bond provided that

(82) (i) when bond a is a single bond, then Z is O, S or N(R.sup.N);

(83) (ii) when bond a is a double bond, then R.sup.2 is absent and Z is N;

(84) (iii) when bond b is a double bond, then R.sup.2 and R.sup.3 are absent and Z is O, S or N(R.sup.N); and

(85) (iv) only one of bonds a and b is a double bond;

(86) R.sup.2 and R.sup.3 are independently hydrogen, hydroxy, C.sub.1-C.sub.6alkyl, or -G.sup.1;

(87) R.sup.4 is hydrogen, halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(NR.sup.N)CH.sub.3, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more groups which are independently halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(NNH.sub.2)CH.sub.3, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6haloalkyl, and the aryl and heteroaryl groups are optionally fused to a 3-8 membered unsaturated heterocyclyl group; and

(88) ring A is a 3-8 membered saturated or unsaturated cycloalkyl or 3-8 membered saturated or unsaturated heterocyclyl group wherein ring A is optionally substituted by one or more groups which are each independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), N(CN), R.sup.4, or G.sup.1;

(89) G.sup.1 is independently -L.sup.1-R.sup.5 wherein

(90) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(91) R.sup.5 is cyano, nitro, NH.sub.2, NH(OH), OH, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(S)R, N(H)C(O)OR, N(OH)C(O)R, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, or P(O)(OR).sub.2; and

(92) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, benzyl, heteroaryl, or heteroarylC.sub.1-C.sub.6alkyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; and

(93) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(94) provided that the compound is not 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, 1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-7-ol, 2,3,4,9-tetrahydro-1H-pyrido[3,4-b)]indole, and 7-methoxy-4,9-dihydro-3H-pyrido[3,4-b)]indol-1-ol.

(95) In an embodiment of the second aspect, G.sup.1 is -L.sup.1-R.sup.5 wherein L.sup.1 is C.sub.1-C.sub.6alkyl- or C.sub.2-C.sub.6alkenyl-, wherein the alkyl or alkenyl group is optionally substituted with one or two groups which are independently OR or N(R.sup.N).sub.2; and R.sup.5 is cyano, NH.sub.2, NH(OH), OH, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(S)R, N(H)C(O)OR, or N(OH)C(O)R.

(96) In an embodiment of the second aspect, G.sup.1 is -L.sup.1-R.sup.5 wherein L.sup.1 is C.sub.1-C.sub.6alkyl-optionally substituted with one group which is OR or N(R.sup.N).sub.2; and R.sup.5 is NH.sub.2, NH(OH), OH, C(O)OR, C(O)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, or N(H)C(O)OR.

(97) In an embodiment of the second aspect, G.sup.1 is -L.sup.1-R.sup.5 wherein L.sup.1 is C.sub.1-C.sub.3alkyl-substituted N(R.sup.N).sub.2, and R.sup.5 is C(O)OR, C(O)NH.sub.2, or C(O)N(H)OH.

(98) In another embodiment of the second aspect, the compound is of one of formulae (II)-(IIe),

(99) ##STR00010##

(100) wherein Q is O, N(H), S; q is 0, 1, or 2, and the remaining variables are as defined for formula (II).

(101) In one embodiment of the second aspect, the compound is of one of formulae (II) and (II)-(II) and G.sup.1 is as defined in any one of the preceding embodiments of the second aspect.

(102) In another embodiment of the second aspect, the compound is of the formula,

(103) ##STR00011##

(104) and the remaining variables are as defined for formula (II).

(105) In an embodiment of the second aspect, the compound is according to one of the formulae (II), and (IIi)-(IIl) and one R.sup.4 is OR, SR, N(R.sup.N).sub.2, C(O)OR, or C(O)N(R.sup.N).sub.2.

(106) In another embodiment of the second aspect, the compound is according to one of the formulae (II), and (IIi)-(IIl) and one R.sup.4 is C(O)OR or C(O)N(R.sup.N).sub.2.

(107) In a third aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (III); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (III); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (III); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (III), (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (III); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (III),

(108) ##STR00012##

(109) or a pharmaceutically acceptable salt thereof, wherein

(110) Z is N, N(R.sup.N), O, or S;

(111) bond a is a single or double bond provided that when bond a is a double bond, then Z is N and R.sup.2a is absent;

(112) R.sup.2 and R.sup.2a are each hydrogen, or R.sup.2 and R.sup.2a taken together form R.sup.D;

(113) ring A is a spiro ring which is either (i) a saturated or unsaturated C.sub.4-C.sub.8cycloalkyl optionally substituted with one or more groups which are each independently R.sup.20 or R.sup.21; or (ii) a saturated or unsaturated 3-8 membered heterocyclyl optionally substituted with one or more groups which are each independently R.sup.20 or R.sup.21;

(114) R.sup.4 is independently hydrogen, halogen, cyano, nitro, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl;

(115) each R.sup.20 is independently R.sup.D, C.sub.3-C.sub.8cycloalkyl, or =heterocyclyl;

(116) each R.sup.21 is independently halogen or -L.sup.1-R.sup.5, wherein

(117) L.sup.1 is a bond, C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(118) R.sup.5 is cyano, nitro, NH.sub.2, NH(OH), OH, C(O)OR, C(O)N(R).sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(S)R, N(H)C(O)OR, N(OH)C(O)R, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, or P(O)(OR).sub.2;

(119) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(120) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(121) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl.

(122) In an embodiment of the third aspect, the compound is of one of formulae (IIa)-(IIId),

(123) ##STR00013##

(124) wherein X is O, S, or NH, and the remaining variables are as defined for formula (III).

(125) In an embodiment of the third aspect, the compound is of one of formulae (IIIe)-(IIIh),

(126) ##STR00014##

(127) wherein X is O, S, or NH, and the remaining variables are as defined for formula (III).

(128) In an embodiment of the third aspect, the compound is of one of formulae (III) and (IIIe)-(IIIh) and R.sup.21 is -L.sup.1-R.sup.5.

(129) In another embodiment of the third aspect, the compound is of one of formulae (III) and (IIIe)-(IIIh) and R.sup.21 is -L.sup.1-R.sup.5, wherein L.sup.1 is a bond or C.sub.1-C.sub.6alkyl- optionally substituted with OR or N(R.sup.N).sub.2.

(130) In an embodiment of the third aspect, the compound is of one of formulae (III) and (IIIe)-(IIIh) and R.sup.21 is -L.sup.1-R.sup.5, wherein L.sup.1 is a bond or C.sub.1-C.sub.6alkyl- optionally substituted with OR or N(R.sup.N).sub.2; and R.sup.5 is cyano, NH.sub.2, NH(OH), OH, C(O)OR, C(O)N(R).sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(O)OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, or P(O)(OR).sub.2.

(131) In an embodiment of the third aspect, the compound is of one of formulae (III) and (IIIe)-(IIIh) and R.sup.21 is -L.sup.1-R.sup.5, wherein L.sup.1 is a bond or C.sub.1-C.sub.6alkyl- optionally substituted with OR or N(R.sup.N).sub.2; and R.sup.5 is NH.sub.2, C(O)OR, C(O)N(R).sub.2, or C(O)N(H)OH.

(132) In a fourth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (IV); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IV); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (IV); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (IV); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IV); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IV),

(133) ##STR00015##

(134) or a pharmaceutically acceptable salt thereof, wherein

(135) bond a is a single or double bond;

(136) Y is R.sup.D;

(137) both X are S or N(R.sup.N);

(138) R.sup.1 and R.sup.2 are independently C.sub.1-C.sub.6alkyl, OR, N(R.sup.N).sub.2, or SR;

(139) or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form

(140) (i) a fused phenyl ring optionally substituted with one or more groups which are independently halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, OR, N(R.sup.N).sub.2, or SR; or

(141) (ii) a fused 5-8 membered heterocyclyl ring optionally substituted with one or more groups which are independently R.sup.D, C.sub.1-C.sub.6alkyl, OR, N(R.sup.N).sub.2, or SR;

(142) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, cyano, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(143) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(144) each R.sup.N is independently (i) hydrogen, hydroxyl, cyano, or amino; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(145) provided that when X and Z are both N(R.sup.N), then one is not NH.

(146) In an embodiment of the fourth aspect, the compound is of formulae (IVa),

(147) ##STR00016##

(148) wherein R.sup.1, R.sup.2, and R.sup.N are as defined for formula (IV).

(149) In an embodiment of the fourth aspect, the compound is of formulae (IV) or (IVa), and R.sup.1 and R.sup.2 are independently OR, or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form a fused 5-8 membered heterocyclyl ring.

(150) In an embodiment of the fourth aspect, the compound is of formulae (IV) or (IVa), and each R.sup.N is independently hydrogen, hydroxyl, or C.sub.1-C.sub.6alkyl optionally substituted with one halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy or carbamoyl group.

(151) In another embodiment of the fourth aspect, the compound is of formulae (IVb),

(152) ##STR00017##

(153) wherein R.sup.N is as defined for formula (IV).

(154) In an embodiment of the fourth aspect, the compound is of formulae (IV) or (IVb), and each R.sup.N is independently hydrogen, hydroxyl, or C.sub.1-C.sub.6alkyl optionally substituted with one halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy or carbamoyl group.

(155) In another embodiment of the fourth aspect, the compound is of formulae (IVc),

(156) ##STR00018##

(157) wherein R.sup.1, R.sup.2, and Y are as defined for formula (IV).

(158) In an embodiment of the fourth aspect, the compound is of formulae (IV) or (IVc), and R.sup.1 and R.sup.2 each SR, or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form a fused 5-8 membered heterocyclyl ring optionally substituted with R.sup.D, C.sub.1-C.sub.6alkyl, OR, N(R.sup.N).sub.2, or SR.

(159) In an embodiment of the fourth aspect, the compound is of formulae (IV) or (IVc), and R.sup.1 and R.sup.2 each SR, or R.sup.1 and R.sup.2 taken together with the carbon atoms to which they are attached form a fused 5-8 membered heterocyclyl ring optionally substituted with R.sup.D, C.sub.1-C.sub.6alkyl, OR, N(R.sup.N).sub.2, or SR, wherein each R is independently hydrogen or C.sub.1-C.sub.6alkyl, substituted with one halogen, hydroxyl, cyano, C.sub.1-C.sub.6alkoxy, amino, carboxy, or carbamoyl group.

(160) In a fifth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (V); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (V); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (V); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (V); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (V); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (V),

(161) ##STR00019##

(162) or a pharmaceutically acceptable salt thereof, wherein

(163) X, Y, and Z are independently N, N.sup.+(R.sup.3), N(R.sup.3), C(R.sup.4), O, or S; provided (i) one and only one of X, Y, and Z is N(R.sup.3), O, or S, (ii) no more than one of X, Y, and Z is N.sup.+(R.sup.3); (iii) when one of X, Y, and Z is N(R.sup.3), O, or S and the other two are both C(R.sup.4), then R.sup.1 and R.sup.2 taken together are not a phenyl ring; (iv) when X and Z are N(R.sup.3) and N or N and N(R.sup.3), then R.sup.3 is not hydrogen; (v) provided that when one of X, Y, and Z is N.sup.+(R.sup.3), then a pharmaceutically acceptable anion is present; and (vi) R.sup.1, R.sup.2, and R.sup.3 or R.sup.4 are not simultaneously H.

(164) R.sup.1, R.sup.2, and R.sup.4 are independently hydrogen, halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, N(H)NH.sub.2, C(O)R, C(O)N(R.sup.N).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6halo alkyl, C.sub.1-C.sub.6 alkyl-OR, C.sub.1-C.sub.6alkyl-SR, C.sub.1-C.sub.6alkyl-N(R.sup.N).sub.2, C.sub.1-C.sub.6alkyl-C(O)OR, C.sub.1-C.sub.6alkyl-C(O)N(R.sup.N).sub.2, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl, or G.sup.1, wherein the aryl and heteroaryl groups are optionally substituted with one or more groups which are independently halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6halo alkyl, C.sub.1-C.sub.6 alkyl-OR, C.sub.1-C.sub.6alkyl-SR, C.sub.1-C.sub.6alkyl-N(R.sup.N).sub.2, C.sub.1-C.sub.6 alkyl-C(O)OR, or C.sub.1-C.sub.6 alkyl-C(O)N(R.sup.N).sub.2;

(165) R.sup.3 is hydroxyl, amino, cyano, R.sup.N or G.sup.1;

(166) or R.sup.1 and R.sup.2 taken together with the atoms to which they are attached form a fused ring which is G.sup.2;

(167) or R.sup.3 and R.sup.4, when present on adjacent atoms, taken together with the atoms to which they are attached form a fused ring which is G.sup.2;

(168) or two R.sup.4, when present on adjacent carbon atoms, taken together with the atoms to which they are attached form a fused ring which is G.sup.2;

(169) G.sup.2 is (i) a saturated or unsaturated 4-8 membered cycloalkyl optionally substituted with one or more groups which are each independently R.sup.20 or R.sup.21;

(170) (ii) a saturated or unsaturated 4-8 membered heterocyclyl optionally substituted with one or more groups which are each independently R.sup.20 or R.sup.21;

(171) (iii) phenyl optionally substituted with one or more R.sup.21 groups, or

(172) (iv) a 5 or 6 membered heteroaryl group optionally substituted with one or more R.sup.21 groups; wherein

(173) each R.sup.20 is independently R.sup.D, C.sub.3-C.sub.8cycloalkyl, or =heterocyclyl; and

(174) each R.sup.21 is independently halogen, hydroxyl, amino, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6halo alkyl, or G.sup.1;

(175) each G.sup.1 is independently C(CH.sub.3)NOCH.sub.2C(O)OH, C(CH.sub.3)NOCH.sub.2C(O)NH.sub.2, C(CH.sub.3)NOC(O)C(O)NH.sub.2, C(O)NH(R.sup.70), W-L.sup.1-R.sup.5 or -L.sup.10-R.sup.50, wherein

(176) R.sup.70 is (i) phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, OCH.sub.3 or OH; or (ii) a 5 or 6 membered heteroaryl, optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH;

(177) W is a bond, S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), N(R.sup.N)C(O), O, S, or N(R.sup.N);

(178) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(179) R.sup.5 is cyano, nitro, amino, OR, mercapto, NH(OH), NHN(H)R, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, N(H)C(O)OR, N(OH)C(O)R, C(O)CF.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, SC(NH)NH.sub.2, N(H)S(O)R, N(H)S(O).sub.2R, C(O)S(OR), C(O)S(N(R).sub.2), N(H)SC(O)CH.sub.3, P(O)(OR).sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, C(O)N(H)NC(H)R, C(O)N(H)N(H)R, SC(NH)NH.sub.2, C(O)NH(R.sup.70), C(S)NH(R.sup.70), NHC(O)R.sup.70, NHC(S)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, or N(H)C(S)SR.sup.8, wherein

(180) R.sup.8 is -L.sup.2-G.sup.4, wherein

(181) L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, N(R.sup.N)C(O)R, N(R.sup.N)C(O)OR, C(O)OR, C(O)N(R).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl; and

(182) G.sup.4 is (i) hydrogen; (ii) aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(183) (iii) saturated or unsaturated heterocyclyl, each optionally substituted with one or more groups which are each independently R.sup.D, halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(184) or (iv) cyano, N(R.sup.N).sub.2, NR.sup.N(OH), OR, ONH.sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, or P(O)(OR).sub.2;

(185) L.sup.10 is a bond or C.sub.1-C.sub.6alkyl-,

(186) R.sup.50 is a group of the formula,

(187) ##STR00020##

(188) wherein q is 0 or 1; r is 0, 1, or 2;

(189) bonds d and e are independently a single or double bond;

(190) each R.sup.6 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, or phenyl;

(191) each Q is independently O or S;

(192) each T is independently is O, S, or N(R.sup.N); and

(193) X.sup.1 and X.sup.2 are both hydrogen or X.sup.1 and X.sup.2 taken together form R.sup.D;

(194) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(195) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(196) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(197) provided that (i) one and only one G.sup.1 is present; (ii) no more than one G.sup.2 is present; (iii) the compound is not 2-amino-3-(1H-azaindol-3-yl)propanoic acid; and 2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid; and (iv) when G.sup.1 is CH.sub.2).sub.1-3N(H)C(S)S-L.sup.2-G.sup.4, then L.sup.2 is not methylene.

(198) In an embodiment of the fifth aspect, the compound is according to one of formulae (Va)-(Vj),

(199) ##STR00021##

(200) and the remaining variables are as defined for formula (V).

(201) In another embodiment of the fifth aspect, the compound is according to one of formulae (Vk)-(Vo),

(202) ##STR00022##

(203) and the remaining variables are as defined for formula (V).

(204) In an embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.1-R.sup.5.

(205) In an embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- or C.sub.2-C.sub.6alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one groups which is OR or N(R.sup.N).sub.2.

(206) In a an embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- or C.sub.2-C.sub.6alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one groups which is OR or N(R.sup.N).sub.2; and R.sup.5 is cyano, nitro, amino, hydroxyl, mercapto, NH(OH), NHN(H)R, C(O)OR, C(O)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(O)OR, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, or P(O)(OR).sub.2.

(207) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- and R.sup.5 is N(H)C(S)SR.sup.8.

(208) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is W-L.sup.1-R.sup.5 wherein W is S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), N(R.sup.N)C(O), O, S, or N(H).

(209) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is W-L.sup.1-R.sup.5, wherein W is S(O), S(O).sub.2, C(O)N(R.sup.N), O, S, or N(H).

(210) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is W-L.sup.1-R.sup.5, wherein W is S(O) or S(O).sub.2.

(211) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is W-L.sup.1-R.sup.5, wherein W is C(O)N(R.sup.N).

(212) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is W-L.sup.1-R.sup.5, wherein W is O, S, or N(H).

(213) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.10-R.sup.50.

(214) In an embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is a bond

(215) In an embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is a bond; and R.sup.50 is a group of the formula,

(216) ##STR00023##

(217) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is C.sub.1-C.sub.6alkyl-.

(218) In another embodiment of the fifth aspect, the compound is of any one of formulae (V) and (Va)-(Vo), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is C.sub.1-C.sub.6alkyl-; and R.sup.50 is a group of the formula,

(219) ##STR00024##

(220) In a sixth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (VI); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VI); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (VI); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (VI); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VI); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VI),

(221) ##STR00025##

(222) or a pharmaceutically acceptable salt thereof, wherein

(223) Z is C(R.sup.4), N, or N.sup.+(R.sup.3), and Z.sup.1 is C(R.sup.4), or N, provided that at least one of Z and Z.sup.1 is N, and when Z is N.sup.+(R.sup.3), then a pharmaceutically acceptable anion is present;

(224) R.sup.1, R.sup.2, and R.sup.4 are independently hydrogen, halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, C(O)R, C(O)O(R), C(O)N(R.sup.N).sub.2, S(O)R, S(O).sub.2R, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl, or G.sup.1;

(225) or R.sup.1 and R.sup.2 taken together with the atoms to which they are attached form a fused

(226) (i) phenyl ring optionally substituted with one or more R.sup.4;

(227) (ii) pyridyl or pyridiniumyl ring, each optionally substituted with one or more R.sup.4; or

(228) (iii) 4-8 membered saturated or unsaturated cycloalkyl or 4-8 membered saturated or unsaturated heterocyclyl ring, each optionally substituted with one or more R.sup.D or R.sup.4;

(229) R.sup.3 is R.sup.N or G.sup.1;

(230) each G.sup.1 is independently -L.sup.1-R.sup.5, -Q-L.sup.1-R.sup.5, -L.sup.10-R.sup.50, -Q-L.sup.10-R.sup.50, C(O)N(H)R.sup.NN(H)C(O)R.sup.N, C(O)N(H)R.sup.70, N(H)C(S)SR.sup.70, or -Q-L.sup.1-R.sup.70, wherein

(231) Q is O, S, or N(R.sup.N);

(232) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(233) R.sup.70 is (i) phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH; or (ii) a 5 or 6 membered heteroaryl, optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH;

(234) R.sup.5 is cyano, nitro, amino, hydroxyl, mercapto, NH(OH), N(R)N(H)C(O)NH.sub.2, C(O)R, C(O)CF.sub.3, C(O)CH.sub.3, C(O)OR, C(O)NH.sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, C(O)N(H)OH, C(NH)NH.sub.2, C(NO H)NH.sub.2, C(NNH.sub.2)R, C(H)NN(H)C(O)R; N(H)C(O)OR, N(OH)C(O)R, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, C(O)S(OR), C(O)S(N(R).sub.2), N(H)SC(O)CH.sub.3, P(O)(OR).sub.2, C(O)N(H)NCH(C.sub.1-C.sub.6alkyl), NHC(O)R.sup.70, NHC(S)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, NHC(S)N(H)NH.sub.2, N(H)C(S)SR.sup.8, or C(S)N(H)N(H)C(O)NH.sub.2, wherein

(235) R.sup.8 is -L.sup.2-G.sup.4, wherein

(236) L.sup.2 is C.sub.2-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl; and

(237) G.sup.4 is (i) aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(238) (ii) saturated or unsaturated heterocyclyl, each optionally substituted with one or more groups which are each independently R.sup.D, halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(239) or (iii) cyano, N(R.sup.N).sub.2, NR.sup.N(OH), OR, ONH.sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, or P(O)(OR).sub.2; and

(240) L.sup.10 is a bond or L.sup.1;

(241) R.sup.50 is a group of the formula,

(242) ##STR00026##

(243) wherein q is 0 or 1; r is 0, 1, or 2;

(244) bonds d and e are independently a single or double bond;

(245) each X is independently O or S;

(246) X.sup.1 and X.sup.2 are both hydrogen or X.sup.1 and X.sup.2 taken together form R.sup.D; and

(247) each Y is independently O, S, or N(R.sup.N),

(248) each R.sup.6 is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, or phenyl;

(249) each R is independently (i) hydrogen or (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each is optionally substituted with one or more groups which are independently halogen, hydroxyl, cyano, nitro, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; and

(250) each R.sup.D is O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN);

(251) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or C.sub.2-C.sub.6alkynyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(252) provided that (i) one and only one G.sup.1 is present; (ii) the compound is not 2-amino-3-(quinolin-3-yl)propanoic acid; and (iii) when G.sup.1 is (CH.sub.2).sub.1-3N(H)C(S)S-L.sup.2-G.sup.4, then L.sup.2 is not methylene.

(253) In an embodiment of the sixth aspect, the compound is of any one of formulae (VIa)-(VIe),

(254) ##STR00027##

(255) and the remaining variables are as defined for formula (VI).

(256) In an embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -L.sup.1-R.sup.5.

(257) In an embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-.

(258) In an embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is cyano, nitro, amino, hydroxyl, mercapto, NH(OH), C(O)R, C(O)CF.sub.3, C(O)OR, C(O)NH.sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, C(O)N(H)OH, N(H)C(O)R.sup.70, N(H)C(S)R.sup.70, N(H)C(O)OR, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, P(O)(OR).sub.2, or N(H)C(S)SR.sup.8.

(259) In another embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -L.sup.10-R.sup.50.

(260) In an embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -L.sup.10-R.sup.50, wherein R.sup.50 is a group of the formula,

(261) ##STR00028##

(262) In another embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is C(O)N(H)R.sup.70.

(263) In another embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is N(H)C(S)SR.sup.70.

(264) In another embodiment of the sixth aspect, the compound is of any one of formulae (VI) and (VIa)-(VIe), and G.sup.1 is -Q-L.sup.1-R.sup.70.

(265) In a seventh aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (VII); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VII); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (VII); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (VII); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VII); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VII),

(266) ##STR00029##

(267) or a pharmaceutically acceptable salt thereof, wherein

(268) n is 0, 1, 2, or 3;

(269) R.sup.1, R.sup.2, and R.sup.4 are independently hydrogen, halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, N(R.sup.N)(OR), C(O)R, C(H)(R.sup.N)ONH.sub.2, C(H)(R.sup.8)ONH.sub.2, C(O)O(R), C(O)N(R.sup.N).sub.2, S(O)R, S(O).sub.2R, C.sub.1-C.sub.6alkyl, hydroxyC.sub.1-C.sub.6alkyl, aminoC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6halo alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or G.sup.1;

(270) or R.sup.1 and R.sup.2 taken together with the atoms to which they are attached form

(271) (i) a fused phenyl ring optionally substituted with one or more R.sup.4 groups;

(272) (ii) a 6-membered fused unsaturated heterocyclyl ring optionally substituted with one to three groups which are independently R.sup.D or R.sup.4;

(273) (iii) a 6-membered fused unsaturated cycloalkyl ring optionally substituted with one to three R.sup.4 groups;

(274) (iv) a 4- or 5-membered fused unsaturated heterocyclyl ring optionally substituted with one to three groups which are independently R.sup.D, halogen, cyano, nitro, OR, SR, N(R.sup.N).sub.2, N(R.sup.N)(OR), C(O)R, C(O)O(R), C(O)N(R.sup.N).sub.2, S(O)R, S(O).sub.2R, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl,

(275) each G.sup.1 is independently C(O)NH(R.sup.70), C(H)NN(H)C(R.sup.D)NH.sub.2, -Q-L.sup.1-R.sup.5, or -L.sup.10-R.sup.50, or -L.sup.10-R.sup.500, wherein

(276) R.sup.70 is (i) phenyl optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH; or (ii) a 5 or 6 membered heteroaryl, optionally substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH;

(277) Q is a bond, C(O), S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), N(R.sup.N)C(O), O, S, N(R.sup.N), CH(R)O, CH(R)S, or CH(R)N(R.sup.N);

(278) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(279) R.sup.5 is cyano, nitro, NH.sub.2, NH(OH), N(R)N(H)C(O)NH.sub.2, OH, ONH.sub.2, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, C(H)NN(H)C(O)R; N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, OC(O)NH.sub.2, ON(H)C(NH)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, C(O)S(OR), C(O)S(N(R).sub.2), N(H)SC(O)CH.sub.3, P(O)(OR).sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)R.sup.70, NHC(S)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, NHC(S)N(H)NH.sub.2, N(H)C(S)SR.sup.8, or C(S)N(H)N(H)C(O)NH.sub.2, wherein

(280) R.sup.8 is -L.sup.2-G.sup.4, wherein

(281) L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl; and

(282) G.sup.4 is (i) aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(283) (ii) saturated or unsaturated heterocyclyl, each optionally substituted with one or more groups which are each independently R.sup.D, halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl;

(284) or (iii) cyano, N(R.sup.N).sub.2, NR.sup.N(OH), OR, ONH.sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)OR, N(H)C(O)NH.sub.2, N(OH)C(O)R, or P(O)(OR).sub.2; and

(285) L.sup.10 is a bond or L.sup.1,

(286) R.sup.50 is a group of the formula,

(287) ##STR00030##

(288) wherein q is 0 or 1; r is 0, 1 or 2;

(289) bonds d and e are independently a single or double bond;

(290) each R.sup.6 is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, or phenyl;

(291) each X is independently O, N(R.sup.N), or S;

(292) X.sup.1 and X.sup.2 are both hydrogen or X.sup.1 and X.sup.2 taken together form R.sup.D; and each Y is independently O, S, or N(R.sup.N), and

(293) R.sup.500 is N(R.sup.N)C(NH)N(H)R.sup.501, wherein R.sup.501 is hydrogen, NH.sub.2, or C(NH)NH.sub.2;

(294) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(295) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(296) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(297) provided that

(298) (i) one and only one G.sup.1 is present; and

(299) (ii) the compound is not 2-amino-4-(2-aminophenyl)butanoic acid; and 2-amino-4-(2-amino-3-hydroxyphenyl)butanoic acid;

(300) (iii) when G.sup.1 is (CH.sub.2).sub.1-3N(H)C(S)S-L.sup.2-G.sup.4, then L.sup.2 is not methylene; and

(301) (iv) the compound is not of the formula,

(302) ##STR00031##

(303) In an embodiment of the seventh aspect, the compound is according to formulae (VIIa) or (VIIb),

(304) ##STR00032##

(305) and the remaining variables are as defined for formula (VII).

(306) In another embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is C(O)NH(R.sup.70).

(307) In another embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is C(H)NN(H)C(R.sup.D1)NH.sub.2, wherein R.sup.D1 is O, N(OH), or N(H).

(308) In another embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5.

(309) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- or C.sub.2-C.sub.6alkenyl-, wherein the alkyl or alkenyl, or alkynyl group is optionally substituted with one OR or N(R.sup.N).sub.2.

(310) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- or C.sub.2-C.sub.6alkenyl-, wherein the alkyl or alkenyl, or alkynyl group is optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is cyano, NH.sub.2, NH(OH), OH, ONH.sub.2, C(O)OR, C(O)NH.sub.2, C(O)R, C(NH)NH.sub.2, C(NOH)NH.sub.2, C(O)N(H)OH, N(H)C(O)R.sup.70, N(H)C(O)OR, N(H)C(O)NH.sub.2, OC(O)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, N(H)SC(O)CH.sub.3, P(O)(OR).sub.2, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)NHR.sup.70, NHC(S)NHR.sup.70, or N(H)C(S)SR.sup.8.

(311) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is cyano, NH.sub.2, NH(OH), OH, ONH.sub.2, C(O)OR, C(O)NH.sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)R.sup.70, C(O)CF.sub.3, C(O)N(H)R.sup.70, C(S)N(H)R.sup.70, NHC(O)NHR.sup.70, or NHC(S)NHR.sup.70.

(312) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), R.sup.5 is ONH.sub.2.

(313) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is ONH.sub.2.

(314) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- and R.sup.5 is ONH.sub.2.

(315) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.3alkyl- and R.sup.5 is ONH.sub.2 and R.sup.4 is halogen, nitro, OR, or CF.sub.3.

(316) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.3alkyl- and R.sup.5 is ONH.sub.2, R.sup.4 is halogen, nitro, OR, CF.sub.3 and n=1, 2 or 3.

(317) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and R.sup.4 is C(H)(R.sup.N)ONH.sub.2.

(318) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and R.sup.4 is C(H)(R.sup.8)ONH.sub.2.

(319) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is C(O)N(H)R.sup.70 or C(S)N(H)R.sup.70.

(320) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is C(O)N(H)R.sup.70 or C(S)N(H)R.sup.70, wherein R.sup.70 is phenyl substituted with one or two groups which are each independently halogen, C.sub.1-C.sub.6alkyl, COOH, NH.sub.2, SH, or OH.

(321) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is C(O)N(H)R.sup.70 or C(S)N(H)R.sup.70, wherein R.sup.70 is phenyl substituted with one or two groups which are each independently NH.sub.2, SH, or OH.

(322) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl- optionally substituted with one OR or N(R.sup.N).sub.2; and R.sup.5 is C(O)N(H)R.sup.70 or C(S)N(H)R.sup.70, wherein R.sup.70 is thiazolyl.

(323) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8.

(324) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2; and G.sup.4 is aryl or heteroaryl, each optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(325) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2; and G.sup.4 is phenyl optionally substituted with one or more groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(326) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2; and G.sup.4 is phenyl substituted with one or two groups which are each independently halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, or C.sub.1-C.sub.6 alkyl.

(327) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2; and G.sup.4 is a saturated or unsaturated heterocyclyl, each optionally substituted with one or more groups which are each independently R.sup.D, halogen, OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, OC(O)R, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl, or heterocyclyl.

(328) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- optionally substituted with one or more groups which are each independently OR, N(R.sup.N).sub.2, C(O)OR, C(O)N(R.sup.N).sub.2; and G.sup.4 is cyano, N(R.sup.N).sub.2, NR.sup.N(OH), OR, ONH.sub.2, C(O)OR, C(O)N(R.sup.N).sub.2, C(O)R, C(O)N(H)OH, N(H)C(O)NH.sub.2, or P(O)(OR).sub.2.

(329) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- substituted with one N(R.sup.N).sub.2, or C(O)OR.sub.2; and G.sup.4 is N(R.sup.N).sub.2, C(O)OR, or C(O)N(R.sup.N).sub.2.

(330) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.1-R.sup.5, wherein L.sup.1 is C.sub.1-C.sub.6alkyl-; and R.sup.5 is N(H)C(S)SR.sup.8, wherein R.sup.8 is -L.sup.2-G.sup.4, wherein L.sup.2 is C.sub.1-C.sub.6 alkyl- substituted with one N(R.sup.N).sub.2; and G.sup.4 is C(O)OR or C(O)N(R.sup.N).sub.2.

(331) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is C(O), S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), N(R.sup.N)C(O), O, S, N(R.sup.N), CH(R)O, CH(R)S, or CH(R)N(R.sup.N).

(332) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is C(O), S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), N(R.sup.N)C(O).

(333) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is C(O), S(O), S(O).sub.2, C(O)N(R.sup.N), C(O)O, C(O)S, OC(O), or N(R.sup.N)C(O).

(334) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is C(O) or S(O).sub.2.

(335) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is C(O)N(R.sup.N).

(336) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is O, S, or N(R.sup.N).

(337) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -Q-L.sup.1-R.sup.5, wherein Q is CH(R)O, CH(R)S, or CH(R)N(R.sup.N).

(338) In another embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.10-R.sup.50.

(339) In an embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is a bond and R.sup.50 is a group of the formula,

(340) ##STR00033##

(341) In another embodiment of the seventh aspect, the compound is according to formulae (VII), (VIIa) or (VIIb), and G.sup.1 is -L.sup.10-R.sup.50, wherein L.sup.10 is C.sub.1-C.sub.6alkyl- and R.sup.50 is a group of the formula,

(342) ##STR00034##

(343) In a eighth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (VIII); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VIII); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (VIII); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (VIII); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VIII); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (VIII),

(344) ##STR00035##

(345) or a pharmaceutically acceptable salt thereof, wherein

(346) bond a is a single or double bond;

(347) Y is O, S, or N(R.sup.10), wherein

(348) R.sup.10 is (i) hydrogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, or cyano; or (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl;

(349) Z is O, S, or N(R.sup.20), wherein

(350) R.sup.20 is hydrogen, C.sub.1-C.sub.6alkyl, C(O)R, C(O)OR, C(O)N(R).sub.2, S(O)R, or S(O).sub.2R;

(351) R.sup.1 is C.sub.1-C.sub.6alkyl-COOR, or aryl optionally substituted with halogen;

(352) R.sup.1a is hydrogen, COOR, or C(O)N(R).sub.2;

(353) R.sup.2 is hydrogen, C(O)R, or hydroxyl;

(354) R.sup.3 is hydrogen or hydroxyl; and

(355) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, aryl, or arylC.sub.1-C.sub.6alkyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl.

(356) In an embodiment of the eighth aspect, the compound is according to formulae (VIIIa),

(357) ##STR00036##

(358) and the remaining variables are as defined for formula (VIII).

(359) In a ninth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (IX); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IX); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (IX); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (IX); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IX); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (IX),

(360) ##STR00037##

(361) or a pharmaceutically acceptable salt thereof, wherein

(362) R is hydrogen or -L.sup.1-R.sup.1, wherein

(363) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR, or N(R.sup.N).sub.2; and

(364) R.sup.1 is hydrogen, cyano, nitro, NH.sub.2, NH(OH), OH, ONH.sub.2, C(O)OR, C(O)N(H)R, C(S)N(H)R, C(O)R, C(R.sup.D)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(S)R, N(H)C(O)OR, N(OH)C(O)R, OC(O)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O).sub.2R, S(O)OR, S(O).sub.2OR, S(O)N(R).sub.2, S(O).sub.2N(R).sub.2, N(H)S(O)R, N(H)S(O).sub.2R, P(O)(OR).sub.2, NHC(O)NHR, NHC(S)NHR, SC(S)N(R).sub.2, or N(R)C(S)SR,

(365) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(366) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(367) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl.

(368) In an tenth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of Formula (Xa, Xb, or Xc); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (Xa, Xb, or Xc); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (Xa, Xb, or Xc); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of Formula (Xa, Xb, or Xc); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (Xa, Xb, or Xc); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of Formula (Xa, Xb, or Xc),

(369) ##STR00038##

(370) or a pharmaceutically acceptable salt thereof, wherein

(371) R.sup.1 is, when present, hydrogen or C.sub.1-C.sub.6alkyl, and

(372) R is -L.sup.1-R.sup.1, wherein

(373) L.sup.1 is C.sub.1-C.sub.6alkyl-, C.sub.2-C.sub.6alkenyl-, C.sub.2-C.sub.6alkynyl-, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted with one or two groups which are independently phenyl, halogen, OR or N(R.sup.N).sub.2; and

(374) R.sup.1 is hydrogen, cyano, nitro, NH.sub.2, NH(OH), OH, ONH.sub.2, C(O)OR, C(O)N(H)R, C(S)N(H)R, C(O)R, C(R.sup.D)NH.sub.2, C(O)N(H)OH, N(H)C(O)R, N(H)C(S)R, N(H)C(O)OR, N(OH)C(O)R, OC(O)NH.sub.2, C(O)CF.sub.3, C(O)CH.sub.3, S(O)R, S(O)OR, S(O)N(R).sub.2, N(H)S(O)R, S(O).sub.2R, S(O).sub.2OR, S(O).sub.2N(R).sub.2, N(H)S(O).sub.2R, P(O)(OR).sub.2, NHC(O)NHR, NHC(S)NHR, SC(S)N(R).sub.2, or N(R)C(S)SR,

(375) each R is independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl or benzyl, wherein each of group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl;

(376) each R.sup.D is independently O, S, N(R.sup.N), N(OR), N(NH.sub.2), or N(CN); and

(377) each R.sup.N is independently (i) hydrogen; (ii) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, or benzyl, wherein each group is optionally substituted with one or more groups which are independently halogen, hydroxyl, C.sub.1-C.sub.6alkoxy, amino, carboxy, and carbamoyl; or (iii) formyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)OC.sub.1-C.sub.6alkyl, C(O)N(H)C.sub.1-C.sub.6alkyl, or S(O).sub.2C.sub.1-C.sub.6alkyl.

(378) In an eleventh aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount any compound listed in Tables 1-11; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of any compound listed in Tables 1-11; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of any compound listed in Tables 1-11; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and any compound listed in Tables 1-11; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of any compound listed in Tables 1-11; and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of any compound listed in Tables 1-11.

(379) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 1.

(380) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 2.

(381) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 3.

(382) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 4.

(383) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 5.

(384) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 6.

(385) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 7.

(386) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 8.

(387) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 9.

(388) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 10.

(389) In an embodiment of the eleventh aspect, the compound is any one compound listed in Table 11.

(390) TABLE-US-00001 TABLE 1 Cmpd # Structure Name 00001 phenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00002 0 4-methoxyphenethyl 2-(1H- indol-3- yl)ethylcarbamodithioate 00003 4-fluorophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00004 4-bromophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00006 2-phenylpropyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00007 3-bromophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00008 3-chlorophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00009 4-methylphenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00010 3-methoxyphenethyl 2-(1H- indol-3- yl)ethylcarbamodithioate 00012 2-fluorophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00020 3-methylphenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00021 0 2-chlorophenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00030 2-(1H-indol-3-yl)ethyl 2-(1H- indol-3- yl)ethylcarbamodithioate 00047 2-(3-methylnaphthalen-2- yl)ethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00053 2-(2,3- dihydrobenzo[b][l,4]dioxin-6- yl)ethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00062 naphthalen-2-ylmethyl 2-(2,3- dihydrobenzofuran-3- yl)ethylcarbamodithioate 00078 3-((1H-indol-3-yl)methyl)-2- thioxothiazolidin-4-one 00080 3-((1H-indol-3- yl)methyl)oxazolidine-2-thione 00239 2-(benzo[b]thiophen-3-yl)acetic acid 00288 2-(4-chloro-1H-indol-3- yl)acetamide 00293 2-(indolin-7-yl)acetic acid 00307 0 2-(benzo[b]thiophen-4-yl)acetic acid 00325 3-(5-amino-1H-indol-3- yl)propanoic acid 00327 3-(2-hydroxyethyl)-1H-indol-5- ol 00335 2-hydroxy-2-(1H-indol-3- yl)acetic acid 0352 5-amino-1H-indole-3- carboxylic acid 00386 N-hydroxy-3-(1H-indol-3- yl)propanamide 00388 N-hydroxy-2-(1H-indol-3- yl)acetamide 00390 N-hydroxy-2-(9H-pyrido[3,4- b]indol-9-yl)acetamide 00391 N-hydroxy-2-(8H- isothiazolo[5,4-b]indol-8- yl)acetamide 00392 N-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)-N- hydroxyacetamide 00552 0 1-(2(1H-indol-3-yl)ethyl)-3- hydroxy-2-methylpyridin- 4(1H)-one 00553 1-(3-(1H-indol-3-yl)propyl)-3- hydroxy-2-methylpyridin- 4(1H)-one 00554 1-((1H-indol-3-yl)methyl)-3- hydroxy-2-methylpyridin- 4(1H)-one 00555 1-(2-(benzo[b]thiophcn-3- yl)ethyl)-3-hydroxy-2- methylpyridin-4(1H)-one 00562 1-(2-(1H-indol-3-yl)ethyl)-3- hydroxypyridin-4(1H)-one 00563 1-(3-(1H-indol-3-yl)propyl)-3- hydroxypyridin-4(1H)-one 00564 1-((1H-indol-3-yl)methyl)-3- hydroxypyridin-4(1H)-one 00565 1-(3-(1H-indol-3-yl)propyl)-3- (thiazol-2-yl)thiourea 00566 5-(2-(1H-indol-3-yl)ethyl)-1- hydroxypyridin-2(1H)-one 00568 1-((1H-indol-3-yl)methyl)-3- (thiazol-2-yl)thiourea 00571 0 N-(3-(1H-indol-3-yl)propyl)-N- hydroxyacetamide 00577 N-(3-(1H-indol-3-yl)propyl)-2- hydroxybenzothioamide 00588 N-(2-aminophenyl)-4-(1H- indol-3-yl)butanamide 00589 1-(1H-indol-3-yl)-2- (methylamino)ethanol 00590 2-amino-1-(5-methoxy-1H- indol-3-yl)ethanol 00592 N-(2-aminophenyl)-3-(1H- indol-3-yl)propanamide 00596 N-((1H-indol-3- yl(methyl)benzothioamide 00601 5-(2-(1H-indol-3- yl)ethylidene)pyrimidine- 2,4,6(1H,3H,5H)-trione 00603 N-(2-(1H-indol-3-yl)ethyl)-N- hydroxyacetamide 00604 1,1,1-trifluoro-5-(1H-indol-3- yl)pentan-2-one 00606 0 2-(1H-indol-3-yl)ethanol 00611 N-((1H-indol-3-yl)methyl)-N- hydroxyacetamide 00613 6-(3-(1H-indol-3- yl)propyl)quinolin-8-ol 00630 5-(3-(1H-indol-3- yl)propylidene)pyrimidine- 2,4,6(1H,3H,5H)-trione 00632 N-(2-(benzo[b]thiophen-3- yl)ethyl)-2- hydroxybenzothioamide 00636 1-(2-(benzo[b]thiophen-3- yl)ethyl)-3-hydroxypyridin- 4(1H)-one 00637 1,1,1-trifluoro-4-(1H-indol-3- yl)butan-2-one 00644 N-(2-(1H-indol-3-yl)ethyl)-2- hydroxybenzothioamide 00646 N-((1H-indol-3-yl)methyl)-2- hydroxybenzothioamide 00655 5-((1H-indol-3- yl)methyl)quinolin-8-ol 00660 00 (E)-3-(1H-indol-3- yl)acrylimidamide 00667 01 5-(2-(1H-indol-3- yl)ethylidene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 00672 02 N-(2-(benzo[b]thiophen-3- yl)ethyl)-2- hydroxybenzothioamide 00673 03 N-(3-(1H-indol-3- yl)propyl)benzothioamide 00695 04 (E)-4-(1H-indol-3-yl)but-2- enimidamide 00717 05 4-(indolin-1-yl)butan-2-one 00725 06 1-(2-(1H-indol-3-yl)ethyl)-3- phenylthiourea 00729 07 (E)-5-(1H-indol-3-yl)pent-2- enimidamide 00737 08 3-(2,3-dioxoindolin-1- yl)propanoic acid 00739 09 N-(2-aminophenyl)-3- (benzo[b]thiophen-3- yl)propanamide 00741 0 (E)-3-(9H-pyrido[3,4-b]indol-9- yl)acrylimidamide 00745 3-(5-methyl-1H-indol-3- yl)propan-1-amine 00749 5-(3-(1H-indol-3- yl)propylidene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 00758 2-(5-methoxy-1H-indol-3- yl)acetic acid 00764 N-(2-(5-bromo-1H-indol-3- yl)ethyl)hydroxylamine 00789 2-(5-methylbenzo[b]thiophen- 3-yl)acetic acid 00796 2-(5-chlorobenzo[b]thiophen-3- yl)acetic acid 00813 N-(2-(benzo[b]thiophen-3- yl)ethyl)-N-hydroxyacetamide 00819 2-(1H-indol-1-yl)acetamide 00820 2-(3-(hydroxymethyl)-1H- indol-1-yl)acetic acid 00840 0 2-(5-bromo-1H-indol-3- yl)acetic acid 00843 2-(5-bromo-1H-indol-3- yl)acetamide 00850 (4S,5R)-3-((1H-indol-3- yl)methyl)-4-methyl-5- phenyloxazolidine-2-thione 00852 2-(1-methyl-1H-indol-3- yl)acetic acid 00872 4-(benzo[b]thiophen-3-yl)- 1,1,1-trifluorobutan-2-one 00882 5-((1H-indol-3- yl)methylene)pyrimidine- 2,4,6(1H,3H,5H)-trione 00888 5-(2-(1H-indol-3- yl)ethyl)quinolin-8-ol 00894 2-(5-bromo-1H-indol-3- yl)ethanol 00898 N-(2-aminophenyl)-2-(3- (thiazol-2-yl)-1H-indol-1- yl)acetamide 00924 3-((1H-indol-3-yl)methyl)-4,5- dimethylthiazole-2(3H)-thione 00931 0 N-(2-aminophenyl)-2-(8H- isothiazolo[5,4-b]indol-8- yl)acetamide 00940 N-(1-(9H-pyrido[3,4-b]indol-9- yl)ethyl)-N-hydroxyacetamide 00949 5-(2-(benzo[b]thiophen-3- yl)ethyl)quinolin-8-ol 00950 N-(2-(benzo[b]thiophen-3- yl)ethyl)benzothioamide 00952 (S)-3-((1H-indol-3-yl)methyl)- 4-isopropylthiazolidine-2- thione 00953 2-(3-formyl-1H-indol-1- yl)acetamide 00957 5-(2-(benzo[b]thiophen-3- yl)ethylidene)pyrimidine- 2,4,6(1H,3H,5H)-trione 00963 (E)-3-(1H-indol-3- yl)acrylonitrile 00989 5-(2-(benzo[b]thiophen-3- yl)ethylidene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 00998 N-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)-2- hydroxybenzothioamide 01001 0 2-(3-propionyl-1H-indol-1- yl)acetamide 01007 1-(2-(benzo[b]thiophen-3- yl)ethyl)-3-(thiazol-2- yl)thiourea 01009 1,1,1-trifluoro-3-(9H- pyrido[3,4-b]indol-9-yl)propan- 2-one 01015 5-((1H-indol-3-yl)methylene)- 2-thioxodihydropyrimidine- 4,6(1H,5H)-dione 01017 N-hydroxy-2-(3-(thiazol-2-yl)- 1H-indol-1-yl)acetamide 01027 (E)-4-(benzo[b]thiophen-3- yl)but-2-enimidamide 01043 1-(2-(benzo[b]thiophen-3- yl)ethyl)-3-phenylthiourea 01048 1-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)-3-phenylthiourea 01060 2-(6-cyano-1H-indol-1- yl)acetamide 01063 1-(benzo[b]thiophen-3- ylmethyl)urea 01087 0 N-((9H-pyrido[3,4-b]indol-9- yl)methyl)benzothioamidc 01091 methyl 2-(1-methyl-1H-indol-3- yl)ethylcarbamodithioate 01094 1-((9H-pyrido[3,4-b]indol-9- yl)methyl)-3-hydroxypyridin- 4(1H)-one 01114 5-((3-(thiazol-2-yl)-1H-indol-1- yl)methyl)quinolin-8-ol 01119 2-(3-cyano-1H-indol-1- yl)acetamide 01120 1-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)-3-(thiazol-2- yl)thiourea 01125 1-hydroxy-5-((3-(thiazol-2-yl)- 1H-indol-1-yl)methyl)pyridin- 2(1H)-one 01127 N-(2-aminophenyl)-2-(9H- pyrido[3,4-b]indol-9- yl)acetamide 01128 (E)-4-(benzo[b]thiophen-3- yl)but-2-enenitrile 01133 N-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)benzothioamide 01135 0 5-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)quinolin-8-ol 01143 2-hydroxy-N-((3-(thiazol-2-yl)- 1H-indol-1- yl)methyl)benzothioamide 01153 2-(3-formyl-2-methyl-1H-indol- 1-yl)acetamide 01165 3-hydroxy-1-((3-(thiazol-2-yl)- 1H-indol-1-yl)methyl)pyridin- 4(1H)-one 01169 (E)-3-(9H-pyrido[3,4-b]indol-9- yl)acrylonitrile 01183 1-((8H-isothiazolo[5,4-b]indol- 8-yl)methyl)-3-hydroxypyridin- 4(1H)-one 01185 (E)-3-(3-(thiazol-2-yl)-1H- indol-1-yl)acrylonitrile 01188 N-hydroxy-N-((3-(thiazol-2-yl)- 1H-indol-1- yl)methyl)acetamide 01190 4-((8H-isothiazolo[5,4-b]indol- 8-yl(methyl)-1-hydroxypyridin- 2(1H)-one 01200 5-((9H-pyrido[3,4-b]indol-9- yl)methyl)-1-hydroxypyridin- 2(1H)-one 01206 0 methyl 2-(1-(2-methoxyethyl)- 1H-indol-3- yl)ethylcarbamodithioate 01214 methyl 2-(1-benzyl-1H-indol-3- yl)ethylcarbamodithioate 01219 N-((3-(thiazol-2-yl)-1H-indol- 1-yl)methyl)benzothioamide 01228 methyl 2-(1-isopropyl-1H- indol-3-yl)- ethylcarbamodithioate 01230 5-((8H-isothiazolo[5,4-b]indol- 8-yl)methylene)pyrimidine- 2,4,6(1H,3H,5H)-trione 01232 5-((3-(thiazol-2-yl)-1H-indol-1- yl)methylene)pyrimidine- 2,4,6(1H,3H,5H)-trione 01233 (E)-3-(3-(thiazol-2-yl)-1H- indol-1-yl)acrylimidamide 01235 (E)-3-(8H-isothiazolo[5,4- b]indol-8-yl)acrylimidamide 01238 1,1,1-trifluoro-3-(3-(thiazol-2- yl)-1H-indol-1-yl)propan-2-one 01241 5-((3-(thiazol-2-yl)-1H-indol-1- yl)methylene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 01244 0 1,1,1-trifluoro-3-(8H- isothiazolo[5,4-b]indol-8- yl)propan-2-one 01246 5-((2-((1Z,3Z)-penta-1,3- dienyl)-1H-pyrrolo[2,3- c]pyridin-1-yl)methyl)quinolin- 8-ol 01247 1-(thiazol-2-yl)-3-((3-(thiazol- 2-yl)-1H-indol-1- yl)methyl)thiourea 01249 (E)-3-(8H-isothiazolo[5,4- b]indol-8-yl)acrylonitrile 01254 5-((8H-isothiazolo[5,4-b]indol- 8-yl)methylene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 01256 methyl 2-(1-cyclopentyl-1H- indol-3-yl)- ethylcarbamodithioate 01258 -((9H-pyrido[3,4-b]indol-9- yl)methyl)-3-(thiazol-2- yl)thiourea 01259 1-((9H-pyrido[3,4-b]indol-9- yl)methyl)-3-phenylthiourea 01260 (S)-2-amino-3-((2R,3R)-2- hydroperoxyindolin-3- yl)propanoic acid 01261 (S)-2-amino-3-((2R,3S)-2- hydroperoxyindolin-3- yl)propanoic acid 01262 0 (S)-2-amino-3-((2S,3R)-2- hydroperoxyindolin-3- yl)propanoic acid 01263 (S)-2-amino-3-((2S,3S)-2- hydroperoxyindolin-3- yl)propanoic acid 01264 (S)-2-amino-3-((2S,3S)-2- cyanoindolin-3-yl)propanoic acid 01265 (S)-2-amino-3-((2R,3R)-2- cyanoindolin-3-yl)propanoic acid 01266 (S)-2-amino-3-((2S,3R)-2- cyanoindolin-3-yl)propanoic acid 01267 (S)-2-amino-3-((2R,3S)-2- cyanoindolin-3-yl)propanoic acid 01268 (S)-2-amino-3-((R)-3- cyanoindolin-3-yl propanoic acid 01269 (S)-2-amino-3-((S)-3- cyanoindolin-3-yl)propanoic acid 01270 (S)-2-amino-3-((S)-3- hydroperoxyindolin-3- yl)propanoic acid 01271 (S)-2-amino-3-((R)-3- hydroperoxyindolin-3- yl)propanoic acid 01274 00 2-amino-3-(2- (hydroxymethyl)indolin-3- yl)propanoic acid 01275 01 2-amino-3-(3- (hydroxymethyl)indolin-3- yl)propanoic acid 01277 02 (2S)-2-amino-3-(2,3- dihydroxyindolin-3- yl)propanoic acid 01278 03 (2S)-2-amino-3-(3-hydroxy-2- oxoindolin-3-yl)propanoic acid 01279 04 2-amino-3-(2-(hydroxyamino)- 1H-indol-3-yl)propanoic acid 01280 05 2-amino-3-(2-(hydroxyamino)- 1-methyl-1H-indol-3- yl)propanoic acid 01281 06 2-amino-3-(2- (hydroxyamino)indolin-3- yl)propanoic acid 01282 07 2-amino-3-(2-(hydroxyamino)- 1-methylindolin-3-yl)propanoic acid 01283 08 (Z)-2-amino-3-(2- (hydroxyimino)indolin-3- yl)propanoic acid 01284 09 (Z)-2-amino-3-(2- (hydroxyimino)-1- methylindolin-3-yl)propanoic acid 01285 0 2-amino-3-(2-(aminooxy)-1H- indol-3-yl(propanoic acid 01286 2-amino-3-(2-(aminooxy)-1- methyl-1H-indol-3- yl)propanoic acid 01287 2-amino-3-(2- (aminooxy)indolin-3-yl)- propanoic acid 01288 2-amino-3-(2-(aminooxy)-1- methylindolin-3-yl)propanoic acid 01291 2-amino-3-(2- (methoxymethoxy)-1H-indol-3- yl)propanoic acid 01292 2-amino-3-(2- (methoxymethoxy)-1-methyl- 1H-indol-3-yl)propanoic acid 01293 N-hydroxy-3-(1H-indol-2- yl)propanamide 01294 N-hydroxy-3-(indolin-2- yl)propanamide 01295 N-(2-(1H-indol-2-yl)ethyl)-N- hydroxyacetamide 01296 N-hydroxy-N-(2-(indolin-2- yl)ethyl)acetamide 01298 0 methyl 3-(indolin-2-yl)propyl- carbamodithioate 01299 N-hydroxy-3-(1H-indol-1- yl)propanamide 01300 N-hydroxy-3-(indolin-1- yl)propanamide 01301 N-(2-(1H-indol-1-yl)ethyl)-N- hydroxyacetamide 01302 N-hydroxy-N-(2-(indolin-1- yl)ethyl)acetamide 01305 3-(1H-indol-3- yl)propane(thioperoxoic)O- acid 01306 SO-methyl 3-(1H-indol-3- yl)propane(thioperoxoate) 01307 SO-2-(1H-indol-3-yl)ethyl ethane(thioperoxoate) 01308 S-(3-(1H-indol-3- yl)propanoyl)- thiohydroxylamine 01309 N-(2-(1H-indol-3-yl)ethyl)-S- acetylthiohydroxylamine 01310 0 dimethyl 4-(1H-indol-3-yl)-2- oxobutylphosphonate 01361 (S)-2-amino-3-((2R,3R)-2-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01362 (2S)-2-amino-3-((3S)-2,3- dihydroxyindolin-3- yl)propanoic acid 01364 (S)-2-amino-3-((2R,3S)-2- (hydroxylmethyl)indolin-3- yl)propanoic acid 01367 1-(2-(1H-indol-3-yl)ethyl)-5- hydroxy-2-methylpyridin- 4(1H)-one 01370 (S)-2-amino-3-((S)-3- (hydroxylmethyl)indolin-3- yl)propanoic acid 01371 (S)-2-amino-3-((2R,3R)-2- (hydroxylmethyl)indolin-3- yl)propanoic acid 01372 (S)-2-amino-3-((2S,3R)-2- (hydroxylmethyl)indolin-3- yl)propanoic acid 01373 (S)-2-amino-3-((2R,3S)-2-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01374 (S)-2-amino-3-((2S,3S)-2- (hydroxylmethyl)indolin-3- yl)propanoic acid 01375 0 (S)-2-amino-3-((2S,3R)-2-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01376 (S)-2-amino-3-((2S,3S)-2-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01378 (S)-2-amino-3-((S)-3-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01379 (S)-2-amino-3-((R)3-(2- hydroxyethyl)indolin-3- yl)propanoic acid 01382 (S)-2-amino-3-((S)-3-hydroxy- 2-oxoindolin-3-yl)propanoic acid 01383 (S)-2-amino-3-((R)3-hydroxy- 2-oxoindolin-3-yl)propanoic acid 01387 1-(3-(1H-indol-3-yl)propyl)-5- hydroxy-2-methylpyridin- 4(1H)-one 01391 2-amino-3-(1H-indol-2- yl)propanoic acid 01392 naphthalen-2-ylmethyl (2,3- dihydrobenzofuran-3- yl)methylcarbamodithioate 01403 2-amino-3-(indolin-2- yl)propanoic acid 01418 0 2-amino-3-(3-(hydroxymethyl)- 1-methylindolin-3-yl)propanoic acid 01419 2-amino-3-(3-(hydroxymethyl)- 3H-indol-3-yl)propanoic acid 01424 2-(7-methyl-2-oxo-2H- chromcn-3-yl)ethyl 2-(1H- indol-3- yl)ethylcarbamodithioate 01438 2-amino-3-(1-hydroxy-2- oxoindolin-3-yl)propanoic acid 01443 1-((1H-indol-3-yl)methyl)-5- hydroxy-2-methylpyridin- 4(1H)-one 01444 2-amino-3-(1H-indol-1- yl)propanoic acid 01445 2-amino-3-(indolin-1- yl)propanoic acid 01446 methyl 3-(1H-indol-1- yl)propylcarbamodithioate 01447 methyl 3-(indolin-1-yl)propyl- carbamodithioate

(391) TABLE-US-00002 TABLE 2 Cmpd # Structure Name 00523 ethyl 1,1-dimethyl-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylate 00525 0 1-(pentan-3-yl)-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylic acid 00526 3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole-3- carboxylic acid 00527 (S)-methyl 2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylate 00528 (S)-ethyl 2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole-3- carboxylate 00530 (S)-1-methyl-4,9-dihydro- 3H-pyrido[3,4-b]indole-3- carboxylic acid 00531 (1R,3R)-methyl 1- (benzo[d][1,3]dioxol-5-yl)- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-3- carboxylate 00532 methyl 1-p-tolyl-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylate 00533 1-(3- (trifluoromethyl)phenyl)- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-3- carboxylic acid 00535 1-(2-bromo-5-(pyridin-2- ylmethoxy)phenyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-3-carboxylic acid 00539 3,4-dihydropyrano[3,4- b]indol-1(9H)-one 00541 0 l-methyl-4,9-dihydro-3H- pyrido[3,4-b]indol-6-ol 00545 1-(3,4-dimethoxyphenyl)-6- methoxy-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 00546 1-phenyl-4,9-dihydro-3H- pyrido[3,4-b]indole 00549 3-allyl-2- mercaptobenzofuro[3,2- d]pyrimidin-4(3H)-one 00550 2-(4-oxobenzofuro[3,2- d]pyrimidin-3(4H)-yl)acetic acid 01272 2-amino-3-(2,2a,3,7b- tetrahydrooxeto[3,2-b]indol- 7b-yl)propanoic acid 01273 2-amino-3-(2,2a,7,7a- tetrahydrooxeto[2,3-b]indol- 2a-yl)propanoic acid 01276 3a,8a-dihydroxy- 1,2,3,3a,8,8a- hexahydropyrrolo[2,3- b]indole-2-carboxylic acid 01289 2,3,4,9-tetrahydro- [1,2]oxazino[6,5-b]indole-3- carboxylic acid 01290 9-methyl-2,3,4,9-tetrahydro- [1,2]oxazino[6,5-b]indole-3- carboxylic acid 01311 0 dimethyl 2-oxo-2,3,4,9- tetrahydro-1H-carbazol-1- ylphosphonate 01365 (2S)-2-amino-3-((7bS)-3,7b- dihydro-2aH- [1,2]dioxeto[3,4-b]indol-7b- yl)propanoic acid 01366 3,3a,8,8a-tetrahydro-2H- furo[2,3-b]indole 01368 (S)-2-amino-3-((3aR,8bS)- 3,3a,4,8b-tetrahydro-1H- furo[3,4-b]indol-8b- yl)propanoic acid 01369 (S)-2-amino-3-((3aS,8aS)- 3,3a,8,8a-tetrahydro-2H- furo[2,3-b]indol-3a- yl)propanoic acid 01380 (S)-2-amino-3-((3aS,8bS)- 4,8b-dihydro-3aH- [1,3]dioxolo[4,5-b]indol-8b- yl)propanoic acid 01381 (2S,3aR,8aS)-3a,8a- dihydroxy-1,2,3,3a,8,8a- hexahydropyrrolo[2,3- b]indole-2-carboxylic acid 01385 (2S,3aS,8aR)-3a,8a- dihydroxy-1,2,3,3a,8,8a- hexahydropyrrolo[2,3- b]indole-2-carboxylic acid 01388 sodium 2-oxo-1,2- dihydrobenzofuro[2,3-d]- pyrimidin-4-olate 01390 (2S)-2-amino-2- (2,3,4,4a,9,9a- hexahydropyrano[2,3- b]indol-4-yl)acetic acid 01410 0 3,3a,8,8a-tetrahydro-2H- furo[2,3-b]indol-2-one 01413 (2S)-2-amino-2-(3,3a,8,8a- tetrahydro-2H-furo[2,3- b]indol-3-yl)acetic acid 01425 (2S)-2-amino-2-((3aR,8aS)- 3a-hydroxy-3,3a,8,8a- tetrahydro-2H-furo[2,3- b]indol-3-yl)acetic acid 01427 (2S)-2-amino-2-((4aR,9aS)- 4a-hydroxy-2,3,3,4a,9,9a- hexahydropyrano[2,3- b]indol-4-yl)acetic acid 01429 6-methoxy-4,9-dihydro-1H- pyrido[3,4-b]indol-3(2H)- one 01430 (2R)-2-amino-2- (l,3,4,4a,5,9b- hexahydrothiopyrano[4,3- b]indol-1-yl)acetic acid 01431 6-methoxy-4,9-dihydro-1H- pyrido[3,4-b]indol-3(2H)- one 01432 4,9-dihydro-1H-pyrido[3,4- b]indole-1,3(2H)-dione 01433 pyrano[3,4-b]indole- 1,3(4H,9H)-dione 01434 (3S)-3-amino-3,3a,8,8a- tetrahydro-2H-furo[2,3- b]indol-2-one 01448 00 (S)-2-amino-3-((3aS,8bS)- 3,3a,4,8b-tetrahydro-2H- furo[3,2-b]indol-8b- yl)propanoic acid 01449 01 2,3,4,4a,5,9b- hexahydropyrano[3,2- b]indole 01458 02 (S)-2-amino-3-((2aS,7bS)- 2,2a,3,7b- tetrahydrooxeto[3,2-b]indol- 7b-yl)propanoic acid 01459 03 2,3,4,4a,9,9a- hexahydropyrano[2,3- b]indole 01460 04 (2S)-2-amino-2- (1,3,4,4a,5,9b- hexahydropyrano[4,3- b]indol-1-yl)acctic acid 01461 05 1,3,4,4a,5,9b- hexahydropyrano[4,3- b]indole 01470 06 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1-one 01479 07 (S)-2-amino-3-((2aR,7aS)- 2,2a,7,7a- tetrahydrooxeto[2,3-b]indol- 2a-yl)propanoic acid 01490 08 1,3,4,4a,5,9b- hexahydrothiopyrano[4,3- b]indole

(392) TABLE-US-00003 TABLE 3 Cmpd # Structure Name 01363 09 (2S,4S)-4-amino-3H- spiro[furan-2,3-indoline]- 2,5(4H)-dione 01377 0 (2R,4S)-4-amino-3H- spiro[furan-2,3-indoline]- 2,5(4H)-dione 01402 4,5-dihydro-2H-spiro[furan- 3,3-indole]-5-carboxylic acid 01414 1-hydroxyspiro[indole-3,3- pyrrolidine]-5-carboxylic acid 01417 4,5-dihydro-2H- spiro[indole-3,3-thiophene]- 5-carboxylic acid 01439 (S)-2-thioxospiro[indoline- 3,5-oxazolidin]-2-one 01451 (S)-2-thioxospiro[indoline- 3,5-thiazolidin]-2-one 01452 1-hydroxyspiro[indoline- 3,3-pyrrolidine]-5- carboxylic acid 01455 spiro[indoline-3,3- pyrrolidin]-2-one 01456 4,5-dihydro-2H-spiro[furan- 3,3-indolin]-2-one 01457 spiro[indoline-3,2-oxiran]- 2-one 01462 0 3H-spiro[furan-2,3- indoline] 01463 1,2- dihydrodispiro[cyclopentane- 1,2-oxirane-3,3-indole] 01464 (S)-spiro[indoline-3,5- oxazolidine]-2,2-dione 01471 l-methyl-4,5-dihydro-2H- spiro[indoline-3,3- thiophene]-5-carboxylic acid 01472 1-methyl-4,5-dihydro-2H- spiro[furan-3,3-indoline]-5- carboxylic acid 01473 1,1-dimethylspiro[indoline- 3,3-pyrrolidine]-5- carboxylic acid 01474 1-hydroxy-1- methylspiro[indoline-3,3- pyrrolidine]-5-carboxylic acid 01475 4,5-dihydro-2H- spiro[indoline-3,3- thiophene]-5-carboxylic acid 01476 4,5-dihydro-2H-spiro[furan- 3,3-indoline]-5-carboxylic acid 01489 1-methylspiro[indole-3,3- pyrrolidine]-5-carboxylic acid 01491 0 1-methylspiro[indoline-3,3- pyrrolidine]-5-carboxylic acid

(393) TABLE-US-00004 TABLE 4 Cmpd # Structure Name 00218 4,5-bis (2-hydroxyethylthio)- 1,3-dithiol-2-one 00738 3-(3-methyl-2-oxo-2,3- dihydro-1H- benzo[d]imidazol-1- yl)propanoic acid 01069 4,5-dihydroxy-1,3- bis(hydroxylmethyl)- imidazolidin-2-one 01110 4,5-dihydroxy-1,3- bis(methoxymethyl)- imidazolidin-2-one 01129 4,5-bis (2-aminoethylthio)- 1,3-dithiole-2-thione 01160 4-hydroxy-1,3- bis(hydroxymethyl) -5- methoxyimidazolidin- 2-one 01181 1-ethyl-3-propyl-1H- benzo[d]imidazol- 2(3H)- imine 01192 3,3-(2-oxo- 1,3-dithiole-4,5- diyl)bis- (sulfanediyl) dipropanenitrile 01202 1-tert-butyl- 4,5-dihydroxy- 3-methylimidazolidin- 2-one 01222 0 4,5-dihydroxy-1- (hydroxymethyl)-3- (methoxymethyl) imidazolidin- 2-one 01237 4,6-diethyldihydro- 3aH- [1,3]dioxolo [4,5-d]imidazol- 5(4H)-one 01242 6-hydroxy-6,7- dihydro-5H- [1,3]dithiolo[4,5- b][1,4]dithiepin- 2-one 01245 6,7-dihydro-5H- [1,3]dithiolo[4,5-b] [1,4]dithiepin-2-one 01251 5,6,7,8-tetrahydro- [1,3]dithiolo[4,5- b][1,4]dithiocine- 2-thione 01252 5,6-dihydro- [1,3]dithiolo[4,5- b][1,4]dithiin-2-one 01420 1-butyl-3- hydroxy-1H- benzo[d]imidazol- 2(3H)-one 01421 1-hydroxy-3- methyl-1H- benzo[d]imidazol- 2(3H)-one 01422 1,3-dihydroxy- 1H- benzo[d]imidazol- 2(3H)-one

(394) TABLE-US-00005 TABLE 5 Cmpd # Structure Name 00157 (E)-5-(thiophen-2- ylmethylene)-2- thioxoimidazolidin-4-one 00209 0 2-(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)acetamide 00214 N-benzyl-3-nitro-1H- pyrazole-5-carboxamide 00217 (2-(allylthio)-1-(3- fluorobenzyl)-1H-imidazol- 5-yl)methanol 00219 (E)-2-(1-(thiophen-2- yl)ethylideneaminooxy) acetamide 00224 (1,3-dimethyl-1H- thieno[2,3-c]pyrazol-5- yl)methanol 00225 2-(1H- benzo[d][1,2,3]triazol-1- yl)acetamide 00233 2-(thiophen-2- ylsulfonyl)acetamide 00240 2-(2-hydroxy-1H- benzo[d]imidazol-1-yl)- acetamide 00268 3-(2-amino-2- oxoethyl)benzo[d]thiazol-3- ium chloride 00379 3,3-bithiophene-4,4- diyldimethanol 00593 0 2-(2-phenylthiophen-3- yl)acetic acid 00599 3-amino-3-(5- methylthiophen-2- yl)propanoic acid 00602 3-amino-3-(5-methylfuran- 2-yl)propanoic acid 00621 4-amino-3-(5- chlorothiophen-2- yl)butanoic acid 00649 N-(2-mercaptophenyl)furan- 2-carboxamide 00650 3-(thiophen-2-yl)propanoic acid 00668 2-(2-(allylthio)-1H- benzo[d]imidazol-1- yl)acetic acid 00671 N-(2-amino-5- methoxyphenyl)furan-2- carboxamide 00697 2-(1H- benzo[d][1,2,3]triazol-1-yl)- 2-hydroxyacetic acid 00722 N-(5-methoxy-2- methylphenyl)thiophene-2- carboxamide 00753 0 3-(1-methyl-1H-pyrazole-5- carboxamido)propanoic acid 00761 N-(5-chloro-2- methylphenyl)thiophene-2- carboxamide 00781 2-(1-benzyl-1H-imidazol-2- ylthio)acetic acid 00791 2-hydroxy-N- ((4-phenyl-1H-imidazol-1- yl)methyl)benzothioamide 00828 (1-pentyl-1H- benzo[d]imidazol-2- yl)methanol 00835 2-(thiophen-2- ylthio)acetamide 00836 3-nitro-N-(pyridin-2-yl)-1H- pyrazole-5-carboxamide 00855 2-(2-methyl-4,5,6,7- tetrahydro-2H-indazol-3- yl)acetic acid 00857 2-(2-methyl-4-nitro-1H- imidazol-1-yl)acetamide 00861 methyl 3-amino-3- (thiophen-2-yl)propanoate 00867 0 N-(3-methylpyridin-4- yl)thiophene-2-carboxamide 00868 2-(thieno[2,3-d]pyrimidin-4- ylamino)ethanol 00870 5-((4-phenyl-1H-imidazol- l-yl)methyl)quinolin-8-ol 00874 2-(2-(hydroxymethyl)-1H- benzo[d]imidazol-1- yl)ethanol 00883 N-(2-aminophenyl)-4- phenyl-1H-imidazole-1- carboxamide 00887 1,2-diamino-3-(2- hydroxyethyl)-1H- benzo[d]imidazol-3-ium chloride 00891 (1-isobutyl-1H- benzo[d]imidazol-2-yl)- methanol 00892 2-(5-methyl-3-nitro-1H- pyrazol-1-yl)acetamide 00897 5-nitro-N-(pyridin-2- yl)furan-2-carboxamide 00906 1-(1-(2-methylallyl)-1H- benzo[d]imidazol-2- yl)ethanol 00910 0 1-(1-methyl-1H- benzo[d]imidazol-2- yl)ethanamine 00913 3-(3,5-dimethyl-4-nitro-1H- pyrazol-1-yl)propanoic acid 00916 6-(2-hydroxyethylamino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one 00918 (E)-2-(1-(thiophen-2- yl)ethylideneaminooxy)acetic acid 00921 2-(5-methyl-4-nitro-1H- pyrazol-1-yl)acetic acid 00927 (1-(2-methylallyl)-1H- benzo[d]imidazol-2- yl)methanol 00930 (1-(2-ethoxyethyl)-1H- benzo[d]imidazol-2- yI)methanol 00944 2-(6-amino-9H-purin-9- yl)ethanol 00959 3-(1-benzyl-1H-imidazol-2- ylthio)propanenitrile 00961 (1-allyl-1H- benzo[d]imidazol-2-yl)- methanol 00965 00 (1-propyl-1H- benzo[d]imidazol-2-yl)- methanol 00977 01 2-(5-amino-2- (hydroxymethyl)-1H-benzo- [d]imidazol-1-yl)ethanol 00979 02 1-(1-allyl-1H- benzo[d]imidazol-2-yl)- ethanol 00981 03 2-(2-propyl-1H- benzo[d]imidazol-1-yl)- acetamide 00999 04 2-(2-methyl-1H- benzo[d]imidazol-1-yl)- ethanol 01004 05 (E)-3-(4-phenyl-1H- imidazol-1-yl)acrylonitrile 01008 06 N-((4-phenyl-1H-imidazol- 1-yl )methyl)benzothioamide 01012 07 (1-(prop-2-ynyl)-1H- benzo[d]imidazol-2- yl)methanol 01018 08 2-(1-propyl-1H- benzo[d]imidazol-2-yl)- acetic acid 01021 09 2-(1H-benzo[d]imidazol-1- yl)ethanol 01034 0 2-(5-methyl-3,4-dinitro-1H- pyrazol-1-yl)acetic acid 01045 5-((4-phenyl-1H-imidazol- 1-yl)methylene)pyrimidine- 2,4,6(1H,3H,5H)-trione 01057 2-(3-(difluoromethyl)-5- methyl-4-nitro-1H-pyrazol- 1-yl)acetic acid 01064 N-(5-methylisoxazol-3- yl)thiophene-2-carboxamide 01071 2-(1H-benzo[d]imidazol-1- yl)acetamide 01078 2-(2-(methylamino)-1H- benzo[d]imidazol-1- yl)ethanol 01115 2-(methyl(7- methylthieno[3,2- d]pyrimidin-4- yl)amino)ethanol 01124 2-(ethyl(1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)amino)ethanol 01142 5-((4-phenyl-1H-imidazol- 1-yl)methylene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 01146 2-(1H-imidazol-5-yl)ethyl carbamimidothioate 01147 0 2-(4-chloro-5-methyl-3- nitro-1H-pyrazol-1- yl)acetamide 01159 1 -phenyl-3-((4-phenyl-1H- imidazol-1- yl)methyl)thiourea 01171 9-(2-hydroxyethyl)-3H- purine-6(9H)-thione 01173 1-((4-phenyl-1H-imidazol- 1-yl)methyl)-3-(thiazol-2- yl)thiourea 01179 2-(4-cyano-5-methyl-3- nitro-1H-pyrazol-1- yl)acetamide 01191 (1-methyl-3- (trifluoromethyl)-1H-thieno- [2,3-c]pyrazol-5- yl)methanol 01205 2-(4-acetyl-5-methyl-1H- 1,2,3-triazol-1-yl)acetamide 01225 2-(4-bromo-5-methyl-3- nitro-1H-pyrazol-1- yl)acetamide 01234 (2,2-dibromo-3,3- bithiophene-4,4-diyl)- dimethanol 01255 3-(carboxymethyl)-2,4- dimethylbenzo[d]thiazol-3- ium chloride 01440 0 N-hydroxy-4-(4,5,6,7- tetrahydro-1H-indol-3- yl)butanamide 01442 N-hydroxy-N-(3-(4,5,6,7- tetrahydro-1H-indol-3- yl)propyl)acetamide

(395) TABLE-US-00006 TABLE 6 Cmpd # Structure Name 00155 (E)-5-((4,6- dimethylpyrimidin-2- ylamino)methylene)-2- thioxoimidazolidin-4-one 00220 2-(quinazolin-4- ylthio)acetamide 00662 2-(quinolin-4- ylamino)acetic acid 00678 N-(3-hydroxyphenyl) nicotinamide 00687 5-oxo-5-(pyridin-3- ylamino)pentanoic acid 00699 3-(nicotinamido)propanoic acid 00732 3-(2-chloronicotinamido) propanoic acid 00766 N-(2-hydroxyphenyl) nicotinamide 00767 0 N-(5-amino-2- methylphenyl)nicotinamide 00772 2-(quinolin-2-yl)ethanol 00787 2-(quinazolin-4- ylamino)ethanol 00809 N-(2-chloropyridin-3- yl)isonicotinamide 00834 N-(6-methylpyridin-2- yl)nicotinamide 00902 N-(2,5- dichlorophenyl)isonicotinamide 00929 (R)-1-(2-amino-4- methylquinolin-3-yl)ethanol 00955 1-(quinazolin-4- ylthio)propan-2-one 00960 2-(4-nitropyridin-3- ylamino)ethanol 00967 4-(hydroxymethyl)quinolin-3-ol 01011 0 2-(quinazolin-4- yloxy)acetamide 01016 1-(2-amino-2- oxoethyl)quinolinium chloride 01066 N-(4H-1,2,4-triazol-4- yl)isonicotinamide 01089 2-chloro-N-(4H-1,2,4- triazol-4-yl)nicotinamide 01141 5-(pyridin-4- ylmethyl)thiazolidine- 2,4-dione 01199 3-amino-1-(2-amino-2- oxoethyl)quinolinium chloride

(396) TABLE-US-00007 TABLE 7 Cmpd # Structure Name 00077 3-benzyl-1,3-thiazinane-2- thione 00079 3-benzyl-2- thioxothiazolidin-4-one 00081 3-benzyloxazolidine-2- thione 00138 2-amino-3- (benzylcarbamothioylthio)- propanoic acid 00140 0 2-amino-3-(3-phenylpropyl- carbamo- thioylthio)propanoic acid 00148 (Z)-5-(benzo[d][1,3]dioxol- 5-ylmethylene)-2- thioxothiazolidin-4-one 00150 (Z)-5-(4- (dimethylamino)benzylidene)- 2-thioxo-1,3-thiazinan-4- one 00154 (E)-5-((4-oxo-4H-chromen- 3-yl)methylene)-2- thioxoimidazolidin-4-one 00221 5-(4-fluorobenzyl)-2- iminothiazolidin-4-one 00261 3-(2,5- dimethylphenyl)butanoic acid 00262 5-(4- hydroxybenzyl)imidazolidine- 2,4-dione 00282 3-(3-nitrophenyl)butanoic acid 00291 2-(2-methyl-1-oxo-1,2- dihydroisoquinolin-4- yl)acetic acid 00292 2-(4-hydroxy-3- methoxyphenyl)- acetimidamide 00313 0 3-(4-fluorophenyl)-3- oxopropanoic acid 00317 O-(3- nitrobenzyl)hydroxylamine 00346 2-(6- propylbenzo[d][1,3]dioxol- 5-yl)acetic acid 00360 N-(3,4-dichlorophenyl)-3- hydroxypropanamide 00389 1-hydroxy-4- phenethylpyridin-2(1H)-one 00394 2-(4-iminoquinolin-1(4H)- yl)acetamide 00567 3-amino-3-(naphthalen-1- yl)propanoic acid 00572 (Z)-2-(3- hydroxybenzylidene)- hydrazinecarboximidamide 00587 (Z)-2-(4-hydroxy-3- methoxybenzylidene)- hydrazinecarboximidamide 2-(2-(1H-pyrrol-1- yl)phenyl)acetate 00591 1-(naphthalen-2-ylmethyl)- 3-(thiazol-2-yl)thiourea 00607 0 2-hydroxy-N-(naphthalen-2- ylmethyl)benzothioamide 00616 (E)-2-(2-hydroxy-5- nitrobenzylidene)- hydrazinecarboximidamide 00620 1-(benzhydryloxy)guanidine 00627 4-fluoro-N-(2- mercaptophenyl)benzamide 00634 2-hydroxy-N- phenethylbenzothioamide 00656 N-benzyl-2- hydroxybenzothioamide 00657 1-(naphthalen-2-ylmethyl)- 3-phenylthiourea 00664 5-benzylquinolin-8-ol 00665 (Z)-2-(4-hydroxy-3- iodobenzylidene)- hydrazinecarboximidamide 00683 3-(4- fluorobenzamido)propanoic acid 00686 0 N-(5-methoxy-2- methylphenyl)benzamide 00688 1-phenethyl-3-(thiazol-2- yl)thiourea 00689 5-oxo-5-phenylpentanoic acid 00691 3-(2,4- difluorophenoxy)propanoic acid 00698 5-benzyl-1-hydroxypyridin- 2(1H)-one 00711 3-(2,5- dimethoxyphenylamino) propanoic acid 00720 3-(2- chlorobenzamido)propanoic acid 00721 2-(benzoylthio)acetic acid 00724 4-amino-3-(3,4- dihydroxyphenyl)butanoic acid 00744 (E)-2-(2-hydroxy-3- nitrobenzylidene) hydrazinecarboxamide 00748 00 (1E,2E)-N-hydroxy-2-(3- nitro-benzylidene) hydrazinecarboximidamide 00752 01 3-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yloxy)propanoic acid 00755 02 2-amino-1- (benzo[d][1,3]dioxol-5-yl)- ethanol 00760 03 O-(4- carboxybenzyl)hydroxylamine 00762 04 O-(3- fluorobenzyl)hydroxylamine 00773 05 3-(4- chlorophenoxy)propanoic acid 00774 06 O-(4- fluorobenzyl)hydroxylamine 00775 07 2-(2- carbamoylphenoxy)acetic acid 00778 08 2-amino-1-(4- methoxyphenyl)ethanol 00786 09 3-(naphthalen-2- ylmethyl)oxazolidine-2- thione 00788 0 3-amino-N-(4- methylpyridin-2-yl)- benzamide 00801 (E)-N-hydroxy-2-(2- phenoxyphenyl)- acetimidamide 00808 2-amino-1-(2-chloro-3,4- dimethoxyphenyl)ethanol 00810 N-(5-amino-2- chlorophenyl)benzamide 00811 O-(2- nitrobenzyl)hydroxylamine 00827 N-hydroxy-2-(naphthalen-2- yl)acetamide 00830 3-(naphthalen-2-ylmethyl)- 2-thioxothiazolidin-4-one 00848 N-(2,5- dimethylphenyl) hydrazinecarboximidamide 00849 2-(2,5- dimethoxyphenyl)acetimidamide 00862 N-benzyl-N- hydroxyacetamide 00864 0 N-benzylbenzothioamide 00869 O-(2- fluorobenzyl)hydroxylamine 00880 5-(naphthalen-2- ylmethyl)quinolin-8-ol 00889 N-hydroxy-2- phenylacetamide 00890 5-(3- aminobenzyl)thiazolidine- 2,4-dione 00895 3-fluoro-N-(4H-1,2,4- triazol-4-yl)benzamide 00900 2-(4- hydroxyphenyl)acetimidamide 00914 O-(3,4- dichlorobenzyl)hydroxylamine 00917 N-(2- hydroxyethyl)benzo[d][1,3] dioxole-5-carboxamide 00920 N-benzyl-1H-imidazole-4- carboxamide 00922 0 N-(2,6- dimethylphenyl)hydrazine- carboximidamide 00934 O-(4- (trifluoromethyl)benzyl)- hydroxylamine 00945 5-(4-nitrophenylamino)-5- oxopentanoic acid 00947 (4S,5R)-4-methyl-3- (naphthalen-2-ylmethyl)-5- phenyloxazolidine-2-thione 00951 4,5-dimethyl-3-(naphthalen- 2-ylmethyl)thiazole-2(3H)- thione 00964 N-o- tolylhydrazinecarboximidamide 00969 1-(2,5-dimethylbenzyl)urea 00970 O-(4- methoxybenzyl)hydroxylamine 00974 (Z)-2-(benzhydryloxy)-N- hydroxyacetimidamide 00976 (Z)-2-(4-hydroxy-3- nitrobenzylidene)- hydrazinecarboxamide 00978 0 N-hydroxy-N- phenethylacetamide 00982 5-(2- phenylethylidene)pyrimidine- 2,4,6(1H,3H,5H)-trione 00990 5-phenethylquinolin-8-ol 00994 (Z)-2-(4-hydroxy-3- methoxy-5- nitrobenzylidene) hydrazinecarboxamide 00995 3-(naphthalen-2-ylmethyl)- 1,3-thiazinane-2-thione 00996 1-phenethyl-3- phenylthiourea 01013 5-(2-chlorophenyl)-2- iminothiazolidin-4-one 01014 O-(4- nitrobenzyl)hydroxylamine 01028 5-(2,4- dimethylphenylamino)-5- oxopentanoic acid 01031 (2-amino-6- nitrophenyl)methanol 01033 0 O-(4- chlorobenzyl)hydroxylamine 01039 2-(5-chloro-2- nitrophenylamino)ethanol 01051 (E)-3-(naphthalen-2- yl)acrylonitrile 01056 1-ethyl-1-phenylguanidine 01059 1-(2-methoxybenzyl)urea 01062 5-(2-phenylethylidene)-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 01065 4-nitrobenzyl carbamate 01070 N1-(4-nitrobenzyl)ethane- 1,2-diamine 01076 N-phenethylbenzothioamide 01077 2-(2- fluorophenyl)acetimidamide 01081 0 (S)-4-isopropyl-3- (naphthalen-2-ylmethyl)- thiazolidine-2-thione 01083 (E)-2-hydrazono-5-(4- methoxybenzyl)thiazolidin- 4-one 01088 2-(2,4- difluorophenyl)acetimidamide 01099 2-imino-5-(2- methylbenzyl)thiazolidin-4- one 01100 (E)-4-phenylbut-2- enimidamide 01101 1-benzyl-3-phenylthiourea 01107 N- (benzyl)imidodicarbonimidic diamide 01116 5-benzyl-2- iminothiazolidin-4-one 01131 1-(2-chlorobenzyl)urea 01138 4-((2-aminoethoxy)(o- tolyl)methyl)phenol 01139 0 2-(2-oxo-2H-chromen-4- yl)acetic acid 01140 5-benzylidenepyrimidine- 2,4,6(1H,3H,5H)-trione 01144 N-(2-trifluromethyl-4- chloro)imidodicarbonimidic diamide 01145 (Z)-ethyl 2-acetamido-3-(4- fluorophenyl)acrylate 01149 (E)-3-(naphthalen-2- yl)acrylimidamide 01151 5-(4- methylbenzyl)thiazolidine- 2,4-dione 01156 N-(2-bromo-4- fluoro)imidodicarbonimidic diamide 01168 5-(2-chlorobenzyl)-2- iminothiazolidin-4-one 01170 1-phenethylguanidine 01174 (2-amino-4- nitrophenyl)methanol 01177 0 N-(2-methyl-3- chloro)imidodicarbonimidic diamide 01193 1,1,1-trifluoro-3- phenylpropan-2-one 01197 5-benzylidene-2- thioxodihydropyrimidine- 4,6(1H,5H)-dione 01209 (E)-2-amino-2-oxoethyl 2- acetamido-3-phenylacrylate 01210 cinnamimidamide 01217 N-(2,6- dimethyl)imidodicarbonimidic diamide 01218 5-(naphthalen-2- ylmethylene)-2-thioxodi- hydropyrimidine- 4,6(1H,5H)-dione 01229 N-(2-methyl-6- chloro)imidodicarbonimidic diamide 01231 N-(2,6- difluorophenyl) imidodicarbonimidic diamide 01248 cinnamonitrile

(397) TABLE-US-00008 TABLE 8 Cmpd # Structure Name 00347 0 2-(2-chlorophenyl)-5-imino- 2,5-dihydrofuran-3,4-diol 00356 1-(3,4-dihydroxy-5- (hydroxymethyl)- tetrahydrofuran-2-yl)-5- fluoro-1H-imidazole-4- carboxamide 00871 2-(2-fluoro-1H-imidazol-1- yl)-5-(hydroxyl- methyl)tetrahydrofuran-3,4- diol 01042 2-(5-fluoro-1H-imidazol-1- yl)-5- (hydroxymethyl) tetrahydrofuran- 3,4-diol 01111 4-acetyl-5-(2-fluorophenyl)- 3-hydroxy-1H-pyrrol-2(5H)- one 01150 4-acetyl-3-hydroxy-5- phenylfuran-2(5H)-one 01163 4-acetyl-5-(2-chlorophenyl)- 3-hydroxy-1H-pyrrol-2(5H)- one 01187 4-acetyl-5-(2-fluorophenyl)- 3-hydroxyfuran-2(5H)-one 01198 4-acetyl-5-(2-chlorophenyl)- 3-hydroxyfuran-2(5H)-one 01226 4-acetyl-5-(2-fluorophenyl)- 3-hydroxy-1-methyl-1H- pyrrol-2(5H)-one 01240 00 4-acetyl-5-(2-chlorophenyl)- 3-hydroxy-1-methyl-1H- pyrrol-2(5H)-one

(398) TABLE-US-00009 TABLE 9 Cmpd # Structure Name 01465 01 imidazo[5,1- a]isoquinoline 01469 02 3-butylimidazo[5,1- a]isoquinoline 01481 03 2-amino-2- (imidazo[5,1- a]isoquinolin-3- yl)acetic acid 01482 04 N-hydroxy-2- (imidazo[5,1- a]isoquinolin-3- yl)acetamide 01483 05 N- hydroxyimidazo[5,1- a]isoquinoline-3- carboxamide

(399) TABLE-US-00010 TABLE 10 Cmpd # Structure Name 01386 06 2-amino-6-butyl-6,7- dihydroquinazoline- 4,5,8(3H)-trione 01394 07 2-amino-6-butyl-6,7- dihydroquinazoline- 4,5,8(3H)-trione 01395 08 2-amino-6-butyl-3-methyl- 6,7-dihydroquinazoline- 4,5,8(3H)-trione 01396 09 2-amino-3-methyl-6-propyl- 6,7-dihydroquinazoline- 4,5,8(3H)-trione 01398 0 2-amino-3-(2-amino-3- methyl-4,5,8-trioxo- 3,4,5,6,7,8- hexahydroquinazolin- 6-yl)propanoic acid 01400 2-(2-amino-3-methyl-4,5,8- trioxo-3,4,5,6,7,8- hexahydroquinazolin-6-yl)- N-hydroxyacetamide 01401 2-(2-amino-4,5,8-trioxo- 3,4,5,6,7,8- hexahydroquinazolin-6- yl)-N-hydroxyacetamide 01406 2-amino-3-(2-amino-4-oxo- 4,4a,5,8-tetrahydropteridin- 6-yl)propanoic acid 01411 2-amino-6-propyl-6,7- dihydroquinazoline- 4,5,8(3H)-trione 01478 2-amino-3-(2-amino-4-oxo- 4,4a,5,8-tetrahydropteridin- 6-yl)propanoic acid 01480 2-(2-amino-4-oxo-3,4- dihydropteridin-6-yl)-N- hydroxyacetamide 01484 2-amino-6-butylpteridin- 4(3H)-one 01485 2-amino-6-butyl-4a,5- dihydropteridin-4(8H)-one 01486 2-amino-6-propylpteridin- 4(3H)-one 01487 0 2-amino-6-butyl-4a,5- dihydropteridin-4(8H)-one 01488 2-amino-3-(2-amino-4-oxo- 3,4-dihydropteridin-6- yl)propanoic acid

(400) TABLE-US-00011 TABLE 11 Cmpd # Structure Name 00027 methyl 6-(1H-indol-3- yl)hexylcarbamodithioate 00028 methyl 1-(1H-indol-3-yl)-2- methylpropan-2- ylcarbamodithioate 00063 naphthalen-2-ylmethyl 2- (chroman-3- yl)ethylcarbamodithioate 00064 naphthalen-2-ylmethyl thiochroman-3- ylcarbamodithioate 00141 isopropyl 2-(benzylthio- carbonothioylamino)acetate 00142 p-tolyl phenylcarbamodithioate 00144 2,4-dinitrophenyl cyclohexylcarbamodithioate 00145 2-bromobenzyl sulpholan-2- yl carbamodithioate 00146 0 2-bromo-4-nitrobenzyl sulpholan-2-yl carbamodithioate 00147 ethyl pyridin-2- ylcarbamodithioate 00149 (E)-5-(1-acetyl-2- oxoindolin-3-ylidene)-2- thioxothiazolidin-4-one 00151 (5-oxo-1-phenyl-2- thioxoimidazolidin-4- yl)methyl phenylcarbamodithioate 00152 4,6-diphenyl-1,3,5- thiadiazinane-2-thione 00167 naphthalene-1,2-dione 00168 naphthalen-1-ol 00210 3-(1H-pyrrol-1- yl)thiophene-2-carboxylic acid 00215 3-imino-3-(2- iminopiperidin-1-yl)- propanamide 00216 1-(2-(2,4- difluorophenyl)thiazolidin- 3-yl)ethanone 00222 0 2-(benzylthio)pyrimidine- 4,6-diol 00226 2-([1,2,4]triazolo[4,3- a]pyridin-3-ylthio)acetamide 00230 2-amino-5-(2- chlorophenyl)thiazole-4- carboxylic acid 00252 2,4-bis(allyloxy)-1- ethylbenzene 00254 1H-indole-2,3-dicarboxylic acid 00256 2-(5-nitro-1H-indol-3- yl)ethanamine 00267 3-(3-oxo-2,3-dihydro-1H- indazol-1-yl)propanoic acid 00269 4-oxo-4-(pyrrolidin-1- yl)butanoic acid 00271 3-amino-N,N- diethylbenzamide 00272 ethyl 3,5-dihydroxybenzoate 00281 0 decahydronaphthalene-2,3- diol 00289 1-(3,3- dimethylbicyclo[2.2.1]hepta n-2-yl)ethanone 00300 2,6-dihydroxypyrimidin-4- ylphosphonic acid 00305 2-(hydroxymethyl)-6-(1- methylhydrazinyl)- tetrahydro-2H-pyran-3,4,5- triol 00309 7-amino-8- hydroxyquinoline-5-sulfinic acid 00310 2-methyl-2- phenylhydrazinecarboxamide 00311 N-(2- aminophenyl)formohydrazide 00312 2-oxo-2-(2- phenylhydrazinyl)acetamide 00319 6-hydroxypyridine-2,3- dicarboxylic acid 00320 2,7-dihydroxyquinoline-5,8- dione 00324 0 N,N-dimethyl-2-oxo-2- phenylacetamide 00332 N-ethyl-N- phenylcarbamimidoyl cyanide 00334 1H-pyrazolo[3,4- d]pyrimidin-4(2H)-one 00337 4-hydroxy-7- methylpyrano[4,3-b]pyran- 2,5-dione 00342 6,7-dihydroxy-4- methylchroman-2-one 00343 6,7-dihydroxy-2-oxo-2H- chromene-4-carboxylic acid 00345 6- (benzyl(methyl)amino)pyrimidine- 2,4-diol 00348 1-methyl-4-(2- methylhydrazinyl)-1H- pyrazolo[3,4-d]pyrimidine 00352 5-amino-1H-indole-3- carboxylic acid 00363 (6Z,8Z)-4-hydroxy-5H- benzo[7]annulen-5-one 00364 0 (E)-acenaphthylen-1(2H)- ylidenehydrazine 00366 2,3,4,5-tetrahydro-1H- benzo[d]azepin-1-ol 00367 6,7,8,9-tetrahydro-5H- benzo[7]annulene-2,9-diol 00368 1-methyl-2,3-dihydro-1H- indene-4,7-diol 00378 4-hydroxy-3-methyl-1- phenyl-1H-pyrazol-5(4H)- one 00380 2,3-diphenyl-2,5- dihydrofuran 00382 2-(2-hydroxy-7,7-dimethyl- 3-oxobicyclo[2.2.1]heptan- 1-yl)acetic acid 00385 5,5- dimethylbicyclo[2.1.1]hexane- 2-carboxylic acid 00396 1-(iminomethyl)naphthalen- 2-ol 00398 6,7-dihydroxy-4- methylquinolin-2(1H)-one 00464 0 2-((3-methyl-1,4-dioxo-1,4- dihydronaphthalen-2- yl)methyl)isoindoline-1,3- dione 00477 3,3-methylenebis(2- hydroxynaphthalene-1,4- dione) 00507 2,5-dioxopyrrolidin-1-yl 4- (7-oxo-7H-furo[3,2- g]chromen-9- yloxy)butanoate 00515 2- hydroxybenzo[d]naphtho[2,3- b]furan-6,11-dione 00516 chrysene-1,4-dione 00561 N-((1H-indol-3-yl)methyl)- 2-(2-thioxo-2,3- dihydrothiazol-4- yl)acetamide 00578 4-amino-4-oxo-2- phenylbutanoic acid 00586 N1-((1H-indol-3- yl)methyl)ethane-1,2- diamine 00605 3,6-dihydroxy-2- methylbenzoic acid 00608 5-phenylthiazole-4- carboxylic acid 00610 0 4-(pyridin-3-yl)-1H-pyrrole- 3-carboxylic acid 00622 3-((1H-indol-3- yl)methylthio)-2-methyl- 1,2-dihydro-1,2,4-triazine- 5,6-dione 00623 N-o- tolylhydrazinecarbothioamide 00628 2-(benzylamino)phenol 00645 3-(3-oxo-1H-indazol-2(3H)- yl)propanoic acid 00658 2-(2-methylfuran-3- carboxamido)pentanedioic acid 00663 6-chloro-2-(3- fluorobenzylthio)pyrimidin- 4-amine 00669 (Z)-N-hydroxy-1H-indole- 3-carboximidamide 00670 6,8-dihydroxy-3-methyl-1H- isochromen-1-one 00675 N-(4-fluorobenzyl)-2,5- dimethoxyaniline 00681 00 2-cyclobutoxybenzamide 00682 01 2-methyl-3-(naphthalen-2- ylmethylthio)-1,2-dihydro- 1,2,4-triazine-5,6-dione 00685 02 2-(benzylthio)-6- methylpyrimidin-4-amine 00690 03 2-(5-phenyl-1H-tetrazol-1- yl)acetamide 00692 04 6-chloro-2-(2- fluorobenzylthio)pyrimidin- 4-amine 00700 05 2-(1H-pyrrol-1- yl)benzohydrazide 00701 06 N-(naphthalen-2-ylmethyl)- 2-(2-thioxo-2,3- dihydrothiazol-4- yl)acetamide 00705 07 2-(benzylthio)-6- chloropyrimidin-4-amine 00707 08 4-phenylisoxazole-3,5-diol 00714 09 4-(indolin-3-yl)-4- oxobutanoic acid 00716 0 (2E,4E,6Z)-2-(furan-2- ylmethylamino)-5- nitrocyclohepta-2,4,6- trienone 00718 2-(5-bromo-1H-indol-3- yl)ethanamine 00727 4-oxo-4-(5-oxo-1,4- diazepan-1-yl)butanoic acid 00740 3- (nitroso(phenyl)amino)propanoic acid 00746 N-benzyl-5-methylpyrazine- 2-carboxamide 00750 4-(4-(2- hydroxyethyl)piperazin-1- yl)-4-oxobutanoic acid 00751 3-(cyclohexa-1,5- dienylmethylthio)-2-methyl- 1,2-dihydro-1,2,4-triazine- 5,6-dione 00757 benzofuran-2,3-dicarboxylic acid 00759 pyrrolidin-1-yl(o- tolyl)methanone 00768 2-(1H-inden-3-yl)acetic acid 00770 0 N-(2- nitrophenyl) hydrazinecarbothioamide 00777 3-([1,2,4]triazolo[4,3- a]pyridin-3-yl)propan-1- amine 00782 5-methoxy-4-oxo-4H-pyran- 2-carboxylic acid 00783 2-(2- bromoethoxy)benzamide 00784 7-ethyl-2,3- dihydrobenzo[b][1,4]dioxine- 6-carboxylic acid 00793 2-(3- chlorobenzylthio)pyrimidine- 4,6-diol 00797 N-ethyl-N- phenylcarbamimidothioic acid 00799 6-amino-2-(thiophen-2- ylmethylthio)pyrimidin-4-ol 00803 6-amino-2- (benzylthio)pyrimidin-4-ol 00805 1-butyl-2-hydrazinyl-1H- benzo[d]imidazole 00806 0 2-(1-methyl-1H-indol-3- ylthio)acetic acid 00807 3-methyl-N-phenyl-1H- pyrazole-5-carbohydrazide 00812 4-oxo-4-(piperazin-1- yl)butanoic acid 00814 6-amino-2-(pyridin-3- ylmethylthio)pyrimidin-4-ol 00815 2-(phthalazin-1-ylthio)acetic acid 00821 4-oxo-4-(piperidin-1- yl)butanoic acid 00822 1,2,3,4-tetrahydroquinoline- 8-carboxylic acid 00824 5-nitro-N-phenylfuran-2- carboxamide 00837 N,2-dihydroxybenzamide 00856 3-hydroxy-5-nitrobenzoic acid 00858 0 2-amino-3-nitrobenzoic acid 00875 1,3-dimethyl-1H-thieno[2,3- c]pyrazole-5-carboxylic acid 00877 1-phenyl-2-(pyridin-4- yl)ethanone 00881 1-(5-amino-2,4- dihydroxyphenyl)propan-1- one 00886 4-phenyl-1,2,5-oxadiazol-3- ol 00896 (E)-N-(2-(1H-imidazol-4- yl)ethyl)formohydrazonamide 00899 1-ethyl-1H- benzo[d]imidazole-2- sulfonic acid 00901 5-(diethylamino)-2- hydroxybenzoic acid 00903 4-hydroxypyridine-2,6- dicarboxylic acid 00905 2-hydroxybenzo[d]thiazole- 5,7-dicarboxylic acid 00909 0 2-hydroxy-5- thioureidobenzoic acid 00912 2-(1-methyl-1H-indol-3- ylthio)acetamide 00915 1-benzoylpiperidine-3- carboxylic acid 00919 3-methyl-4-phenyl-1,2,3- oxadiazol-3-ium-5-olate 00932 1-propyl-1H- benzo[d]imidazol-2-amine 00935 N,N-dimethyl-4-phenyl-1H- pyrazol-3-amine 00938 (E)-2-oxo-2-(2-(1- (thiophen-2-yl)- ethylidene)hydrazinyl)acetamide 00939 2-amino-3,4- dimethoxybenzoic acid 00943 (2- methoxyphenyl)(morpholino) methanone 00946 1-(2-isopropylphenyl)urea 00954 0 2-(4-amino-4H-1,2,4- triazol-3-ylthio)acetamide 00958 8-methoxyquinoline-2,4-diol 00966 (1-allyl-1H-indol-3- yl)methanol 00973 N-(pentan-2-yl)thiophene-2- carboxamide 00975 2-fluoro-N-(furan-2- ylmethyl)-4-nitroaniline 00980 1-((2R,4S,5S,E)-3- (chloromethylene)-4,5- dihydroxytetrahydrofuran-2- yl)pyrimidine-2,4(1H,3H)- dione 00983 N-(2,5- dichlorophenyl)pyrazine-2- carboxamide 00984 methyl ethyl(phenyl) carbamimidothioate 00988 4-formamido-3-phenyl- 1,2,5-oxadiazole 2-oxide 00991 (1H-imidazol-2- yl)(thiophen-2- yl)methanone 00993 0 (2- ethoxyphenyl)(morpholino) methanone 00997 4- ((methylamino)methyl)quinolin- 2(1H)-one 01000 (3-methyl-4-phenyl-1,2,3- oxadiazol-3-ium-5-yl)amide 01003 (E)-4- ((hydroxyimino)methyl)-3- phenyl-1,2,5-oxadiazole 2- oxide 01010 5-methoxy-1,2- dihydrocyclobutabenzene-1- carboxylic acid 01019 N- allylbenzo[d][1,3]dioxole-5- carboxamide 01020 2-hydroxy-5-(N- methylsulfamoyl)benzamide 01022 1-ethyl-1H- benzo[d]imidazol-2(3H)-one 01024 2,3- dihydrobenzo[b][1,4]dioxine- 5-carboxamide 01026 1,3-bis(allyloxy)benzene 01029 0 1-isopropyl-1H- benzo[d]imidazol-2(3H)-one 01030 N-benzyl-1H-1,2,4-triazole- 5-carboxamide 01036 1-(2,3-dihydro-1H-inden-1- yl)guanidine 01037 2-(1-(methylamino)ethyl)-3- propylquinazolin-4(3H)-one 01038 1H-pyrazole-1,4,5- tricarboxylic acid 01040 2-(4-(pyridin-2-yl)-4H- 1,2,4-triazol-3-ylthio)acetic acid 01041 N- propylbenzo[d][1,3]dioxole- 5-carboxamide 01044 allyl 2-(allyloxy)benzoate 01046 methyl 2,3-dihydroxy-1- naphthoate 01052 2-chloro-N-(3- methoxypropyl)-N-phenyl- acetamide 01058 0 2-(4- chlorophenylcarbonothioyl) hydrazinecarboxamide 01061 (E)-N- butylidenebenzohydrazide 01067 2-(pyrrolidin-1-yl)thiazol- 4(5H)-one 01068 N-allylthiophene-2- carboxamide 01072 1,2,3,4- tetrahydroisoquinoline- 6,7-diol 01073 N-(2-oxo-2H-chromen-3- yl)acetamide 01074 2-(2-methylindolizin-3-yl)- 2-oxoacetic acid 01075 1-methylisoquinoline-6,7- diol 01079 2-benzo[4,5]thiazolo[2,3- c][l,2,4]triazol-3-ylsulfanyl- acetamide 01080 2,4- bis(allyloxy)benzaldehyde 01082 00 3-(cyclohexa-1,5- dienylmethyl)oxazolidine-2- thione 01090 01 (E)-N-butylidenethiophene- 2-carbohydrazide 01092 02 pyrrolo[1,2-a]quinoxalin- 4(5H)-one 01093 03 l-((2R,3R,4S,5S,6R)-3,4,5- trihydroxy-6- (hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thiourea 01096 04 N-(3-methoxypropyl)-2- methylfuran-3-carboxamide 01098 05 1-(furan-2- carbonyl)piperidine-3- carboxylic acid 01104 06 (E)-N- butylidenepicolinohydrazide 01105 07 (E)-4-chloro-N- propylidenebenzohydrazide 01106 08 5,8-dihydroxy-3,4- dihydronaphthalen-2(1H)- one 01108 09 3,4-dihydro- [1,4]diazepino[3,2,1- hi]indol-2(1H)-one 01109 0 N,N-diethyl-3,5- dimethoxybenzamide 01113 1H-benzo[d][1,2,3]triazole- 1-carboximidamide 01118 2-amino-2-oxoethyl 2- (methylthio)nicotinate 01121 3-(2-oxoazepan-1- yl)propanamide 01123 (Z)-4,5,8,9-tetrahydro-2H- pyrrolo[1,2-a][1,3]diazepin- 7(3H)-one 01126 2-(allyloxy)-3- methylbenzamide 01130 quinoline-3,4-dicarboxylic acid 01134 3-(cyclohexa-1,5- dienylmethyl)-2- thioxothiazolidin-4-one 01137 2-(benzylthio)-6- methylpyrimidin-4-ol 01148 2-methyl-3- (methylamino)quinazolin- 4(3H)-one 01152 0 (4S,5R)-3-(cyclohexa-1,5- dienylmethyl)-4-methyl-5- phenyloxazolidine-2-thione 01154 (Z)-2-hydrazono-2-(pyridin- 2-yl)ethanol 01158 (E)-N-((E)-but-2- enylidene)thiophene-2- carbohydrazide 01161 3-hydroxy-5-(thiophen-2- yl)cyclohex-2-enone 01164 4-(pyrrolidin-1-yl)-1H- imidazol-2(5H)-one 01167 4-hydroxy-2-mercapto-5- methyl-7H-pyrano[2,3- d]pyrimidin-7-one 01175 4-ethoxy-3-phenyl-1,2,5- oxadiazole 2-oxide 01178 4-amino-1-naphthoic acid 01180 7-chloro-3- methylbenzofuran-2- carboxylic acid 01182 4-hydroxy-2,5-dimethyl-7H- pyrano[2,3-d]pyrimidin-7- one 01184 0 2-(piperidin-1-yl)thiazol- 4(5H)-one 01189 4-amino-1-butyl-5,6- dihydropyrimidin-2(1H)-one 01194 2-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3-yl)acetonitrile 01195 5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diol 01196 1,10b-dihydropyrazolo[ 1,5- c]quinazolin-5(6H)-one 01204 4,7,8-trihydroxy-1-oxo- 1,2,3,4-tetrahydro- isoquinoline 01207 2-methoxy-4,7- dimethylpyrido[2,3-d]- pyrimidin-5(8H)-one 01212 (E)-6-((9H-pyrido[3,4- b]indol-9-yl)- methylene)piperazine-2,3,5- trione 01213 4-oxo-2,3,4,5-tetrahydro- 1H-benzo[b][1,4]diazepine- 1-carboxamide 01215 (E)-3-((9H-pyrido[3,4- b]indol-9-yl)methylene)-6- thioxopiperazine-2,5-dione 01220 0 2-mercapto-5,7- dimethylpyrido[2,3- d]pyrimidin-4(3H)-one 01224 2,4,7-trimethylpyrido[2,3- d]pyrimidin-5(8H)-one 01236 3,4- dichlorobenzo[b]thiophene- 2-carboxylic acid 01239 2-(benzylthio)-4,5- diphenylthiazole 01243 2-((1H-indol-3- yl)methylthio)-4,5- diphenylthiazole 01250 2,2,4,4-tetramethyl-3,3- bithiophene 01253 N-allyl-N-((1-(2- fluorophenyl)-1H-pyrrol-2- yl)methyl)prop-2-en-1- amine 01257 4,4-dibromo-2,2-dimethyl- 3,3-bithiophene 01360 methyl 2-(1H-indol-3- yl)propylcarbamodithioate 01384 3,4-dihydro-1H- [1,4]oxazino[4,3-a]indole 01389 0 potassium 1,4-dioxo-1,4- dihydronaphthalene-2- sulfonate 01393 8-butyl-2,2,4,4- tetramethylphenazine- 1,3(2H,4H)-dione 01397 1H-naphtho[1,2-d]imidazol- 9-ol 01399 naphthalen-2-ylmethyl 2- (thiochroman-3- yl)ethylcarbamodithioate 01404 naphthalen-2-ylmethyl chroman-3- ylmethylcarbamodithioate 01407 8-butyl-2,2,4,4-tetramethyl- 5,10-dihydrophenazine- 1,3(2H,4H)-dione 01408 2,2,4,4- tetramethylphenazine- 1,3(2H,4H)-dione 01409 2,2,4,4-tetramethyl-5,10- dihydrophenazine- 1,3(2H,4H)-dione 01412 3-hydroxy-2- methylquinazolin-4(3H)-one 01415 (2S)-2-amino-3-(3,4,10,10a- tetrahydro-1H- [1,4]oxazino[4,3-a]indol-10- yl)propanoic acid 01416 0 3-hydroxyquinazoline- 2,4(1H,3H)-dione 01423 3-butyl-1-hydroxyindolin-2- one 01435 2-butyl-3- hydroxyquinazolin-4(3H)- one 01436 naphthalen-2-ylmethyl 3-(2- oxobenzo[d]oxazol-3(2H)- yl)propylcarbamodithioate 01450 1H-naphtho[l,2- d]imidazole-1,9-diol 01453 (1aR,1bS,6bR,6cS)- 1b,2,6b,6c-tetrahydro-1aH- oxireno[3,4]cyclobuta[1,2- b]indole 01454 3,4,10,10a-tetrahydro-1H- [1,4]oxazino[4,3-a]indole 01467 11- hydroxybenzo[g]furo[3,2- b]quinoxaline- 5,10(4H,11H)-dione

(401) In a twelfth aspect, the compounds as provided as listed in Table 12.

(402) TABLE-US-00012 TABLE 12 Cmpd # Structure Name 00001 phenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00002 4-methoxyphenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00003 0 4-fluorophenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00004 4-bromophenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00006 2-phenylpropyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00007 3-bromophenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00008 3-chlorophenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00009 4-methylphenethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00010 3-methoxyphenethyl 2-(1H-indol- 3-yl)ethylcarbamodithioate 00023 (6,7-Dimethoxy-2-oxo-2H- chromen-4-yl)methyl 2-(1H-indol- 3-yl)ethyl-carbamodithioate 00030 2-(1H-indol-3-yl)ethyl 2-(1H- indol-3-yl)ethylcarbamodithioate 00038 (2-Methylquinolin-6-yl)methyl 2- (1H-indol-3- yl)ethylcarbamodithioate 00047 0 2-(3-methylnaphthalen-2-yl)ethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00049 4-((2-(1H-indol-3- yl)ethylcarbamothioylthio) methyl)-2-oxo-2H-chromen-7-yl acetate 00050 Benzo[d][l,3]dioxol-5-ylmethyl 2- (1H-indol-3- yl)ethylcarbamodithioate 00052 Benzo[d]isoxazol-3-ylmethyl 2- (1H-indol-3- yl)ethylcarbamodithioate 00053 2-(2,3- dihydrobenzo[b][1,4]dioxin-6- yl)ethyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00065 (6-Bromobenzo[d][1,3]dioxol-5- yl)methyl 2-(1H-indol-3- yl)ethylcarbamodithioate 00066 Methyl 2,4- dimethylphenethyl-carbamodithioate 00069 Methyl 2-(pyridin-4- yl)ethylcarbamodithioate 00786 3-(naphthalen-2- ylmethyl)oxazolidine-2-thione 00830 3-(naphthalen-2-ylmethyl)-2- thioxothiazolidin-4-one

(403) In a thirteenth aspect is provided a compound of the formula (XIII),

(404) ##STR00890##

(405) or a pharmaceutically acceptable salt thereof, wherein

(406) L.sup.1 is C.sub.2-C.sub.6alkyl-;

(407) X is O or S;

(408) ring D is an aryl or heteroaryl group, each optionally substituted with one to four R groups;

(409) R.sup.1 is -L.sup.2-R.sup.2, wherein L.sup.2 is C.sub.2-C.sub.6alkyl-; and R.sup.2 is (i) hydrogen; (ii) aryl optionally substituted with one to four R groups; or (iii) heteroaryl optionally substituted with one to four R groups; and

(410) each R is independently halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, OR.sup.3, SR.sup.3, N(R.sup.3).sub.2, OC(O)R.sup.3, C(O)OR.sup.3, C(O)N(R.sup.3).sub.2, N(R.sup.3)C(O)R.sup.3, S(O)R.sup.3, or S(O).sub.2R.sup.3, wherein each R.sup.3 is independently hydrogen or C.sub.1-C.sub.6alkyl;

(411) provided that when ring D is an aryl or unsubstituted indol-3-yl, benzofuran-3-yl, or benzothien-3-yl group, and L.sup.1 is C.sub.2-C.sub.3alkyl-, then (a) R.sup.2 is not hydrogen.

(412) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is aryl.

(413) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is heteroaryl.

(414) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is phenyl, naphthyl, azulenyl, indolyl, benzothienyl, benzofuranyl, pyridyl, pyrazinyl, pyrimidinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, quinolinyl, or quinazolinyl, each optionally substituted with one to four R groups.

(415) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is phenyl or naphthyl, each optionally substituted with one to four R groups.

(416) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is indolyl, benzothienyl, benzofuranyl, pyridyl, pyrazinyl, pyrimidinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, quinolinyl, or quinazolinyl, each optionally substituted with one to four R groups.

(417) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is indolyl, benzothienyl, benzofuranyl, quinolinyl, or quinazolinyl, each optionally substituted with one to four R groups.

(418) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein ring D is indolyl, benzothienyl, or benzofuranyl, each optionally substituted with one to four R groups.

(419) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein X is S.

(420) In an embodiment of the thirteenth aspect, the compound is according to formula (XIII), wherein X is O.

(421) In an embodiment of the thirteenth aspect, the compound is according to one of formulae (XIIIa-c),

(422) ##STR00891##

(423) In an embodiment of the thirteenth aspect, the compound is according to one of formulae (XIII and XIIIa-c), wherein L.sup.1 is CH.sub.2CH.sub.2.

(424) In an embodiment of the thirteenth aspect, the compound is according to one of formulae (XIII and XIIIa-c), wherein L.sup.2 is CH.sub.2CH.sub.2.

(425) In an embodiment of the thirteenth aspect, the compound is according to one of formulae (XIII and XIIIa-c), wherein L.sup.1 and L.sup.2 are both is CH.sub.2CH.sub.2.

(426) In an embodiment of the thirteenth aspect, the compound is a compound listed in Table 12.

(427) In a fourteenth aspect, methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount a compound of formula (XXI); (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (XXI); (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (XXI); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound of formula (XXI), (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (XXI); and (f) treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound of formula (XXI),

(428) ##STR00892##

(429) and pharmaceutically acceptable salts thereof, wherein

(430) ring A is aryl, heteroaryl, C.sub.5-C.sub.10 cycloalkyl, or heterocyclyl, each optionally substituted with one or more R.sup.A groups, wherein

(431) each R.sup.A is independently halogen, cyano, nitro, N(R.sup.A1).sub.2, OR.sup.A1, ON(R.sup.A1).sub.2, N(R.sup.A1)N(R.sup.A1).sub.2, SR.sup.A1, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)OR.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, N(R.sup.A1)C(O)OR.sup.A1, N(R.sup.A1)C(O)N(R.sup.A1).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A1).sub.2, OR.sup.A1, ON(R.sup.A1).sub.2, N(R.sup.A1)N(R.sup.A1).sub.2, SR.sup.A1, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)OR.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, N(R.sup.A1)C(O)OR.sup.A1, or N(R.sup.A1)C(O)N(R.sup.A1).sub.2, wherein

(432) each R.sup.A1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.A2).sub.2, OR.sup.A2, ON(R.sup.A2).sub.2, N(R.sup.A2)N(R.sup.A2).sub.2, SR.sup.A2, C(O)R.sup.A2, C(O)OR.sup.A2, C(O)N(R.sup.A2).sub.2, S(O)R.sup.A2, S(O)OR.sup.A2, S(O)N(R.sup.A2).sub.2, S(O).sub.2R.sup.A2, S(O).sub.2OR.sup.A2, S(O).sub.2N(R.sup.A2).sub.2, OC(O)R.sup.A2, OC(O)OR.sup.A2, OC(O)N(R.sup.A2).sub.2, N(R.sup.A2)C(O)OR.sup.A2, or N(R.sup.A2)C(O)N(R.sup.A2).sub.2, wherein

(433) each R.sup.A2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl; and

(434) L is a bond or X-L.sup.1-, wherein

(435) X is bonded to A, and is a bond, O, S, N(R.sup.X), C(Y), S(O), S(O).sub.2, C(O)O, OC(O), OC(O)O, OC(O)N(R.sup.X), N(R.sup.X)C(O)O, C(O)N(R.sup.X), N(R.sup.X)C(O), N(R.sup.X)C(O)N(R.sup.X), S(O)O, OS(O), S(O)N(R.sup.X), N(R.sup.X)S(O), S(O).sub.2O, OS(O).sub.2, S(O).sub.2N(R.sup.X), N(R.sup.X)S(O).sub.2, C.sub.1-C.sub.3 alkylO, C.sub.1-C.sub.3alkylS, C.sub.1-C.sub.3alkylN(R.sup.X), C.sub.1-C.sub.3alkylC(Y), C.sub.1-C.sub.3alkylS(O), C.sub.1-C.sub.3alkylS(O).sub.2, C.sub.1-C.sub.3alkylC(O)O, C.sub.1-C.sub.3alkylOC(O), C.sub.1-C.sub.3alkylOC(O)O, C.sub.1-C.sub.3alkylN(R.sup.X)C(O)O, C.sub.1-C.sub.3alkylOC(O)N(R.sup.X), C.sub.1-C.sub.3 alkyl-C(O)N(R.sup.X), C.sub.1-C.sub.3alkylN(R.sup.X)C(O), C.sub.1-C.sub.3 alkylN(R.sup.X)C(O)N(R.sup.X), C.sub.1-C.sub.3alkylS(O)O, C.sub.1-C.sub.3alkylOS(O), C.sub.1-C.sub.3alkylS(O)N(R.sup.X), C.sub.1-C.sub.3alkylN(R.sup.X)S(O), C.sub.1-C.sub.3alkylS(O).sub.2O, C.sub.1-C.sub.3alkylOS(O).sub.2, C.sub.1-C.sub.3alkylS(O).sub.2N(R.sup.X), or C.sub.1-C.sub.3alkylN(R.sup.X)S(O).sub.2, wherein

(436) each R.sup.X is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(437) Y is O, S, or NH; and

(438) L.sup.1 is C.sub.1-C.sub.6alkyl-, or C.sub.2-C.sub.6alkenyl-, wherein the alkyl and alkenyl are each optionally substituted with one or two R.sup.L groups, wherein

(439) each R.sup.L is independently halogen, cyano, nitro, N(R.sup.L1).sub.2, OR.sup.L1, ON(R.sup.L1).sub.2, N(R.sup.L1)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)R.sup.L1, SR.sup.L1, C(O)R.sup.L1, C(O)OR.sup.L1, C(O)N(R.sup.L1).sub.2, S(O)R.sup.L1, S(O)OR.sup.L1, S(O)N(R.sup.L1).sub.2, S(O).sub.2R.sup.L1, S(O).sub.2OR.sup.L1, S(O).sub.2N(R.sup.L1).sub.2, OC(O)R.sup.L1, OC(O)OR.sup.L1, OC(O)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)OR.sup.L1, N(R.sup.L1)C(O)N(R.sup.L1).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylC.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, or C.sub.1-C.sub.6 alkylheterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or two halogen, cyano, nitro, N(R.sup.L1).sub.2, OR.sup.L1, ON(R.sup.L1).sub.2, N(R.sup.L1)N(R.sup.L1).sub.2, SR.sup.L1, C(O)R.sup.L1, C(O)OR.sup.L1, C(O)N(R.sup.L1).sub.2, S(O)R.sup.L1, S(O)OR.sup.L1, S(O)N(R.sup.L1).sub.2, S(O).sub.2R.sup.L1, S(O).sub.2OR.sup.L1, S(O).sub.2N(R.sup.L1).sub.2, OC(O)R.sup.L1, OC(O)OR.sup.L1, OC(O)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)R.sup.L1, N(R.sup.L1)C(O)OR.sup.L1, or N(R.sup.L1)C(O)N(R.sup.L1).sub.2, wherein

(440) each R.sup.L1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.L2).sub.2, OR.sup.L2, ON(R.sup.L2).sub.2, N(R.sup.L2)N(R.sup.L2).sub.2, SR.sup.L2, C(O)R.sup.L2, C(O)OR.sup.L2, C(O)N(R.sup.L2).sub.2, S(O)R.sup.L2, S(O)OR.sup.L2, S(O)N(R.sup.L2).sub.2, S(O).sub.2R.sup.L2, S(O).sub.2OR.sup.L2, S(O).sub.2N(R.sup.L2).sub.2, OC(O)R.sup.L2, OC(O)OR.sup.L2, OC(O)N(R.sup.L2).sub.2, N(R.sup.L2)C(O)OR.sup.L2, or N(R.sup.L2)C(O)N(R.sup.L2).sub.2, wherein

(441) each R.sup.L2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(442) A preferred subgenus of the fourteenth aspect includes compounds in which ring A is substituted with at least one R.sup.A. Preferably, ring A is substituted with one or two R.sup.A. More preferably, ring A is substituted with two R.sup.A.

(443) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more R.sup.A groups.

(444) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more R.sup.A groups, provided that ring A is not piperidinyl. Compounds of this subgenus are preferably used for treating cancer, infectious disease, trauma, and age-related cataracts as described herein below, although they are also suitable for the other uses described in the Methods of Use section hereinbelow.

(445) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is aryl or heteroaryl optionally substituted with one or more R.sup.A groups. Preferably, ring A is aryl or heteroaryl, each substituted with one or two R.sup.A groups.

(446) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is aryl optionally substituted with one or more R.sup.A groups. Preferably, ring A is phenyl or naphthyl, each substituted with one or two R.sup.A groups. More preferably, ring A is phenyl substituted with one or two R.sup.A groups. Even more preferably, ring A is phenyl substituted with one or two R.sup.A groups, wherein at least one R.sup.A group is meta- or ortho- to L.

(447) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzooxazolinyl, benzimidazolidinyl, benzothioxazolinyl, cromanyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, benzo[d][1,3]dioxolyl, tetrahydronaphthyl, indenyl, or dihydroindenyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups.

(448) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is tetrahydroquinolinyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzothienyl, 4,5,6,7-tetrahydrobenzo-furanyl, 4,5,6,7-tetrahydroindolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 4,5,6,7-tetrahydrobenzo-thioxazolyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups.

(449) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is heteroaryl optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups. Preferably, ring A is pyrrolyl, furanyl, thienyl, benzothienyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothioxazolyl, benzotriazolyl, quinolinyl, or quinazolinyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups. More preferably, ring A is pyridinyl, pyrimidinyl, pyrazinyl, or 1,3,5-triazinyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups. In an alternative embodiment, ring A is benzothienyl, indolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothioxazolyl, or benzotriazolyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups. Preferably, ring A is benzothienyl, indolyl, or benzofuranyl, each optionally substituted with one or more R.sup.A groups, or preferably, each substituted with one or two R.sup.A groups.

(450) Another preferred subgenus of the fourteenth aspect includes compounds in which ring A is C.sub.5-C.sub.10 cycloalkyl substituted with one or two R.sup.A groups. Preferably, ring A is C.sub.5-C.sub.7 cycloalkyl substituted with one or two R.sup.A groups.

(451) In a preferred subgenus of any of the preceding subgenera of the fourteenth aspect,

(452) (a) at least one R.sup.A is halogen, cyano, nitro, N(R.sup.A11).sup.2, OR.sup.A11, ON(R.sup.A11).sub.2, N(R.sup.A11)N(R.sup.A11).sub.2, SR.sup.A11, C(O)OR.sup.A11, C(O)OR.sup.A11, C(O)N(R.sup.A11).sub.2, S(O)R.sup.A11, S(O)OR.sup.A11, S(O)N(R.sup.A11).sub.2, S(O).sub.2R.sup.A11, S(O).sub.2OR.sup.A11, S(O).sub.2N(R.sup.A11).sub.2, OC(O)R.sup.A11, OC(O)OR.sup.A11, OC(O)OR.sup.A11, OC(O)N(R.sup.A11).sub.2, N(R.sup.A11)C(O)OR.sup.A11, or N(R.sup.A11)C(O)N(R.sup.A11).sub.2, each R.sup.A11 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sup.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)OR.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O)R.sup.A12, S(O)OR.sup.A12, S(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, wherein each R.sup.A12 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(453) (b) at least one R.sup.A is halogen, cyano, nitro, NH.sub.2, OH, ONH.sub.2, NHNH.sub.2, C(O)OH, or C(O)NH.sub.2.

(454) (c) only one R.sup.A is present and R.sup.A is halogen, cyano, nitro, NH.sub.2, OH, ONH.sub.2, NHNH.sub.2, C(O)OH, or C(O)NH.sub.2;

(455) (d) at least one R.sup.A is N(R.sup.A11).sub.2 or OR.sup.A11, wherein each R.sup.A11 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sup.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)OR.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O)R.sup.A12, S(O)OR.sup.A12, S(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, wherein each R.sup.A12 is independently hydrogen, or C.sub.1-C.sub.6 alkyl;

(456) (e) at least one R.sup.A is NHR.sup.A11 or OR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sup.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen, C.sub.1-C.sub.6 alkyl

(457) (f) at least one R.sup.A is NHR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sup.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkyl. Even more preferably, only one R.sup.A is present and R.sup.A is NHR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sup.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen, C.sub.1-C.sub.6 alkyl;

(458) (g) at least one R.sup.A is C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(459) (h) at least one R.sup.A is -aryl or -heteroaryl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl.

(460) (i) only one R.sup.A is present and R.sup.A is -aryl or -heteroaryl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(461) (j) one of two R.sup.A are present and one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(462) (k) one or two R.sup.A are present, one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, where the optionally substituted phenyl is ortho or meta to L;

(463) (l) one or two R.sup.A are present, one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, where the optionally substituted phenyl is ortho to L;

(464) (m) at least one R.sup.A is C.sub.1-C.sub.6 alkyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O(OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl.

(465) (n) at least one R.sup.A is C.sub.1-C.sub.6 alkyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(466) (o) at least one R.sup.A is C.sub.1-C.sub.6 alkyl substituted with one or two groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl; or

(467) (p) only one R.sup.A is present and R.sup.A is C.sub.1-C.sub.6 alkyl substituted with one or two groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl.

(468) A preferred subgenus of any of the preceding subgenera includes compounds in which L is

(469) (a) a bond;

(470) (b) X-L.sup.1, wherein L.sup.1 is -linear C.sub.1-C.sub.6alkyl- optionally substituted with one or two R.sup.L groups

(471) (c) -linear C.sub.1-C.sub.6alkyl- substituted with one or two R.sup.L groups

(472) (d) -linear C.sub.1-C.sub.6alkyl- substituted with one R.sup.L group;

(473) (e) -linear C.sub.1-C.sub.3alkyl- substituted with one R.sup.L group;

(474) (f). -linear C.sub.1-C.sub.6alkyl-,

(475) (g) CH(R.sup.L) or

(476) (h) CH.sub.2.

(477) A preferred subgenus of any of the preceding subgenera includes compounds in which X is

(478) (a) a bond;

(479) (b) O, S, or N(R.sup.X);

(480) (c) O;

(481) (d) C(Y), S(O), S(O).sub.2, OC(O), N(R.sup.X)C(O), N(R.sup.X)S(O), OS(O).sub.2, or N(R.sup.X)S(O).sub.2;

(482) (e) C(O), C(NH), or N(H)C(O);

(483) (f) C.sub.1-C.sub.3alkylOC(O), C.sub.1-C.sub.3alkylN(R.sup.X)C(O), C.sub.1-C.sub.3alkylN(R.sup.X)S(O), C.sub.1-C.sub.3alkylOS(O).sub.2, or C.sub.1-C.sub.3alkylN(R.sup.X)S(O).sub.2;

(484) (g) C.sub.1-C.sub.3alkylN(R.sup.X)C(O); or

(485) (h) C.sub.1-C.sub.2alkylN(H)C(O).

(486) A preferred subgenus of any of the preceding subgenera includes compounds in which

(487) (a) at least one R.sup.L is C.sub.1-C.sub.6 alkyl optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.L11).sub.2, OR.sup.L11, ON(R.sup.L11).sub.2, N(R.sup.L11)N(R.sup.L11).sub.2, SR.sup.L11, C(O)R.sup.L11, C(O)OR.sup.L11, C(O)N(R.sup.L11).sub.2, S(O)R.sup.L11, S(O)OR.sup.L11, S(O)N(R.sup.L11).sub.2, S(O).sub.2R.sup.L11, S(O).sub.2OR.sup.L11, S(O).sub.2N(R.sup.L11).sub.2, OC(O)R.sup.L11, OC(O)OR.sup.L11, OC(O)N(R.sup.L11).sub.2, N(R.sup.L11)C(O)OR.sup.L11, or N(R.sup.L11)C(O)N(R.sup.L11).sub.2, wherein each R.sup.L11 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(488) (b) at least one R.sup.L is C.sub.1-C.sub.6 alkyl-OR.sup.L21, C.sub.1-C.sub.6 alkyl-NHR.sup.L21, C.sub.1-C.sub.6 alkyl-NHC(O)R.sup.L21, C.sub.2-C.sub.6 alkenyl-OR.sup.L21, C.sub.2-C.sub.6 alkenyl-NHR.sup.L21, or C.sub.2-C.sub.6 alkenyl-NHC(O)R.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(489) (c) at least one R.sup.L is N(R.sup.L21).sub.2, OR.sup.L21, ON(R.sup.L21).sub.2, N(R.sup.L21)N(R.sup.L21).sub.2, C(O)R.sup.L21, C(O)OR.sup.L21, C(O)N(R.sup.L21).sub.2, OC(O)R.sup.L21, OC(O)OR.sup.L21, OC(O)N(R.sup.L21).sub.2, N(R.sup.L21)C(O)OR.sup.L21, or N(R.sup.L21)C(O)N(R.sup.L21).sub.2, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(490) or (d) at least one R.sup.L is N(R.sup.L21).sub.2 or OR.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl, is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, C(O)OR.sup.L22, or C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(491) Another preferred genus of the fourteenth aspect includes compounds in which the compound of formula (XXI) is according to one of the formulas (XXII)-(XXIX),

(492) ##STR00893## ##STR00894##

(493) wherein m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

(494) A preferred subgenus of any of the formulas (XXV)-(XXVII) includes compounds in which n is 1, 2, 3, 4, or 5. Preferably, n is 1 or 2. More preferably, n is 1.

(495) A preferred subgenus of any of the formulas (XXII), (XXV), and (XXVIII), includes compounds in which m is 1.

(496) A preferred subgenus of any of the formulas (XXII)-(XXIV), includes compounds in which ring A indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzooxazolinyl, benzimidazolidinyl, benzothioxazolinyl, cromanyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, benzo[d][1,3]dioxolyl, tetrahydronaphthyl, indenyl, or dihydroindenyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups.

(497) Another preferred subgenus of any of the formulas (XXII)-(XXIV), includes compounds in which ring A is

(498) (a) heteroaryl optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups.

(499) (b) pyrrolyl, furanyl, thienyl, imidazolyl, benzothienyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothioxazolyl, benzotriazolyl, quinolinyl, or quinazolinyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups;

(500) (c) pyridinyl, pyrimidinyl, pyrazinyl, or 1,3,5-triazinyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups;

(501) (d) benzothienyl, indolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothioxazolyl, or benzotriazolyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups; or

(502) (e) benzothienyl, indolyl, or benzofuranyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups.

(503) Another preferred subgenus of any of formulas (XXII)-(XXIV), includes compounds in which ring A is tetrahydroquinolinyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzothienyl, 4,5,6,7-tetrahydrobenzo-furanyl, 4,5,6,7-tetrahydroindolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 4,5,6,7-tetrahydrobenzo-thioxazolyl, each optionally substituted with one or more R.sup.A groups, and preferably, substituted with one or two R.sup.A groups.

(504) Another preferred subgenus of any of formulas (XXII)-(XXIV), includes compounds in which ring A is C.sub.5-C.sub.10 cycloalkyl substituted with one or two R.sup.A groups. Preferably, ring A is C.sub.5-C.sub.7 cycloalkyl substituted with one or two R.sup.A groups.

(505) A preferred subgenus of any of the preceding subgenera of formulas (XXII)-(XXXIII), includes compounds in which

(506) (a) at least one R.sup.A is halogen, cyano, nitro, N(R.sup.A11).sub.2, OR.sup.A11, ON(R.sup.A11).sub.2, N(R.sup.A11)N(R.sup.A11).sub.2, SR.sup.A11, C(O)R.sup.A11, C(O)OR.sup.A11, C(O)N(R.sup.A11).sub.2, S(O)R.sup.A11, S(O)OR.sup.A11, S(O)N(R.sup.A11).sub.2, S(O).sub.2R.sup.A11, S(O).sub.2OR.sup.A11, S(O).sub.2N(R.sup.A11).sub.2, OC(O)R.sup.A11, OC(O)OR.sup.A11, OC(O)N(R.sup.A11).sub.2, N(R.sup.A11)C(O)OR.sup.A11, or N(R.sup.A11)C(O)N(R.sup.A11).sub.2, wherein each R.sup.A11 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sub.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O)R.sup.A12, S(O)OR.sup.A12, S(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, wherein each R.sup.A12 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(507) (b) at least one R.sup.A is halogen, cyano, nitro, NH.sub.2, OH, ONH.sub.2, NHNH.sub.2, C(O)OH, or C(O)NH.sub.2;

(508) (c) only one R.sup.A is present and R.sup.A is halogen, cyano, nitro, NH.sub.2, OH, ONH.sub.2, NHNH.sub.2, C(O)OH, or C(O)NH.sub.2;

(509) (d) at least one R.sup.A is N(R.sup.A11).sub.2 or OR.sup.A11, wherein each R.sup.A11 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sub.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O)R.sup.A12, S(O)OR.sup.A12, S(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, wherein herein each R.sup.A12 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(510) (e) at least one R.sup.A is NHR.sup.A11 or OR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sub.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(511) (f) at least one R.sup.A is NHR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sub.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(512) (g) only one R.sup.A is present and R.sup.A is NHR.sup.A11, wherein R.sup.A11 is phenyl or pyridinyl, each optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.A12).sub.2, OR.sup.A12, ON(R.sup.A12).sub.2, N(R.sup.A12)N(R.sup.A12).sub.2, SR.sup.A12, C(O)R.sup.A12, C(O)OR.sup.A12, C(O)N(R.sup.A12).sub.2, S(O).sub.2R.sup.A12, S(O).sub.2OR.sup.A12, S(O).sub.2N(R.sup.A12).sub.2, OC(O)R.sup.A12, OC(O)OR.sup.A12, OC(O)N(R.sup.A12).sub.2, N(R.sup.A12)C(O)OR.sup.A12, or N(R.sup.A12)C(O)N(R.sup.A12).sub.2, C.sub.1-C.sub.6 alkyl, -aryl, or -heteroaryl, wherein each R.sup.A12 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(513) (h) at least one R.sup.A is C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(514) (i) at least one R.sup.A is -aryl or -heteroaryl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(515) (j) only one R.sup.A is present and R.sup.A is -aryl or -heteroaryl, each optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(516) (j) one of two R.sup.A are present and one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(517) (k) one or two R.sup.A are present, one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, where the optionally substituted phenyl is ortho or meta to X;

(518) (l) one or two R.sup.A are present, one R.sup.A is phenyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, -heteroaryl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, where the optionally substituted phenyl is ortho to X;

(519) (k) one R.sup.A is C.sub.1-C.sub.6 alkyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl;

(520) (l) at least one R.sup.A is C.sub.1-C.sub.6 alkyl optionally substituted with one or more groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(521) (m) at least one R.sup.A is C.sub.1-C.sub.6 alkyl substituted with one or two groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl; or

(522) (n) only one R.sup.A is present and R.sup.A is C.sub.1-C.sub.6 alkyl substituted with one or two groups which are each independently halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A21).sub.2, OR.sup.A21, ON(R.sup.A21).sub.2, N(R.sup.A21)N(R.sup.A21).sub.2, SR.sup.A21, C(O)R.sup.A21, C(O)OR.sup.A21, C(O)N(R.sup.A21).sub.2, S(O)R.sup.A21, S(O)OR.sup.A21, S(O)N(R.sup.A21).sub.2, S(O).sub.2R.sup.A21, S(O).sub.2OR.sup.A21, S(O).sub.2N(R.sup.A21).sub.2, OC(O)R.sup.A21, OC(O)OR.sup.A21, OC(O)N(R.sup.A21).sub.2, N(R.sup.A21)C(O)OR.sup.A21, or N(R.sup.A21)C(O)N(R.sup.A21).sub.2, wherein each R.sup.A21 is independently hydrogen or C.sub.1-C.sub.6 alkyl.

(523) A preferred subgenus of any of the preceding subgenera of formulas (XXII)-(XXXIII), includes compounds in which

(524) (a) X is a bond;

(525) (b) X is O, S, or N(R.sup.X);

(526) (c) X is O;

(527) (d) X is C(Y), S(O), S(O).sub.2, OC(O), N(R.sup.X)C(O), N(R.sup.X)S(O), OS(O).sub.2, or N(R.sup.X)S(O).sub.2;

(528) (e) X is C(O), C(NH), or N(H)C(O);

(529) (f) X is C.sub.1-C.sub.3alkylOC(O), C.sub.1-C.sub.3alkylN(R.sup.X)C(O), C.sub.1-C.sub.3alkylN(R.sup.X)S(O), C.sub.1-C.sub.3alkylOS(O).sub.2, or C.sub.1-C.sub.3alkylN(R.sup.X)S(O).sub.2;

(530) (g) X is C.sub.1-C.sub.3alkylN(R.sup.X)C(O); or

(531) (h) X is C.sub.1-C.sub.2alkylN(H)C(O).

(532) A preferred subgenus of any of the preceding subgenera of formulas (XXII), (XXV), and (XXVIII), includes compounds in which

(533) (a) m is 1, 2, or 3, and X is C(Y), S(O), S(O).sub.2, OC(O), N(R.sup.X)C(O), N(R.sup.X)S(O), OS(O).sub.2, or N(R.sup.X)S(O).sub.2;

(534) (b) m is 1 or 2, and X is C(O), C(NH), or N(H)C(O);

(535) (c) m is 1, 2, or 3, and X is O, S, or N(R.sup.X);

(536) (d) m is 1 or 2, and X is O;

(537) (e) m is 1, 2, or 3, and X is C.sub.1-C.sub.3alkylOC(O), C.sub.1-C.sub.3alkylN(R.sup.X)C(O), C.sub.1-C.sub.3alkylN(R.sup.X)S(O), C.sub.1-C.sub.3alkylOS(O).sub.2, or C.sub.1-C.sub.3alkylN(R.sup.X)S(O).sub.2;

(538) (f) m is 1, 2, or 3, and X is C.sub.1-C.sub.3alkylN(R.sup.X)C(O); or

(539) (g) m is 1 or 2, and X is C.sub.1-C.sub.2alkylN(H)C(O).

(540) A preferred subgenus of any of the preceding subgenera of formulas (XXII)-(XXXIII), includes compounds in which

(541) (a) one R.sup.L is C.sub.1-C.sub.6 alkyl optionally substituted with one or two groups which are each independently halogen, cyano, nitro, N(R.sup.L11).sub.2, OR.sup.L11, ON(R.sup.L11).sub.2, N(R.sup.L11)N(R.sup.L11).sub.2, SR.sup.L11, C(O)R.sup.L11, C(O)OR.sup.L11, C(O)N(R.sup.L11).sub.2, S(O)R.sup.L11, S(O)OR.sup.L11, S(O)N(R.sup.L11).sub.2, S(O).sub.2R.sup.L11, S(O).sub.2OR.sup.L11, S(O).sub.2N(R.sup.L11).sub.2, OC(O)R.sup.L11, OC(O)OR.sup.L11, OC(O)N(R.sup.L11).sub.2, N(R.sup.L11)C(O)OR.sup.L11, or N(R.sup.L11)C(O)N(R.sup.L11).sub.2, wherein each R.sup.L11 is independently hydrogen or C.sub.1-C.sub.6 alkyl;

(542) (b) one R.sup.L is C.sub.1-C.sub.6 alkyl-OR.sup.L21, C.sub.1-C.sub.6 alkyl-NHR.sup.L21, C.sub.1-C.sub.6 alkyl-NHC(O)R.sup.L21, C.sub.2-C.sub.6 alkenyl-OR.sup.L21, C.sub.2-C.sub.6 alkenyl-NHR.sup.L21, or C.sub.2-C.sub.6 alkenyl-NHC(O)R.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(543) (c) one R.sup.L is N(R.sup.L21).sub.2, OR.sup.L21, ON(R.sup.L21).sub.2, N(R.sup.L21)N(R.sup.L21).sub.2, C(O)R.sup.L21, C(O)OR.sup.L21, C(O)N(R.sup.L21).sub.2, OC(O)R.sup.L21, OC(O)OR.sup.L21, OC(O)N(R.sup.L21).sub.2, N(R.sup.L21)C(O)OR.sup.L21, or N(R.sup.L21)C(O)N(R.sup.L21).sub.2, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl; or

(544) (d) one R.sup.L is N(R.sup.L21).sub.2 or OR.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, or C.sub.1-C.sub.6 alkylheteroaryl, wherein each alkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl, is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, C(O)OR.sup.L22, or C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(545) In our study of the activities of the foregoing compounds, we made the following observations and conclusions:

(546) (1) The O in the aminoxy group is essential.

(547) (2) A primary NH.sub.2 group in aminoxy group is required for activity;

(548) (3) The order of RONH.sub.2 is essential

(549) (4) Substitution of the 3-NO.sub.2 group by 3-Cl; 3-Br; 3-I; 3,5-Cl; increases activity 3-fold.

(550) (5) The preferred position for phenyl substitution with small groups is in meta, followed by ortho and para.

(551) (6) Multiple substitutions on the phenyl ring are accepted.

(552) (7) Mono or bicyclic heterocycles, aromatic or non-aromatic can substitute the phenyl ring.

(553) (8) Substitutions of the phenyl ring with another phenyl ring (substituted in para with Cl, OCH.sub.3 or CH.sub.3) is accepted in ortho and in meta. The preferred position of substitution on the main phenyl ring depends on the secondary substituents in the secondary phenyl ring.

(554) (9) A secondary aromatic ring can be linked to the main phenyl ring either directly, or through a linker. The longer the linker, the lesser the activity, though the activity is greatly affected by the nature of the substituents on the secondary phenyl ring.

(555) (10) Several aromatic heterocycles can be joined to the C6 position of the main phenyl ring, alone or in combination with 3-Cl substitution on the main phenyl ring.

(556) (11) Rigidification of the aminoxy group into a co-planar or non co-planar structure with the phenyl ring, generally diminishes compound activity.

(557) (12) Increasing linker length decreases activity.

(558) (13) Linker L substitutions with R.sup.L groups are accepted.

(559) (14) Substitutions of the benzylic position with ester and amides are well tolerated and increase activity compared to the unsubstituted parent compound.

(560) (15) Substitution of the benzylic carbon with a phenyl group via a C0-C3 carbon or ether linker maintains the activity with respect to the unsubstituted benzylic carbon. On the contrary, substitution with a non-aromatic ring such as cyclohexyl or N-morpholino generally reduces the activity (especially for the N-morpholino).

(561) (16) The length of the R.sup.L groups have an influence on the activity. A C0 linker results in the highest activity, followed by a C2 linker and then by a C1 linker, for both aromatic or non-aromatic rings.

(562) (17) Inclusion of an ether linker in R.sup.L increases the activity compared to the corresponding alkyl linker.

(563) The foregoing points are presented as a general guide of preferred characteristics of the compounds of the invention only and are not intended and should not be construed as limiting all aspects or embodiments of the compounds.

(564) In a fifteenth aspect, the invention provides a pharmaceutical composition comprising a compound described in any of the preceding aspects (and any embodiment thereof), and a pharmaceutically acceptable carrier, diluent, or excipient, provided the compound is not 2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-1-(aminooxy)ethane. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.

(565) In a sixteenth aspect, the invention provides a use of compounds of described in any of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase. Medical conditions contemplated in this sixteenth aspect include all the conditions described herein.

(566) In a seventeenth aspect, the invention provides a use of compounds of described in any of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament to stimulate T cell proliferation or to reverse an immunologic state of anergy or immunosuppression.

(567) In an embodiment of the seventeenth aspect, the anergy or immunosuppression is caused by expression of the enzyme indoleamine-2,3-dioxygenase.

(568) In a eighteenth aspect, the invention provides a the use of compounds of described in any of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of immunosuppression associated with cancer, infectious diseases, or viral infections.

(569) In one embodiment of the eighteenth aspect, the invention provides the use of compounds of described in any of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of tumor-specific immunosuppression associated with cancer. Preferably, the cancer is cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia, melanoma, and the like.

(570) In another embodiment of the eighteenth aspect, the invention the use of compounds described in any of the preceding aspects (and any embodiment thereof), as defined above, and embodiments thereof as defined above, for the preparation of a medicament for the treatment of infectious diseases. Preferably, the infections disease is tuberculosis or Leishmaniasis.

(571) In another embodiment of the eighteenth aspect, the invention provides the use of compounds described in any of the preceding aspects (and any embodiment thereof), as defined above, and embodiments thereof as defined above, for the preparation of a medicament for the treatment of infectious diseases where the infectious disease is a viral infection. Preferably, the viral infection is selected from the group consisting of: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, poliovirus, coxsackie virus, and human immunodeficiency virus (HIV). More preferably, the viral infection is human immunodeficiency virus (HIV).

(572) In a nineteenth aspect, the invention provides pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier and a compound of the formula (XL),

(573) ##STR00895##

(574) or a pharmaceutically acceptable salt thereof, wherein

(575) ring A is phenyl, tetrahydronaphthyl, quinolinyl, indolyl, benzothienyl, benzothiazolyl, benzodioxanyl, benzopyranyl, benzofuranyl, pyridyl or pyrimidinyl, each optionally substituted with one or more R.sup.A groups, wherein

(576) each R.sup.A is independently halogen, cyano, nitro, N(R.sup.A1).sub.2, OR.sup.A1, N(R.sup.A1)N(R.sup.A1).sub.2, SR.sup.A1, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)OR.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, N(R.sup.A1)C(O)OR.sup.A1, N(R.sup.A1)S(O).sub.2R.sup.A1, N(R.sup.A1)C(O)OR.sup.A1, N(R.sup.A1)C(O)N(R.sup.A1).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.A1).sub.2, OR.sup.A1, N(R.sup.A1)N(R.sup.A1).sub.2, SR.sup.A1, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)OR.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, N(R.sup.A1)C(O)OR.sup.A1, or N(R.sup.A1)C(O)N(R.sup.A1).sub.2, wherein

(577) each R.sup.A1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.A2).sub.2, OR.sup.A2, N(R.sup.A2)N(R.sup.A2).sub.2, SR.sup.A2, C(O)R.sup.A2, C(O)OR.sup.A2, C(O)N(R.sup.A2).sub.2, S(O)R.sup.A2, S(O)OR.sup.A2, S(O)N(R.sup.A2).sub.2S(O).sub.2R.sup.A2, S(O).sub.2OR.sup.A2, S(O).sub.2N(R.sup.A2).sub.2, OC(O)R.sup.A2, OC(O)OR.sup.A2, OC(O)N(R.sup.A2).sub.2, N(R.sup.A2)C(O)OR.sup.A2, or N(R.sup.A2)C(O)N(R.sup.A2).sub.2, wherein

(578) each R.sup.A2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl; and

(579) L is a bond or C(H)(R.sup.L), wherein

(580) R.sup.L is hydrogen, halogen, cyano, nitro, N(R.sup.L1).sub.2, OR.sup.L1, ON(R.sup.L1).sub.2, N(R.sup.L1)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)R.sup.L1, N(R.sup.L1)S(O).sub.2R.sup.L1, SR.sup.L1, C(O)R.sup.L1, C(O)OR.sup.L1, C(O)N(R.sup.L1).sub.2, S(O)R.sup.L1, S(O)OR.sup.L1, S(O)N(R.sup.L1).sub.2, S(O).sub.2R.sup.L1, S(O).sub.2OR.sup.L1, S(O).sub.2N(R.sup.L1).sub.2, OC(O)R.sup.L1, OC(O)OR.sup.L1, OC(O)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)OR.sup.L1, N(R.sup.L1)C(O)N(R.sup.L1).sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, -heterocyclyl, or C.sub.1-C.sub.6 alkylheterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl, and alkylheterocyclyl is optionally substituted with one halogen, cyano, nitro, N(R.sup.L1).sub.2, N(R.sup.L1)C(O)R.sup.L1, OR.sup.L1, N(R.sup.L1)N(R.sup.L1).sub.2, SR.sup.L1, C(O)R.sup.L1, C(O)OR.sup.L1, C(O)N(R.sup.L1).sub.2, S(O)R.sup.L1, S(O)OR.sup.L1, S(O)N(R.sup.L1).sub.2, S(O).sub.2R.sup.L1, S(O).sub.2OR.sup.L1, S(O).sub.2N(R.sup.L1).sub.2, OC(O)R.sup.L1, OC(O)OR.sup.L1, OC(O)N(R.sup.L1).sub.2, N(R.sup.L1)C(O)OR.sup.L1, or N(R.sup.L1)C(O)N(R.sup.L1).sub.2, wherein

(581) each R.sup.L1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halo en cyano nitro, N(R.sup.L11).sub.2, OR.sup.L11, ON(R.sup.L11).sub.2, N(R.sup.L11)N(R.sup.L11).sub.2, SR.sup.L11, C(O)R.sup.L11, C(O)OR.sup.L11, C(O)N(R.sup.L11).sub.2, S(O)R.sup.L11, S(O)OR.sup.L11, S(O)N(R.sup.L11).sub.2S(O).sub.2R.sup.L11, S(O).sub.2OR.sup.L11, S(O).sub.2N(R.sup.L11).sub.2, OC(O)R.sup.L11, OC(O)OR.sup.L11, OC(O)N(R.sup.L11).sub.2, N(R.sup.L11)C(O)OR.sup.L11, N(R.sup.L11)C(O)N(R.sup.L11).sub.2, wherein each R.sup.L11 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl,

(582) provided that

(583) (i) when ring A is phenyl and R.sup.L is hydrogen, then ring A is substituted with at least one R.sup.A;

(584) (ii) when ring A is phenyl and R.sup.L is hydrogen, COOH, unsubstituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-COOH, or unsubstituted phenyl, then ring A is substituted with at least one R.sup.A that is not halogen, hydroxy, trifluoromethyl, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.4 alkoxy, nitro, amino, C.sub.1-C.sub.4alkylthio, benzyloxy, or OC(O)R.sup.L1;

(585) (iii) when ring A is phenyl and R.sup.L is hydrogen, then R.sup.A is not hydroxy, C(O)N(H)(isopropyl), or CH.sub.2C(O)OR.sup.A1;

(586) (iv) when ring A is phenyl and L is a bond, then ring A is substituted with at least one R.sup.A that is not halogen, nitro, trifluoromethyl, or methyl.

(587) In one embodiment of the nineteenth aspect, the compound is according to formula (XLI),

(588) ##STR00896##

(589) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

(590) In another embodiment of the nineteenth aspect, the compound is according to formula (XLII),

(591) ##STR00897##

(592) or a pharmaceutically acceptable salt thereof, wherein

(593) n is 0, 1, or 2; and

(594) R.sup.B is aryl or heteroaryl, each optionally substituted with one or more halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, -heterocyclyl, N(R.sup.B1).sub.2, OR.sup.B1, N(R.sup.B1)N(R.sup.B1).sub.2, SR.sup.B1, C(O)R.sup.B1, C(O)OR.sup.B1, C(O)N(R.sup.B1).sub.2, S(O)R.sup.B1, S(O)OR.sup.B1, S(O)N(R.sup.B1).sub.2, S(O).sub.2R.sup.B1, S(O).sub.2OR.sup.B1, S(O).sub.2N(R.sup.B1).sub.2, OC(O)R.sup.B1, OC(O)OR.sup.B1, OC(O)N(R.sup.B1).sub.2, N(R.sup.B1)C(O)OR.sup.B1, or N(R.sup.B1)C(O)N(R.sup.B1).sub.2, wherein

(595) each R.sup.B1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, or -heterocyclyl, wherein each alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogen, cyano, nitro, N(R.sup.B2).sub.2, OR.sup.B2, N(R.sup.B2)N(R.sup.B2).sub.2, SR.sup.B2, C(O)R.sup.B2, C(O)OR.sup.B2, C(O)N(R.sup.B2).sub.2, S(O)R.sup.B2, S(O)OR.sup.B2, S(O)N(R.sup.B2).sub.2, S(O).sub.2R.sup.B2, S(O).sub.2OR.sup.B2, S(O).sub.2N(R.sup.B2).sub.2, OC(O)R.sup.B2, OC(O)OR.sup.B2, OC(O)N(R.sup.B2).sub.2, N(R.sup.B2)C(O)OR.sup.B2, or N(R.sup.B2)C(O)N(R.sup.B2).sub.2, wherein

(596) each R.sup.B2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(597) In another embodiment of the nineteenth aspect, the compound is according to formula (XLII),

(598) ##STR00898##

(599) or a pharmaceutically acceptable salt thereof.

(600) In an embodiment of formulae (XLII) and (XLIII), R.sup.B is phenyl optionally substituted with one or more halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; N(R.sup.B1).sub.2, OR.sup.B1, or C(O)OR.sup.B1, wherein each R.sup.B1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, wherein each R.sup.B2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(601) In another embodiment of formulae (XLII) and (XLIII), R.sup.B is phenyl optionally substituted with one halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; N(R.sup.B1).sub.2, OR.sup.B1, or C(O)OR.sup.B1, wherein each R.sup.B1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, wherein each R.sup.B2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(602) In an embodiment of formulae (XLII) and (XLIII), R.sup.B is thienyl, pyrimidinyl, indolyl, or pyridyl.

(603) In another embodiment of the nineteenth aspect, the compound is according to formula (XLIV),

(604) ##STR00899##

(605) or a pharmaceutically acceptable salt thereof.

(606) In an embodiment of formulae (XLIV), R.sup.B is phenyl optionally substituted with one or more halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; N(R.sup.B1).sup.2, OR.sup.B1, or C(O)OR.sup.B1, wherein each R.sup.B1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, wherein each R.sup.B2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(607) In another embodiment of formulae (XLIV), R.sup.B is phenyl optionally substituted with one halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; N(R.sup.B1).sup.2, OR.sup.B1, or C(O)OR.sup.B1, wherein each R.sup.B1 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, wherein each R.sup.B2 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl.

(608) In another embodiment of formulae (XLIV), R.sup.B is thienyl, pyrimidinyl, indolyl, or pyridyl.

(609) In any of formulae (XL)-(XLIV), and any of the preceding embodiments thereof, RL is one of the following:

(610) (a) R.sup.L is hydrogen;

(611) (b) C.sub.1-C.sub.6 alkyl-OR.sup.L21, C.sub.1-C.sub.6 alkyl-NHR.sup.L21, C.sub.1-C.sub.6 alkyl-NHC(O)R.sup.L21, C.sub.2-C.sub.6 alkenyl-OR.sup.L21, C.sub.2-C.sub.6 alkenyl-NHR.sup.L21 or C.sub.2-C.sub.6 alkenyl-NHC(O)R.sup.L21 wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(612) (c) C.sub.1-C.sub.6 alkyl-OR.sup.L21, C.sub.1-C.sub.6 alkyl-NHR.sup.L21, or C.sub.1-C.sub.6 alkyl-NHC(O)R.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(613) (d) C.sub.2-C.sub.6 alkenyl-OR.sup.L21, C.sub.2-C.sub.6 alkenyl-NHR.sup.L21, or C.sub.2-C.sub.6 alkenyl-NHC(O)R.sup.L21, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(614) (e) N(R.sup.L21).sub.2, OR.sup.L21, ON(R.sup.L21).sub.2, N(R.sup.L21)N(R.sup.L21).sub.2, C(O)R.sup.L21, C(O)OR.sup.L21, C(O)N(R.sup.L21).sub.2, OC(O)R.sup.L21, OC(O)OR.sup.L21, OC(O)N(R.sup.L21).sub.2, N(R.sup.L21)C(O)OR.sup.L21, or N(R.sup.L21)C(O)N(R.sup.L21).sub.2, wherein each R.sup.L21 is independently hydrogen, C.sub.1-C.sub.6 alkyl, -aryl, C.sub.1-C.sub.6 alkylaryl, -heteroaryl, C.sub.1-C.sub.6 alkylheteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl(C.sub.3-C.sub.8)cycloalkyl, or -heterocyclyl, wherein alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, and heterocyclyl, is optionally substituted with one or more groups which are each independently halogen, cyano, nitro, N(R.sup.L22).sub.2, OR.sup.L22, ON(R.sup.L22).sub.2, N(R.sup.L22)N(R.sup.L22).sub.2, SR.sup.L22, C(O)R.sup.L22, C(O)OR.sup.L22, C(O)N(R.sup.L22).sub.2, S(O)R.sup.L22, S(O)OR.sup.L22, S(O)N(R.sup.L22).sub.2, S(O).sub.2R.sup.L22, S(O).sub.2OR.sup.L22, S(O).sub.2N(R.sup.L22).sub.2, OC(O)R.sup.L22, OC(O)OR.sup.L22, OC(O)N(R.sup.L22).sub.2, N(R.sup.L22)C(O)OR.sup.L22, or N(R.sup.L22)C(O)N(R.sup.L22).sub.2, wherein each R.sup.L22 is independently hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or C.sub.1-C.sub.6 alkylaryl;

(615) (f) C.sub.1-C.sub.2 alkyl-N(R.sup.L1).sub.2;

(616) (g) C.sub.1-C.sub.2 alkyl-N(R.sup.L1)C(O)R.sup.L1;

(617) (h) C.sub.1-C.sub.2 alkyl-OR.sup.L1;

(618) (i) C.sub.1-C.sub.2 alkyl-C(O)OR.sup.L1;

(619) (j) C.sub.1-C.sub.2 alkyl-C(O)N(R.sup.L1).sub.2;

(620) (k) C.sub.1-C.sub.2 alkyl-N(R.sup.L1)C(O)OR.sup.L1; or

(621) (l) C(O)N(R.sup.L1).sub.2.

(622) In a twentieth aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient, diluent, or carrier and a compound in Table 15 (infra).

(623) In a twenty-first aspect, the invention provides methods for treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a pharmaceutical composition of the nineteenth of twentieth aspects.

(624) In an embodiment of the twenty-first aspect, the immunosuppression is associated with an infectious disease, or cancer.

(625) In another embodiment of the twenty-first aspect, the immunosuppression is associated with an infectious disease and the infectious disease is a viral infection selected from the group consisting of: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).

(626) In an embodiment of the twenty-first aspect, the immunosuppression is immunsupression associated with HIV-1 infection.

(627) In another embodiment of the twenty-first aspect, the immunosuppression is associated with an infectious disease and the infectious disease is tuberculosis or Leishmaniasis.

(628) In another embodiment of the twenty-first aspect, the immunosuppression is associated with a cancer.

(629) In an embodiment of the twenty-first aspect, the immunosuppression is tumor-specific immunosuppression associated with cancer.

(630) In another embodiment of the twenty-first aspect, the immunosuppression is associated with a cancer, wherein the cancer is colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head, or neck cancer, or lymphoma, leukemia, or melanoma.

(631) Definitions

(632) Terms used herein may be preceded and/or followed by a single dash, , or a double dash, , to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read left to right unless a dash indicates otherwise. For example, C.sub.1-C.sub.6alkoxycarbonyloxy and OC(O)C.sub.1-C.sub.6alkyl indicate the same functionality; similarly arylalkyl and -alkylaryl indicate the same functionality.

(633) The term alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

(634) The term linear alkenyl as used herein means straight chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and 3-decenyl.

(635) The term alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

(636) The term alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an alkyl group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CHC(CH.sub.3), CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2.

(637) The term linear alkyl as used herein, means a straight chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Linear alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When a linear alkyl group is a linking group between two other moieties, then it is also a straight chain; examples include, but are not limited to CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2.

(638) The term alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

(639) The term aryl, as used herein, means phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one aromatic ring containing only carbon atoms in the aromatic ring. The bicyclic aryl can be naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to a heterocyclyl. The bicyclic aryl can be attached to the parent molecular moiety through any atom contained within the bicyclic aryl. Representative examples of the bicyclic aryl include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, 2,3-dihydrobenzofuranyl, or benzo[d][1,3]di-oxolyl.

(640) The term arylalkyl and -alkylaryl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

(641) The term carboxy as used herein, means a CO.sub.2H group.

(642) The term cyano as used herein, means a CN group.

(643) The term cyanoalkyl as used herein, means a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

(644) The term cycloalkyl as used herein, means a monocyclic, bicyclic, or tricyclic ring systems, where such groups can be saturated or unsaturated, but not aromatic. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0.sup.3,7]nonane and tricyclo[3.3.1.1.sup.3,7]decane (adamantane).

(645) The term formyl as used herein, means a C(O)H group.

(646) The term halo or halogen as used herein, means Cl, Br, I or F.

(647) The term haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

(648) The term heteroaryl, as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.

(649) The term heteroarylalkyl and -alkylheteroaryl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl, (6-(trifluoromethyl)pyridin-3-yl)methyl, (6-(cyano)pyridin-3-yl)methyl, (2-(cyano)pyridin-4-yl)methyl, (5-(cyano)pyridin-2-yl)methyl, (2-(chloro)pyridin-4-yl)methyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

(650) The term heterocyclyl as used herein, means a monocyclic heterocycle or a bicyclic heterocycle, where such groups can be saturated or unsaturated, but not aromatic. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a cycloalkyl, or a monocyclic heterocycle fused to a cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heterocycle. Representative examples of bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzo dioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl.

(651) The term hydroxy as used herein, means an OH group.

(652) The term hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

(653) The term mercapto as used herein, means a SH group.

(654) The term nitro as used herein, means a NO.sub.2 group.

(655) The term saturated as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.

(656) The term unsaturated as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

(657) As used herein, the term cell is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

(658) As used herein, the term contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, contacting the IDO enzyme with a compound includes the administration of a compound described herein to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the IDO enzyme.

(659) As used herein, the term individual or patient, used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

(660) As used herein, the phrase therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:

(661) (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

(662) (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and

(663) (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

(664) As used here, the terms treatment and treating means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., IDO modulation or tryptophan degradation inhibition).

(665) As used herein, the terms catalytic pocket, catalytic site, active site collectively and indistinctly refer to a region of the enzyme that contains amino acid residues responsible for the substrate binding (charge, hydrophobicity, steric hindrance) and catalytic amino acid residues which act as proton donors or acceptors or are responsible for binding a cofactor and participate in the catalisis of a chemical reaction.

(666) As used herein, the phrase pharmaceutically acceptable salt refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hyrdoiodic, alkanoic such as acetic, HOOC(CH.sub.2).sub.nCOOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

(667) Methods of Use

(668) Compounds described herein can modulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO). The term modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor. Accordingly, compounds described herein can be used in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein. In some embodiments, the compounds described herein can act as inhibitors of IDO. In further embodiments, the compounds described herein can be used to modulate activity of IDO in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound described herein.

(669) Further provided are methods of inhibiting the degradation of tryptophan and preventing the production of N-formylkynurenine in a system containing cells expressing IDO such as a tissue, living organism, or cell culture. In some embodiments methods of altering (e.g., increasing) extracellular tryptophan levels in a mammal comprise administering an effective amount of a compound of composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.

(670) Further provided are methods of inhibiting immunosuppression such as IDO-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein. IDO-mediated immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, infectious diseases (e.g., viral infection), viral replication, etc.

(671) Further provided are methods for treating tumor-specific immunosuppression associated with cancer in a patient by administering to the patient an effective amount of a compound or composition recited herein. Example tumor-specific immunosuppression associated with cancers treatable by the methods herein include immunosuppression associated with cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.

(672) For example, IDO-mediated immunosuppression associated with viral infection, is associated with a viral infection selected from the group consisting of: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).

(673) Further provided are methods for treating immunsupression associated with an infectious disease, e.g., HIV-1 infection, in a patient by administering to the patient an effective amount of a compound or composition recited herein.

(674) In other examples, IDO-mediated immunosuppression associated with and infectious diseases is associated with tuberculosis or Leishmaniasis.

(675) For example, a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for the treatment of a disease state, such as a cancer, can benefit from administering to the patient a therapeutically effective amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or treatment thereof.

(676) Further provided are methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound described herein or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity. An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.

(677) Examples of IDO-associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor. Example cancers treatable by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.

(678) Combination Therapy

(679) One or more additional pharmaceutical agents for treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds described herein for treatment of IDO-associated diseases, disorders or conditions (as noted above) or for enhancing the effectiveness of the treatment of a disease state or condition, such as cancer. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

(680) Suitable antiviral agents contemplated for use in combination with the compounds described herein can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.

(681) Example suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [()FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2,3-dicleoxy-5-fluoro-cytidene); DAPD, (()-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.

(682) Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

(683) Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

(684) Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-), etoposide, and teniposide.

(685) Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

(686) Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.

(687) Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-, etc.).

(688) Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.

(689) Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

(690) Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

(691) Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, N.J.), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

(692) Pharmaceutical Formulations and Dosage Forms

(693) When employed as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions which is a combination of a compound described herein and a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

(694) Also, pharmaceutical compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

(695) In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

(696) Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

(697) The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

(698) The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

(699) For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.

(700) The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

(701) The liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

(702) Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

(703) The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

(704) The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

(705) The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 g/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

(706) The compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.

(707) Screening of IDO Inhibitory Compounds

(708) Molecular Modeling Methods

(709) Protein structure information, typically in the form of the atomic structure coordinates, can be used in a variety of computational or computer-based methods to design, screen for or identify compounds that bind to the catalytic site of IDO. Such information is useful to design improved analogues of known IDO inhibitors or to design novel classes of compounds based on the structure of reaction intermediates of IDOcomplexed with its substrates oxygen and tryptophan.

(710) In one embodiment, compounds whose structure mimics the reaction intermediates of tryptophan dioxygenation catalyzed by IDO can also be deduced from the proposed reaction mechanism.

(711) In still another embodiment, the structure of the IDO catalytic domain and enzyme active site can be used to computationally screen small molecule databases for functional groups or compounds that can bind in whole, or in part, to IDO. In this screening, the quality of fit of such entities or compounds to the binding site may be judged by methods such as estimated interaction energy or by shape complementarity. See, for example, Meng et al., (1992), J. Comp. Chem., 13:505-524.

(712) Compounds fitting the catalytic site serve as a starting point for an iterative design, synthesis and test cycle in which new compounds are selected and optimized for desired properties including affinity, efficacy, and selectivity. For example, the compounds can be subjected to additional modification, such as replacement or addition of R-group substituents of a core structure identified for a particular class of binding compounds, modeling or activity screening if desired, and then subjected to additional rounds of testing.

(713) By modeling is intended to mean quantitative and qualitative analysis of molecular structure and/or function based on atomic structural information and interaction models of a receptor and a ligand agonist or antagonist. Modeling thus includes conventional numeric-based molecular dynamic and energy minimization models, interactive computer graphic models, modified molecular mechanics models, distance geometry and other structure-based constraint models. Modeling is performed using a computer running specialized software.

(714) Molecular Docking

(715) Identification of IDO protein structure complexed with the IDO inhibitor 4-phenylimidazole and identification of the catalytic site structure has made it possible to apply the principles of molecular recognition to evaluate a variety of compound structures which are complementary to the structure of the site. Accordingly, computer programs that employ various docking algorithms can be used to identify compounds that fit into the catalytic site of IDO and can interact with amino acids defining such catalytic pocket, or with its heme cofactor, thus preventing binding and/or processing of its natural substrate, tryptophan. Fragment-based docking can also be used to build molecules de novo inside the catalytic site by placing molecular fragments that have a complementary fit with the site, thereby optimizing intermolecular interactions and subsequently synthesizing molecules that contain several of the molecular fragments that interact with amino acids in the catalytic pocket. Techniques of computational chemistry can further be used to optimize the geometry of the bound conformations.

(716) Docking may be accomplished using commercially available software such as GLIDE (available from Schrodinger, Inc., Portland, Oreg.); DOCK (Kuntz et al., (1982), J. Mol. Biol., 161:269-288, available from University of California, San Francisco, Calif.); AUTODOCK (Goodsell & Olsen, (1990), Proteins: Structure, Function, and Genetics 8:195-202, available from Scripps Research Institute, La Jolla, Calif.; GOLD (Jones, et al., (1995), J. Mol. Biol., 245:43-53, available from the Cambridge Crystallographic Data Centre, 12 Union Road. Cambridge, U.K.; QUANTA (available from Accelrys, a subsidiary of Pharmacopeia, Inc.); SYBYL, (available from Tripos, Inc., 1700 South Hanley Road, St. Louis, Mo.), and ICM (Abagayan, et al., available from MolSoft, L.L.C., 3366 North Torrey Pines Court, Suite 300, La Jolla, Calif.).

(717) Docking is typically followed by energy minimization and molecular dynamics simulations of the docked molecule, using molecular mechanics force fields such as MM2 (see, e.g., Rev. Comp. Chem., 3, 81 (1991)), MM3 (Allinger, N. L., Bowen, J. P., and coworkers, University of Georgia; see, J. Comp. Chem., 17:429 (1996); available from Tripos, Inc., 1699 South Hanley Road, St. Louis, Mo.), CHARMM (see, e.g., B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S. Swaminathan, and M. Karplus, CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations, J. Comp. Chem., 4, 187-217, (1983)), a version of AMBER such as version 7, (Kollman, P. A., et al., School of Pharmacy, Department of Pharmaceutical Chemistry, University of California at San Francisco), and Discover (available from Accelrys, a subsidiary of Pharmacopeia, Inc.).

(718) Constructing Molecules that Bind to IDO

(719) A compound that binds to the catalytic site of IDO, thereby exerting a modulatory or other effect on its function, may be computationally designed and evaluated by means of a series of steps in which functional groups or other fragments are screened and selected for their ability to associate with the individual binding pockets or other areas of the IDO catalytic pocket. One of ordinary skill in the art may use one of several methods to screen functional groups and fragments for their ability to associate with IDO. Selected fragments or functional groups may then be positioned in a variety of orientations, or docked, within the catalytic pocket of IDO as described above.

(720) Specialized computer programs may assist in the process of selecting fragments or functional groups, or whole molecules that can fit into and populate a binding site, or can be used to build virtual libraries of compounds. These include: GRID (Goodford, (1985), J. Med. Chem., 28:849-857, available from Oxford University, Oxford, UK); and MCSS (Miranker & Karplus, (1991), Proteins: Structure, Function and Genetics 11:29-34, available from Accelrys, a subsidiary of Pharmacopeia, Inc., as part of the Quanta package).

(721) Once suitable functional groups or fragments have been selected, they can be assembled into a single compound or inhibitor. Assembly may be performed by visual inspection and by manual model building using software such as QUANTA or SYBYL, while observing the relationship of the fragments to each other in relation to a three-dimensional image of the structure coordinates of IDO catalytic pocket.

(722) Alternatively, fragment assembly can be performed using the software CAVEAT (Bartlett et al., CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules, in Molecular Recognition in Chemical and Biological Problems, Special Pub., Royal Chem. Soc. 78:182-196, (1989); available from the University of California, Berkeley, Calif.); and HOOK (available from Accelrys, a subsidiary of Pharmacopeia, Inc., as part of the Quanta package).

(723) In another embodiment, IDO inhibitor molecules may be designed as a whole or de novo using either an empty active site. Software programs for achieving this include: LUDI (Bohm, J. Comp. Aid. Molec. Design, 6:61-78, (1992), available from Accelrys, a subsidiary of Pharmacopeia, Inc.); LEGEND (Nishibata and Itai, Tetrahedron, 47:8985, (1991), available from Molecular Simulations, Burlington, Mass.); and LeapFrog (available from Tripos, Inc., 1699 South Hanley Road, St. Louis, Mo.).

(724) Quantifying Potential of IDO Binding Molecules

(725) Once a compound has been designed or selected by methods such as those described above, the efficiency with which that compound may bind to the catalytic site of IDO may be tested and optimized by computational evaluation. For example, a compound that has been designed or selected to function as an inhibitor (antagonist) preferably occupies a volume that overlaps with the volume occupied by the native substrate at the active site. An effective IDO inhibitor preferably displays a relatively small difference in energy between its bound and free states (i.e., it has a small deformation energy of binding). Thus, the most efficient inhibitors of IDO should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mol or, even more preferably, not greater than about 7 kcal/mol.

(726) A compound selected or designed for binding to the IDO catalytic site may be further computationally optimized so that in its bound state it would lack repulsive electrostatic interactions with amino acids of the IDO catalytic pocket and it has favorable hydrogen bond formation, attractive electrostatic interactions with such amino acids. Such favorable or repulsive electrostatic interactions include charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the inhibitor and the binding pocket when the inhibitor is bound to it preferably make a neutral or favorable contribution to the enthalpy of binding.

(727) Specific computer software is available to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses fall into approximately three levels of sophistication. The first level of approximation, molecular mechanics, is also the cheapest to compute and can most usefully be used to calculate deformation energies. Molecular mechanics programs find application for calculations on small organic molecules as well as polypeptides, nucleic acids, proteins, and most other biomolecules. Examples of programs which have implemented molecular mechanics force fields include: AMBER (Kollman, P. A., et al., School of Pharmacy, Department of Pharmaceutical Chemistry, University of California at San Francisco); CHARMM (see B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S. Swaminathan, and M. Karplus, CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations, J. Comp. Chem., 4, 187-217, (1983); A. D. MacKerell, Jr., B. Brooks, C. L. Brooks, III, L. Nilsson, B. Roux, Y. Won, and M. Karplus, CHARMM: The Energy Function and Its Parameterization with an Overview of the Program, in The Encyclopedia of Computational Chemistry, 1, 271-277, P. v. R. Schleyer et al., eds, John Wiley & Sons, Chichester, (1998)); and QUANTA/CHARMm (available from Accelrys, a subsidiary of Pharmacopeia, Inc.).

(728) An intermediate level of sophistication comprises the so-called semi-empirical methods, which are relatively inexpensive to compute and are most frequently employed for calculating deformation energies of organic molecules. Examples of program packages that provide semi-empirical capability are MOPAC 2000 (Stewart, J. J. P., et al., available from Schrodinger, Inc., 1500 S.W. First Avenue, Suite 1180, Portland, Oreg.) and AMPAC (Holder, A., et al., available from Tripos, Inc., 1699 South Hanley Road, St. Louis, Mo.).

(729) The highest level of sophistication is achieved by those programs that employ so-called ab initio quantum chemical methods and methods of density functional theory, for example: Gaussian 03, (available from Gaussian, Inc., Carnegie Office Park, Building 6, Suite 230. Carnegie, Pa.); and Q-Chem2.0 (A high-performance ab initio electronic structure program, J. Kong, et al., J. Comput. Chem., 21, 1532-1548, (2000)).

(730) Virtual Screening

(731) Databases containing the structural coordinates of thousands of small molecules can be computationally screened to identify molecules that are likely to bind to the catalytic site of IDO. In such screening, the quality of fit of molecules to the binding site in question may be evaluated by any of a number of methods that are familiar to one of ordinary skill in the art, including shape complementarity (see, e.g., DesJalais, et al., J. Med. Chem., 31:722-729, (1988)) or by estimated energy of interaction (Meng, et al., J. Comp. Chem., 13:505-524, (1992)).

(732) In an method, potential binding compounds may be obtained by rapid computational screening. Such a screening comprises testing a large number, which may be hundreds, or may preferably be thousands, or more preferably tens of thousands, or even more preferably hundreds of thousands of molecules whose formulae are known and for which at least one conformation can be readily computed.

(733) The databases of small molecules include any virtual or physical database, such as electronic and physical compound library databases. Preferably, the molecules are obtained from one or more molecular structure databases that are available in electronic form, for example, the Available Chemicals Directory (ACD), the MDL Drug Data Report and/or the Comprehensive Medicinal Chemistry Database (available from MDL Information Systems, Inc., 14600 Catalina Street, San Leandro, Calif.); the Cambridge Structural Database; the Fine Chemical Database (Rusinko, Chem. Des. Auto. News, 8:44-47 (1993)); the National Cancer Institute database and any proprietary database of compounds with known medicinal properties, as is found in large or small pharmaceutical companies.

(734) The molecules in such databases are preferably stored as a connection table, with or without a 2D representation that comprises coordinates in just 2 dimensions, say x and y, for facilitating visualization on a computer display. The molecules are more preferably stored as at least one set of 3D coordinates corresponding to an experimentally derived or computer-generated molecular conformation. If the molecules are only stored as a connection table or a 2D set of coordinates, then it could be necessary to generate a 3D structure for each molecule before proceeding with a computational screen. Programs for converting 2D molecular structures or molecule connection tables to 3D structures include Converter (available from Accelrys, a subsidiary of Pharmacopeia, Inc.) and CONCORD (A. Rusinko III, J. M. Skell, R. Balducci, C. M. McGarity, and R. S. Pearlman, CONCORD, A Program for the Rapid Generation of High Quality Approximate 3-Dimensional Molecular Structures, (1988) The University of Texas at Austin and Tripos Associates, available from Tripos, Inc., 1699 South Hanley Road, St. Louis, Mo.).

(735) To perform the virtual screening of IDO inhibitory compounds, each 3D structure is docked to the IDO catalytic site using high-throughput screening software. Such a procedure can normally be subjected to a number of user-defined parameters and thresholds according to desired speed of throughput and accuracy of result. Such parameters include the number of different starting positions from which to start a docking simulation and the number of energy calculations to carry out before rejecting or accepting a docked structure. Such parameters and their choices are familiar to one of ordinary skill in the art. Structures from the database can be selected for synthesis to test their ability to modulate nuclear receptor activity if their docked energy is below a certain threshold. Methods of docking are further described elsewhere herein. For example the high throughput virtual screening can be performed by using the computer software GLIDE (Schrodinger, Inc., Portland, Oreg.). GLIDE searches the protein active site for the best possible location and orientation for the docked ligand. Its docking algorithm examines the conformational space, employing a heuristic screening process that eliminates unfavorable conformations. The software generates a score that rewards favorable lipophilic, hydrogen bonding, and metal ligation contacts and penalizes frozen rotatable bonds and steric clashes. In addition, the score takes into account an evaluation of the Coulomb-van der Walls interactions, as well as a small number of potential energy terms that reward hydrogen bond donors found in the active site's hydrophilic regions and penalizes hydrogen bond donors and acceptors found in the hydrophobic regions. The software yields a Docking Score value for each compound, expressed in energy units of kcal/mol.

(736) Alternatively, it is possible to carry out a molecular similarity search for molecules that are potential IDO inhibitors. A similarity search attempts to find molecules in a database that have at least one favorable 3D conformation whose structure overlap favorably with a pharmacophore that has been previously defined as a favorable IDO inhibitor. For example, a pharmacophore may bind to a lipophilic pocket at a particular position, a hydrogen-bond acceptor site at another position and a hydrogen bond donor site at yet another specified position accompanied by distance ranges between them. A molecule that could potentially fit into the active site is one that can adopt a conformation in which a H-bond donor in the active site can reach the H-bond acceptor site on the pharmacophore, a H-bond acceptor in the active site can simultaneously reach the H-bond donor site of the pharmacophore and, for example, a group such as a phenyl ring can orient itself into the lipophilic pocket.

(737) Even where a pharmacophore has not been developed, molecular similarity principles may be employed in a database searching regime (see, for example, Johnson, M. A.; Maggiora, G. M., Eds. Concepts and Applications of Molecular Similarity, New York: John Wiley & Sons (1990)) if at least one molecule that fits well in the IDO catalytic site is known.

(738) In one embodiment, it is possible to search for molecules that have certain properties in common with those of the molecule(s) known to bind. For example, such properties include numbers of hydrogen bond donors or numbers of hydrogen bond acceptors, or overall hydrophobicity within a particular range of values. Alternatively, even where a pharmacophore is not known, similar molecules may be selected on the basis of optimizing an overlap criterion with the molecule of interest.

(739) Considerations of the Rational Design of IDO Inhibitors

(740) Molecules that bind to the IDO catalytic site can be designed by a number of methods, including: 1) structural analogy to known IDO inhibitor or 2) structural analogy to intermediates structures participating in the mechanism of tryptophan dioxygenation catalyzed by IDO.

(741) In another embodiment, IDO inhibitors can be design by mimicking the structures of molecular species representing the transition state of tryptophan dioxygenation. The current understanding of the mechanism catalyzed by IDO involves the formation of an adduct between the indole core of tryptophan, oxygen and the iron atom present in the heme cofactor. Reviewed in Malachowski et al, Drugs of Future 2005, 30(9), 1-9 and Sugimoto H et al., 2006, Proc. Natl. Acad. Sci. USA 103(8), 2611-2616. There are three suggested mechanism proposed for the formation of this adduct that involve an ionic mechanism, a pericyclic mechanism or a radical mechanism. The adduct suffers a molecular reorganization that involves electron transfer with a base aminoacid present at the catalytic site. The molecular reorganization of the adduct proceeds either through a Criegee-type of rearrangement or through a dioxetane retro-cycloaddition mechanism to yield kynurenine and the free enzyme. Further provided are the structures of IDO inhibitory molecules designed by mimicking the structural features of these intermediate molecular species, or structurally modified substrate mimics that do not allow progression of one of the mechanistic steps of the reaction.

(742) The design of molecules that inhibit IDO generally involves consideration of two factors. The molecule must be capable of first physically, and second structurally, associating with IDO. The physical interactions supporting this association can be covalent or non-covalent. For example, covalent interactions may be important for designing irreversible or suicide inhibitors of a protein. Non-covalent molecular interactions that are important in the association of IDO with molecules that bind to it include hydrogen bonding, ionic, van der Waals, and hydrophobic interactions. Structurally, the compound must be able to assume a conformation that allows it to associate with the heme cofactor at the IDO catalytic active site.

(743) In general, the potential inhibitory or binding effect of a compound on IDO may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given compound suggests insufficient interaction and association between it and the IDO active site, synthesis and testing of the compound need not be carried out. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to bind to the IDO catalytic pocket and thereby inhibit its activity. In this manner, synthesis of ineffective compounds may be avoided.

(744) Among the computational techniques that enable the rational design of molecules that bind to IDO, it is key to have access to visualization tools, programs for calculating properties of molecules, and programs for fitting ligand structures into three-dimensional representations of the receptor binding site. Computer program packages for facilitating each of these capabilities have been referred to herein, and are available to one of ordinary skill in the art. Visualization of molecular properties, such as field properties that vary through space, can also be particularly important and may be aided by computer programs such as MOLCAD (Brickmann, J., and coworkers, see, for example, J. Comp.-Aid. Molec. Des., 7:503, (1993); available from Tripos, Inc., 1699 South Hanley Road, St. Louis, Mo.).

(745) A molecular property of particular interest when assessing suitability of drug compounds is its hydrophobicity. An accepted and widespread measure of hydrophobicity is Log P, the Log 10 of the octanol-water partition coefficient. It is customary to use the value of Log P for a designed molecule to assess whether the molecule could be suitable for transport across a cell membrane, if it were to be administered as a drug. Measured values of Log P are available for many compounds. Methods and programs for calculating Log P are also available, and are particularly useful for molecules that have not been synthesized or for which no experimental value of Log P is available. See for example: CLOGP (Hansch, C., and Leo, A.; available from Biobyte, Inc., Pomona, Calif.) and ACD/Log P DB (Advanced Chemistry Development Inc., 90 Adelaide Street West, Suite 702, Toronto, Ontario, Canada).

(746) Labeled Compounds and Assay Methods

(747) Another aspect relates to fluorescent dye, spin label, heavy metal or radio-labeled derivatives of the compounds described herein that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the IDO enzyme in tissue samples, including human, and for identifying IDO enzyme ligands by inhibition binding of a labeled compound. Accordingly, further provided are IDO enzyme assays that contain such labeled compounds.

(748) Further provided are isotopically-labeled compounds of the compounds described herein. An isotopically or radio-labeled compound is a compound described herein where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and a .sup.131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition assays, compounds that incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I, .sup.35S or will generally be most useful. For radio-imaging applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I, .sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most useful.

(749) It is understood that a radio-labeled or labeled compound is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and .sup.82Br.

(750) Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds described herein and are well known in the art.

(751) A radio-labeled compound described herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound described herein to the IDO enzyme. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the IDO enzyme directly correlates to its binding affinity.

(752) Kits

(753) Also included are pharmaceutical kits useful, for example, in the treatment or prevention of IDO-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

(754) The following examples are offered for illustrative purposes, and are not intended to limit the disclosure in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The example compounds below were found to be inhibitors of IDO according to one or more of the assays described herein.

EXAMPLES

General Experimental Methods

(755) All reagents and solvents were purchased from commercial sources and used as received without further purification. The reactions were monitored using analytical thin layer chromatography (TLC) with 0.25 mm EM Science silica gel plates (60E-254). The developed TLC plates were visualized by immersion in potassium permanganate solution followed by heating on a hot plate. Flash chromatography was performed with Selecto Scientific silica gel, 32-63 m particle sizes. All reactions were performed in flame- or oven-dried glassware under a nitrogen atmosphere. All reactions were stirred magnetically at ambient temperature unless otherwise indicated. .sup.1H NMR and .sup.13C NMR spectra were obtained with a Bruker DRX400, Varian VXR300 and VXR400. .sup.1H NMR spectra were reported in parts per million () relative to CDCl.sub.3 (7.27 ppm), CD.sub.3OD (4.80) or DMSO-d.sub.6 (2.50) as an internal reference.

(756) The following compounds were synthesized by known literature procedures: (2-(benzylamino)phenyl)methanol (Organic Letters 2002, 581-584), (3-(benzylamino)phenyl)methanol (European Patent Application 1989, 91 pp), (2-(phenylamino)phenyl)methanol (Journal of Heterocyclic Chemistry 1986, 23, 223-224), tert-butyl 2-hydroxy-2-phenylethylcarbamate (Bioorganic and Medicinal Chemistry 2004, 12, 1483-1491), tert-butyl 3-hydroxy-3-phenylpropylcarbamate (US Patent 2000, 5 pp), methyl 4-hydroxy-4-phenylbutanoate (Journal of Medicinal Chemistry 1986, 230-238), 3-morpholino-1-phenylpropan-1-ol (Chemistry Letters 1978, 11, 1285-1288), 1,2-diphenylethanol (Organic Letters 2006, 8, 773-776), 2-morpholino-1-phenylethanol (Organic Letters 2005, 7, 3649-3651), cyclohexyl(phenyl)methanol (Tetrahedron Letters 1989, 30, 6709-6712), (R)-3-(tert-butyldimethylsilyloxy)-1-phenylpropan-1-ol (Bioorganic and Medicinal Chemistry Letters 2005, 15, 4130-4135), biphenyl-3-ylmethanol (European Journal of Medicinal Chemistry 2007, 42, 293-306), biphenyl-2-ylmethanol (Journal of the American Chemical Society 1999, 121, 9550-9561), (4-methylbiphenyl-3-yl)methanol (Tetrahedron 1994, 50, 8301-16), (4-methylbiphenyl-2-yl)methanol (Tetrahedron Letters 2000, 41, 6415-6418), (4-methoxybiphenyl-2-yl)methanol (Journal of Organic Chemistry 1987, 52, 4953-61), (4-methoxybiphenyl-3-yl)methanol (Synlett 1998, 6, 671-675), 2-hydroxy-N-methyl-2-phenylacetamide (Journal of Organic Chemistry 1992, 57, 5700-7), 2-cyclohexyl-1-phenylethanol (Journal of Organic Chemistry 1936, 1, 288-99), 2-phenoxy-1-phenylethanol (Tetrahedron 2008, 64, 3867-3876).

Example 1

Method A: Syntheses of Dithiocarbamates with Variations in S-Alkyl Groups (Scheme 1)

(757) ##STR00900##

(758) A solution of tryptamine 1 (1.0 equiv) in anhydrous CH.sub.2Cl.sub.2 (10 mL) at 0 C. was treated sequentially with triethylamine (1.1 equiv) then carbon disulfide (1.1 equiv) and stirred for 30 min. After this time, alkyl bromide 2 (1.2 equiv unless indicated otherwise) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 1 M H.sub.2SO.sub.4 and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography (silica, EtOAc/hexanes) afforded the desired product. The dithiocarbamate product typically exists as a 7:3 mixture of tautomers observed by .sup.1H NMR, and are listed with spectral data.

Example 2

Phenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00001]

(759) ##STR00901##

(760) The reaction of 1 with (2-bromoethyl)benzene (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00001 (0.148 g, 35%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.25-7.20 (m, 4H), 7.16-7.13 (m, 1H), 7.07-7.05 (m, 1H), 6.92 (br s, 1H), 4.11-4.06 (m, 2H), 3.48-3.45 (m, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.97-2.94 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.78-3.74 (m), 3.59-3.55 (m), 3.10-3.08 (m), 3.05-3.01 (m); ESI MS m/z 341 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=13.9 min.

Example 3

4-Fluorophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00003]

(761) ##STR00902##

(762) The reaction of 1 with 4-fluorophenethyl bromide (0.6 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00003 (0.084 g, 31%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.13 (m, 4H), 7.08-7.04 (m, 1H), 7.00-6.94 (m, 2H), 6.92 (br s, 1H), 4.11-4.07 (m, 2H), 3.46-3.43 (m, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.94-2.91 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.79-3.75 (m), 3.55-3.52 (m), 3.11-3.09 (m), 3.01-2.98 (m); ESI MS m/z 359 [M+H].sup.+, HPLC (Method 1) 95.3% (AUC), t.sub.R=13.7 min.

Example 4

3-Methoxyphenethyl 2-1H-indol-3-yl)ethylcarbamodithioate [Compound 00010]

(763) ##STR00903##

(764) The reaction of 1 with 3-methoxyphenethyl bromide (0.6 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00010 (0.094 g, 33%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.24-7.19 (m, 2H), 7.16-7.13 (m, 1H), 7.07-7.06 (m, 1H), 6.92 (br s, 1H), 6.83-6.75 (m, 3H), 4.10-4.06 (m, 2H), 3.80 (s, 3H), 3.48-3.45 (m, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.95-2.92 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.79-3.76 (m), 3.59-3.55 (m), 3.10-3.09 (m), 3.02-2.99 (m); ESI MS m/z 371 [M+H].sup.+, HPLC (Method 1) 97.3% (AUC), t.sub.R=13.1 min.

Example 5

4-Methoxyphenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00002]

(765) ##STR00904##

(766) The reaction of 1 with 4-methoxyphenethyl bromide (0.6 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00002 (0.078 g, 28%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.03 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.16-7.13 (m, 3H), 7.08-7.05 (m, 1H), 6.92 (br s, 1H), 6.85-6.82 (m, 2H), 4.10-4.06 (m, 2H), 3.78 (s, 3H), 3.45-3.42 (m, 2H), 3.13 (t, J=6.5, 2H), 2.91-2.88 (m, 2H) and signals due to a minor tautomer (ca. 31%): 3.78-3.76 (m), 3.55-3.52 (m), 3.11-3.09 (m), 2.98-2.95 (m); ESI MS m/z 371 [M+H].sup.+, HPLC (Method 1) 96.5% (AUC), t.sub.R=13.3 min.

Example 6

4-Bromophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00004]

(767) ##STR00905##

(768) The reaction of 1 with 4-bromophenethyl bromide (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00004 (0.245 g, 46%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.43-7.38 (m, 3H), 7.25-7.22 (m, 1H), 7.16-7.05 (m, 4H), 6.92 (br s, 1H), 4.10-4.06 (m, 2H), 3.46-3.42 (m, 2H), 3.14 (t, J=6.5 Hz, 2H), 2.93-2.90 (m, 2H) and signals due to a minor tautomer (ca. 32%): 3.78-3.74 (m), 3.55-3.52 (m), 3.11-3.09 (m), 3.00-2.97 (m); ESI MS m/z 419 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=15.6 min.

Example 7

3-Bromophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00007]

(769) ##STR00906##

(770) The reaction of 1 with 3-bromophenethyl bromide (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00007 (0.329 g, 62%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.42-7.34 (m, 3H), 7.24-7.20 (m, 1H), 7.18-7.13 (m, 3H), 7.07-7.06 (m, 1H), 6.93 (br s, 1H), 4.11-4.06 (m, 2H), 3.46-3.43 (m, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.94-2.91 (m, 2H) and signals due to a minor tautomer (ca. 32%): 3.78-3.74 (m), 3.55-3.52 (m), 3.11-3.09 (m), 3.01-2.98 (m); ESI MS m/z 419 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=15.5 min.

Example 8

3-Methylphenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00020]

(771) ##STR00907##

(772) The reaction of 1 with 1-(2-bromoethyl)-3-methyl-benzene (1.0 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00020 (0.039 g, 22%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.03 (br s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.13 (m, 4H), 7.06-7.02 (m, 3H), 6.92 (br s, 1H), 4.10-4.06 (m, 2H), 3.47-3.44 (m, 2H), 3.13 (t, J=7.0 Hz, 2H) Hz, 2.93-2.90 (m, 2H) and signals due to a minor tautomer (ca. 32%): 3.79-3.75 (m), 3.57-3.54 (m), 3.11-3.09 (m), 3.01-2.98 (m); ESI MS m/z 355 [M+H].sup.+, HPLC (Method 1) 96.3% (AUC), t.sub.R=15.1 min.

Example 9

2-Phenylpropyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00006]

(773) ##STR00908##

(774) The reaction of 1 with 1-bromo-2-phenylpropane (1.2 equiv) was performed as described in Method A. The reaction was at reflux (55 C.) overnight instead of room temperature. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00006 (0.022 g, 5%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.01 (br s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.33-7.20 (m, 6H), 7.15-7.12 (m, 1H), 7.05-7.04 (m, 1H), 6.88 (br s, 1H), 4.08-4.04 (m, 2H), 3.48-3.45 (m, 2H), 3.12-3.06 (m, 3H), 1.53 (s, 3H) and signals due to a minor tautomer (ca. 30%) 3.75-3.71 (m), 3.21-3.18 (m); ESI MS m/z 355 [M+H].sup.+, HPLC (Method 1) 96.2% (AUC), t.sub.R=14.3 min.

Example 10

(6,7-Dimethoxy-2-oxo-2H-chromen-4-yl)methyl 2-(1H-indol-3-yl)ethyl-carbamodithioate [Compound 00023]

(775) ##STR00909##

(776) The reaction of 1 with 4-(bromomethyl)-6,7-dimethoxycoumarin (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00023 (0.063 g, 11%) as an off white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.15 (br s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.40-7.38 (m, 1H), 7.24-7.21 (m, 1H), 7.15-7.12 (m, 2H), 7.05-7.01 (m, 2H), 6.85-6.84 (m, 1H), 6.33 (s, 1H), 4.70 (s, 2H), 4.13-4.09 (m, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.17 (t, J=6.5 Hz, 2H) and signals due to a minor tautomer (ca. 23%): 3.14-3.10 (m); ESI MS m/z 455 [M+H].sup.+, HPLC (Method 1) 96.5% (AUC), t.sub.R=11.5 min, MP=175-177 C.

Example 11

2-(1H-Indol-3-yl)ethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00030]

(777) ##STR00910##

(778) The reaction of 1 with 3-(2-bromoethyl)indole (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00030 (0.086 g, 18%) as an off white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.98-7.93 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.37-7.34 (m, 2H), 7.23-7.18 (m, 2H), 7.15-7.11 (m, 2H), 7.06-7.01 (m, 2H), 6.89 (s, 1H), 4.05-4.02 (m, 2H), 3.53 (t, J=7.5 Hz, 2H), 3.13-3.07 (m, 4H), and signals due to a minor tautomer (ca. 31%): 3.76-3.75 (m), 3.68 (t, J=7.5 Hz), 3.20 (t, J=7.5); ESI MS m/z 380 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=12.4 min, MP=125-127 C.

Example 12

(2-Methylquinolin-6-yl)methyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00038]

(779) ##STR00911##

(780) The reaction of 1 with 6-(bromomethyl)-2-methylquinoline (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00038 (0.079 g, 16%) as an off white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.00-7.93 (m, 2H) 7.71 (s, 1H), 7.63-7.55 (m, 3H), 7.37 (d, J=8.0 Hz, 1H), 7.29-7.20 (m, 2H), 7.14-7.11 (m, 1H), 6.98-6.95 (m, 2H), 4.66 (s, 2H), 4.10-4.06 (m, 2H), 3.12 (t, J=7.0 Hz, 2H), 2.73 (s, 3H), and signals due to a minor tautomer (ca. 27%): 3.79-3.78 (m), 3.12-3.09 (m); ESI MS m/z 392 [M+H].sup.+, HPLC (Method 1) 98.5% (AUC), t.sub.R=8.2 min, MP=72-75 C.

Example 13

(3-Methylnaphthalen-2-yl)methyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00047]

(781) ##STR00912##

(782) The reaction of 1 with 2-bromomethyl-3-methyl-naphthalene (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00047 (0.097 g, 71%) as an off white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.93 (br s, 1H), 7.87 (br s, 1H), 7.76-7.71 (m, 1H), 7.64-7.60 (m, 1H), 7.43-7.35 (m, 4H), 7.21 (t, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.99-6.94 (m, 2H), 4.64 (s, 2H), 4.10-4.06 (m, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.50 (s, 3H), and signals due to a minor tautomer (ca. 33%): 4.7 (s), 3.77-3.76 (m), 3.12-3.08 (m); ESI MS m/z 391 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=16.1 min, MP=129-131 C.

Example 14

(6-Bromobenzo[d][1,3]dioxol-5-yl)methyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00065]

(783) ##STR00913##

(784) The reaction of 1 with 5-bromo-6-bromomethyl-1,3-benzodioxole (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00065 (0.368 g, 66%) as a clear oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.02 (br s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.96 (s, 1H), 6.92 (br s, 1H), 5.94 (s, 2H), 4.58 (s, 2H), 4.09-4.05 (m, 2H), 3.12 (t, J=7.0 Hz, 2H), and signals due to a minor tautomer (ca. 29%): 4.68 (s), 3.77-3.76 (m), 3.11-3.08 (m); ESI MS m/z 450 [M+H].sup.+, HPLC (Method 1) 98.7% (AUC), t.sub.R=14.4 min.

Example 15

Benzo[d]isoxazol-3-ylmethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00052]

(785) ##STR00914##

(786) The reaction of 1 with 3-(bromomethyl)-1,2-benzisoxazole (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00052 (0.304 g, 66%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.03 (br s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.56-7.55 (m, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.32-7.29 (m, 1H), 7.22-7.20 (m, 2H), 7.15-7.10 (m, 1H), 7.07-7.05 (m, 1H), 4.90 (s, 2H), 4.14-4.09 (m, 2H), 3.16 (t, J=6.5 Hz, 2H), and signals due to a minor tautomer (ca. 20%): 5.10 (s), 3.83-3.78 (m), 3.12-3.10 (m); ESI MS m/z 368 [M+H].sup.+, HPLC (Method 1) 98.8% (AUC), t.sub.R=12.4 min.

Example 16

2-Chlorophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00021]

(787) ##STR00915##

(788) The reaction of 1 with 2-chlorophenethyl bromide (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00021 (0.054 g, 11%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.02 (br s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.39-7.29 (m, 2H), 7.24-7.13 (m, 4H), 7.08-7.04 (m, 1H), 6.95 (br s, 1H), 4.11-4.07 (m, 2H), 3.49-3.46 (m, 2H), 3.16-3.13 (m, 2H), 3.11-3.07 (m, 2H), and signals due to a minor tautomer (ca. 30%): 3.80-3.76 (m), 3.60-3.57 (m), 3.18-3.14 (m); ESI MS m/z 375 [M+H].sup.+, HPLC (Method 1) 97.4% (AUC), t.sub.R=16.0 min.

Example 17

4-Methylphenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00009]

(789) ##STR00916##

(790) The reaction of 1 with 4-methylphenethyl bromide (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00009 (0.225 g, 50%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.02 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.08 (m, 5H), 7.03 (s, 1H), 6.91 (br s, 1H), 4.08 (m, 2H), 3.45-3.42 (m, 2H), 3.11 (t, J=7.0 Hz, 2H), 2.93-2.90 (m, 2H), and signals due to a minor tautomer (ca. 32%): 3.77-3.73 (m), 3.56-3.53 (m), 3.10-3.07 (m), 3.00-2.97 (m); ESI MS m/z 355 [M+H].sup.+, HPLC (Method 1) 95.3% (AUC), t.sub.R=16.1 min.

Example 18

4-((2-(1H-Indol-3-yl)ethylcarbamothioylthio)methyl)-2-oxo-2H-chromen-7-yl acetate [Compound 00049]

(791) ##STR00917##

(792) The reaction of 1 with 7-acetoxy-4(bromomethyl) coumarine (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00049 (0.130 g, 28%) as an off white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.18 (br s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.39-7.37 (m, 1H), 7.23-7.20 (m, 1H), 7.15-7.11 (m, 2H), 7.09-7.06 (m, 2H), 7.01-7.00 (m, 1H), 6.49 (s, 1H), 4.66 (s, 2H), 4.11-4.08 (m, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.34 (s, 3H), and signals due to a minor tautomer (ca. 21%): 4.71 (s), 3.83-3.80 (m), 3.12-3.10 (m); ESI MS m/z 453 [M+H].sup.+, HPLC (Method 1) 95.6% (AUC), t.sub.R=11.5 min, MP=132-134 C.

Example 19

3-Chlorophenethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00008]

(793) ##STR00918##

(794) The reaction of 1 with 1-(2-bromoethyl)-3-chlorobenzene (1.2 equiv) was performed as described in Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00008 (0.290 g, 61%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.04 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.27-7.18 (m, 4H), 7.16-7.11 (m, 2H), 7.08-7.06 (m, 1H), 6.93 (br s, 1H) 4.12-4.07 (m, 2H), 3.47-3.44 (m, 2H), 3.14 (t, J=6.5 Hz, 2H), 2.95-2.92 (m, 2H), and signals due to a minor tautomer (ca. 34%): 3.79-3.75 (m), 3.56-3.53 (m), 3.13-3.09 (m), 3.02-2.99 (m); ESI MS m/z 375 [M+H].sup.+, HPLC (Method 1) 97.5% (AUC), t.sub.R=15.4 min.

Example 20

2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl 2-(1H-indol-3-yl)ethyl-carbamodithioate (6, Scheme 2) [Compound 00053]

(795) ##STR00919##

(796) Sodium borohydride (18 mmol, 12 equiv) was added to stirred trifluoroacetic acid (0.19 mL, 1.38 mmol) over a period of 30 min. To the mixture was then added a solution of 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one 4 in CH.sub.2Cl.sub.2 over 30 min. After the addition of 4 was complete, the reaction was stirred at room temperature overnight. After this time, the reaction mixture was diluted with H.sub.2O (75 mL), cooled with an ice/water bath, and pH was adjusted to 12 with the addition of NaOH beads. The aqueous layer was separated, and extracted with CH.sub.2Cl.sub.2 (350 mL). The combined organic solutions were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated to afford crude product which was purified by chromatography (silica, hexanes-EtOAc), affording 5 (55 mg, 15%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 6.79 (d, J=8.0 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.67-6.65 (m, 1H), 4.23 (s, 4H), 3.50 (t, J=8.0 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H).

(797) Coupling of tryptamine 1 with 5 following Method A afforded product 6 (00053, 40 mg, 54% yield) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 08.04 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.07-7.05 (m, 1H), 6.91 (br s, 1H), 6.78-6.68 (m, 3H), 4.25-4.22 (m, 4H), 4.09-4.05 (m, 2H), 3.43-3.40 (m, 2H), 3.13 (t, J=6.5 Hz, 2H), 2.86-2.83 (m. 2H), and signals due to a minor tautomer (ca. 31%): 3.77-3.76 (m), 3.52-3.50 (m), 3.12-3.09 (m), 2.93-2.91 (m); ESI MS m/z 399 [M+H].sup.+, HPLC (Method 1) 97.9% (AUC), t.sub.R=13.1 min.

Example 21

Benzo[d][1,3]dioxol-5-ylmethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00050] (Scheme 4)

(798) ##STR00920##

(799) Piperonyl alcohol (1.25 mmol, 1 equiv) was dissolved in anhydrous CH.sub.2Cl.sub.2 (10 mL) at 0 C., trifluoroacetic anhydride (1.38 mmol, 1.1 equiv) added, and the reaction mixture was stirred for 1 hour, concentrated to about 3 mL. This material was then treated with 1 following general Method A. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00050 (0.103 g, 88%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.03 (br s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.24-7.21 (m, 1H), 7.16-7.13 (m, 1H), 7.04-7.03 (m, 1H), 6.92-6.82 (m, 2H), 6.75-6.74 (m, 1H), 6.68-6.67 (m, 1H), 5.92 (s, 2H), 4.40 (s, 2H), 4.09-4.06 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), and signals due to a minor tautomer (ca. 31%): 5.94 (s), 4.52 (m), 3.77-3.76 (m), 3.11-3.08 (m); ESI MS m/z 371 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=12.6 min.

Example 22

Method B: Syntheses of Dithiocarbamates of the Brassinin Family where the Indole Group is Replaced by Other Cyclic Structures (Scheme 5)

(800) ##STR00921##

(801) To a solution of amine 12 (Scheme 5, 1.0 equiv) in anhydrous CH.sub.2Cl.sub.2 (10 mL) cooled in an ice/water bath were sequentially added triethylamine (1.1 equiv) and then carbon disulfide (1.1 equiv). The solution was stirred for 30 min at 0 C. After this time, methyl iodide (1.2 equiv) was then added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 1 M H.sub.2SO.sub.4 and extracted with EtOAc (310 mL). The combined organic solutions were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated to afford crude material 13 which was purified by chromatography (silica, EtOAc/hexanes). The majority of the dithiocarbamates exist in tautomeric form (25% to 35%) as observed by .sup.1H NMR, and are listed with spectral data.

Example 23

Methyl 3-chlorophenethylcarbamodithioate [Compound 00014]

(802) ##STR00922##

(803) Compound 00014 was synthesized as described in EP 656351 (1995). Briefly, 2-(3-Chlorophenyl)ethylamine (1 equiv) was used as amine 12 (Scheme 5) as described in Method B. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00014 (0.220 g, 69%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.27-7.21 (m, 3H), 7.10 (d, J=7.0 Hz, 1H), 6.93 (br s, 1H), 4.00-3.96 (m, 2H), 2.96 (t, J=7.0 Hz, 2H), 2.62 (s, 3H), and signals due to a minor tautomer (ca. 28%): 3.70-3.69 (m), 2.69 (s); ESI MS m/z 246 [M+H].sup.+, HPLC (Method 1) 98.2% (AUC), t.sub.R=12.0 min.

Example 24

Methyl 2-(pyridin-4-yl)ethylcarbamodithioate [Compound 00069]

(804) ##STR00923##

(805) 4-(2-Aminoethyl)pyridine (1 equiv) was used as amine 12 (Scheme 5) as described in Method B. In addition to the general method, the acidic aqueous layer was neutralized with 1 M NaOH and extracted with EtOAc (330 mL). Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00069 (0.093 g, 26%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) 8.54-8.53 (m, 2H), 7.15 (d, J=5.5 Hz, 2H), 7.02 (br s, 1H), 4.04-4.01 (m, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.64 (s, 3H); ESI MS m/z 213 [M+H].sup.+, HPLC (Method 1) 98.6% (AUC), t.sub.R=9.6 min, MP=94-96 C.

Example 25

Methyl 2,4-dimethylphenethylcarbamodithioate [Compound 00066]

(806) ##STR00924##

(807) 2,4-Dimethylphenethylamine (1 equiv) was used as amine 12 (Scheme 5) as described in Method B. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00066 (0.161 g, 52%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.08 (d, J=7.5 Hz, 1H), 7.03-6.87 (m, 3H), 3.99-3.93 (m, 2H), 2.95-2.86 (m, 2H), 2.60 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H); ESI MS m/z 240 [M+H].sup.+, HPLC (Method 1) 97.5% (AUC), t.sub.R=12.9 min.

Example 26

Method C: Syntheses of Dithiocarbamate Isostere Equivalents (Scheme 9)

(808) ##STR00925##

(809) To a solution of 23 (such as thiazole-2-thiol, 1.0 equiv, RH, n=1) in anhydrous THF (10 mL) cooled in an ice/water bath was added NaH (1.1 eq unless indicated otherwise), and the solution was stirred for 2 h at 0 C. After this time, a bromide 25 (1.2 equiv) was added and the reaction was allowed to warm to room temperature and stirred overnight. Reaction mixture was then quenched by addition of a few drops of H.sub.2O and concentrated. The residue was taken up into EtOAc, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. Purification of the residue by chromatography (silica) afforded the desired product.

Example 27

3-Benzyloxazolidine-2-thione [Compound 00081]

(810) ##STR00926##

(811) Compound 00081 was previously described by Baba, et al, Bull. Chem. Soc. Jpn., 1986, 59(1), 341-343; b) and Y. Nagao, et al, Chem. Pharma. Bull., Jpn., 1988, 36(11), 4293-4300). Its synthesis was achieved by treating 2-Thioxotetrahydro-1,3-oxazole with NaH (3.0 equiv instead of 1.1 equiv) as described in Method C. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00081 (0.198 g, 53%) as a clear oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.38-7.36 (m, 2H), 7.32-7.29 (m, 2H), 7.27-7.25 (m, 1H), 4.35 (t, J=9.0 Hz, 2H), 4.26 (s, 2H), 3.90 (t, J=9.0 Hz, 2H); ESI MS m/z 194 [M+H].sup.+, HPLC (Method 1) 96.2% (AUC), t.sub.R=7.8 min.

Example 28

3-Benzyl-1,3-thiazinane-2-thione [Compound 00077]

(812) ##STR00927##

(813) Synthesis of compound 0077 was performed as described by W. Hanefeld, Archiv der Pharmazie, 1977, 310(5), 409-417; b) W. Hanefeld, et al, J. Heterocycl. Chem. 1997, 34(5), 1621-1624). Briefly, 1,3-Thiazinane-2-thine was treated with 1.5 equiv NaH (instead of 1.1 equiv) as described in Method C. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00077 (0.020 g, 6%) as a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) 7.34-7.22 (m, 5H), 4.23 (s, 2H), 3.77 (t, J=5.7 Hz, 2H), 3.06 (t, J=6.0 Hz, 2H), 1.95-1.88 (m, 2H); ESI MS m/z 224 [M+H].sup.+, HPLC (Method 1) 98.5% (AUC), t.sub.R=7.9 min.

Example 29

3-Benzyl-2-thioxothiazolidin-4-one [Compound 00079]

(814) ##STR00928##

(815) Synthesis of compound 00079 was performed as described in A. Martinez, et al, J. Med. Chem., 2005, 48(23), 7103-7112; and in M. Pulici, et al, Tetrahedron Lett., 2005, 46, 2387-2391). Briefly, rhodanine (1.0 equiv) was used as starting material 23 as described in Method C. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00079 (0.191 g, 57%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.34-7.30 (m, 5H), 4.59 (s, 2H), 3.99 (s, 2H); ESI MS m/z 224 [M+H].sup.+, HPLC (Method 1)>99% (AUC), t.sub.R=10.0 min.

Example 30

3-(Naphthalen-2-ylmethyl)-2-thioxothiazolidin-4-one [Compound 00830]

(816) ##STR00929##

(817) Rhodanine (1.0 equiv) was reacted with 2-(bromomethyl)naphthalene (1.5 equiv) as described in Method C. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00830 (0.093 g, 30%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.86-7.81 (m, 4H), 7.50-7.46 (m, 3H), 4.76 (s, 2H), 4.00 (s, 2H); ESI MS m/z 274 [M+H].sup.+, HPLC (Method 1) 95.8% (AUC), t.sub.R=8.5 min, MP=120-123 C.

Example 31

3-(Naphthalen-2-ylmethyl)oxazolidine-2-thione [Compound 00786]

(818) ##STR00930##

(819) 2-Thioxotetrahydro-1,3-oxazole was reacted with 2-(bromomethyl)naphthalene (1.5 equiv) as described in Method C. Purification by flash chromatography (silica, gradient of 12% EtOAc/Hexanes to 100% EtOAc) afforded product 00786 (0.292 g, 61%) as a yellow oil: .sup.1H NMR (500 MHz, CDCl.sub.3) 7.82-7.79 (m, 4H), 7.50-7.45 (m, 3H), 4.42 (s, 2H), 4.37 (t, J=9.5 Hz, 2H), 3.92 (t, J=9.5 Hz, 2H); ESI MS m/z 244 [M+H].sup.+, HPLC (Method 1) 95.9% (AUC), t.sub.R=8.5 min, MP=120-123 C.

Example 32

2-Methyl-3-(naphthalen-2-ylmethylthio)-1,2-dihydro-1,2,4-triazine-5,6-dione [Compound 00682]

(820) TABLE-US-00013 Entry Scale Yield Conditions 1 1.00 g 1.10 g (58%) K.sub.2CO.sub.3, DMF, 50 C., 3 h,

Example 33

Naphthalen-2-ylmethyl-2-(benzo[b]thiophen-3-yl)ethylcarbamodithioate [Compound 00060]

(821) TABLE-US-00014 Scale Yield Conditions 0.41 g 0.35 g 44, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), 45 (31%) (1.2 equiv), pyridine, 0 C. tort, 15 h; product consistent by ESI-MS and .sup.1H NMR analysis.

Example 34

Naphthalen-2-ylmethyl-2-(benzo[d]isoxazol-3-yl)ethylcarbamodithioate [Compound 00058]

(822) TABLE-US-00015 Reaction Scale Yield Conditions 52 to 53 0.10 g 0.090 g EDCI (1.2 equiv), HOBt (0.5 equiv), NH.sub.3 (1.2 equiv), (89%) DMF, rt, 4 h; product consistent by ESI- MS and .sup.1H NMR analysis. 53 to 54 0.090 g 0.10 g LiAlH.sub.4 (4 equiv), THF, 40 C., overnight; crude (crude) used for next step. 54 to 55 0.14 g 0.04 g Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), 50 (1.2 equiv), (12%) pyridine, 0 C. to r.t.: product consistent by ESI- MS and .sup.1H NMR analysis.

Example 35

Methyl 2-(5,7-dichloro-1H-indol-3-yl)ethylcarbamodithioate [Compound 00042]

(823) TABLE-US-00016 Reaction Scale Yield Conditions 33 to 34 1.00 g 0.46 g PCC (1.2 equiv), rt; 2.5 h, DCM; product consistent (47%) by ESI-MS and .sup.1H NMR analysis. 33 to 34 3.00 g 2.30 g DMSO (2 equiv), Et.sub.3N (5 equiv), (COCl).sub.2 (1.5 (78%) equiv), DCM, -78 C. to rt; product consistent by ESI-MS and .sup.1H NMR analysis. 34 to 35 1.00 g 1.20 g HC(OMe).sub.3 (excess as neat), PTSA (0.1 equiv), rt; (84%) product consistent by ESI-MS and .sup.lH NMR analysis. 37 to 39 0.10 g 0.021 g 37 (1.05 equiv), 35 (1.0 equiv), EtOH/H.sub.2O, 100 C., (16%) 4.5 h; product consistent by ESI-MS and .sup.1H NMR analysis. 37 to 39 0.10 g 0.035 g 37 (1.05 equiv), 35 (1.0 equiv), EtOH/H.sub.2O, 100 C., (27%) overnight; product consistent by ESI-MS and .sup.1H NMR analysis. 37 to 39 0.10 g 0.011 g 37 (1.05 equiv), 35 (1.0 equiv), 4% aq. H.sub.2SO.sub.4, 70 (8.5%) C., 4 h; product consistent by ESI-MS and .sup.1H NMR analysis. 37 to 39 0.50 g 0.138 g 37 (1.05 equiv), 35 (1.0 equiv), EtOH/H.sub.2O, 100 C., (21%) overnight; product consistent by ESI-MS and .sup.lH NMR analysis. 39 to 40 0.090 g 72 mg 39, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 (68%) equiv), pyridine, 0 C. to rt, 15 h; product consistent by ESI-MS and .sup.lH NMR analysis, 97% pure by HPLC.

Example 36

Methyl 2-(4,6-dichloro-1H-indol-3-yl)ethylcarbamodithioate [Compound 00043]

(824) TABLE-US-00017 Reaction Scale Yield Conditions 8 to 9 1.00 g 0.346 g 8, (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, (32%) microwave, 150 C., 15 min; product consistent by LCMS and .sup.1H NMR analysis. 9 to 10 0.320 g 0.240 g 9, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 (55%) equiv), pyridine, 0 C. to rt, 16 h; product consistent by LCMS and .sup.1H NMR analysis.

Example 37

Methyl 2-(4,5,6-trifluoro-1H-indol-3-yl)ethylcarbamodithioate [Compound 00045]

(825) TABLE-US-00018 0 Reaction Scale Yield Conditions 5 to 6 0.250 g 0.050 g Ref 1; 5, NaNO.sub.2 (1.05 equiv), conc. HCl, 0 C., 30 (18%) min followed by SnCl.sub.22H.sub.2O (3.5 equiv), conc. HCl, 0 C. to rt, 1 h; product consistent by .sup.1H NMR and LCMS analysis. 5 to 6 0.500 g 0.450 g Ref 2; 5, NaNO.sub.2 (1.2 equiv), conc. HCl, 0 C., 1 h (81%) followed by SnC1.sub.22H.sub.2O (2.2 equiv), conc. HCl, rt, 1 h; product consistent by .sup.1H NMR and LCMS analysis. 6 to 8 0.430 g 0.122 g 6 (1.05 equiv), 35 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (19%) (1.1 equiv), microwave, 130 C., 10 min; product consistent by .sup.1H NMR and LCMS analysis. 8 to 9 0.120 g 0.105 g 8, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 (61%) equiv), pyridine, 0 C. to rt; product consistent by .sup.1H NMR and LCMS analysis.

Example 38

Methyl 2-(5-amino-1H-indol-3-yl)ethylcarbamodithioate [Compound 00039] and Methyl 2-(5-nitro-1H-indol-3-yl)ethylcarbamodithioate [Compound 00040]

(826) TABLE-US-00019 Reaction Scale Yield Conditions 16 to 17a 1.00 g 0.225 g 16, BH.sub.3THF (3 equiv), 35 C., 4 h followed by CsF, (crude) Na.sub.2CO.sub.3, EtOH, reflux, 16 h; purified by silica gel chromatography; product consistent by .sup.1H NMR gel and LCMS analysis. 17a to 18a 0.100 g 0.048 g 17a, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 (33%) equiv), pyridine, 0 C. to rt, 15 h; product consistent by ESI-MS and .sup.1H NMR analysis. 17a to 17b 0.125 g 0.115 g 17a, H.sub.2, 10% Pd/C (20 mol%), 40 psi, 8 h; product (crude) confirmed by .sup.1H NMR analysis. 17b to 18b 0.115 g 0.035 g 17b, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 (crude) equiv) pyridine 0 C. to rt, 15 h; product consistent by ESI-MS and .sup.1H NMR analysis.

Example 39

Methyl 2-(4,6-bis(trifluoromethyl)-1H-indol-3-yl)ethylcarbamodithioate [Compound 00044]

(827) TABLE-US-00020 Reaction Scale Yield Conditions 6 to 7 0.010 g 0.005 g 6 (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (1.1 (crude) equiv), microwave, 130 C., 15 min; 40% conversion by LCMS analysis. 6 to 7 0.030 g 6 (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (1.1 equiv), microwave, 130 C., 20 min; 30% conversion to desired product By LCMS analysis. 6 to 7 0.040 g 6 (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (1.1 equiv), microwave, 120 C., 10 min followed by 130 C., 10 min; 25% conversion by LCMS analysis. 6 to 7 0.005 g 6 (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (1.1 equiv), microwave, 120 C., 15 min; 45% conversion by LCMS analysis. 6 to 7 0.165 g 0.035 g 6 (1.05 equiv), 2 (1.0 equiv), EtOH/H.sub.2O, conc. HCl (1.1 (crude) equiv), microwave, 120 C., 15 min; 45% conversion by LCMS analysis; 85% pure by HPLC analysis. 7 to 8 0.030 g 0.020 g 3, Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), MeI (1.2 equiv), (51%) pyridine, 0 C. to rt; product consistent by ESI-MS and .sup.1H NMR analysis.

Example 40

benzo[b]thiophen-3-ylmethyl 2-(1H-indol-3-yl)ethylcarbamodithioate [Compound 00054]

(828) TABLE-US-00021 0 SM Scale Yield Conditions 55 8.00 g 1.956 g 55, formaldehyde, HCl (gas), 65 C. (18%) vacuum distillation. NMR. 56 0.274 g 0.068 g tryptamine, CS.sub.2, standard procedure. (14%) 98% by HPLC (254 nm), but ca. 90% by NMR. further purification needed. 55 8.00 g 3.06 g 55, formaldehyde, HCl (gas), 65 C. (28%) vacuum distillation. NMR, GCMS. 56 0.457 g 0.208 g tryptamine, CS.sub.2, standard procedure. (26%) Pure by HPLC and NMR.

Example 41

2-Hydroxy-N-phenethylbenzothioamide [Compound 00634]

(829) TABLE-US-00022 SM Scale Yield Conditions 78 1.380 g 2.388 g (99%) 78 CDI, DKE, 1 h, rt, then 79, overnight rt. Purity: 80% by NMR, 89% by HPLC-MS. 80 2.390 g 0.254 g (10%) 80, toulene, Lawesson's reagent, reflux, 2 h. Purity: 98% by NMR, 100% by HPLC-MS.

Example 42

3-((1H-indol-3-yl)methyl)-2-thioxothiazolidin-4-one [Compound 00078]

(830) TABLE-US-00023 SM Scale Yield Conditions 70 0.22 g 0.132 g 70, MeOH, TEA (1 equiv.), CS.sub.2 (1.5 equiv.), (33%) rt, 30 min. 71(1.05 equiv.), reflux, 1 h; HPLC, NMR.

Example 43

Naphthalen-2-ylmethyl 2-(thiochroman-3-yl)ethylcarbamodithioate [Compound 00064]

(831) ##STR00958##

Example 44

N-((1H-indol-3-yl)methyl)-2-(2-thioxo-2,3-dihydrothiazol-4-yl)acetamide [Compound 00561]

(832) TABLE-US-00024 0 SM Scale Yield Conditions 68 5.00 g 2.70 g (63%) NaOH, EtOH, water, 50 C., 4 h. 69 0.114 g 0.018 g PS-DCC, DCM. HPLC: 87 %. 69 0.26 g 0.10 g CDI, DCE, N.sub.2, rt.

Example 45

N-Benzyl-2-hydroxybenzothioamide [Compound 00656]

(833) TABLE-US-00025 SM Scale Yield Conditions 78 6.90 g 10.100 g 78, CDI, CHCl.sub.3, 1 h, rt, then 89, overnight, rt. (89 %) Purity: 60% by NMR, 88% by HPLC-MS. 90 10.10 g 0.647 g 90, toulene, Lawesson's reagent, reflux, 2 h. (6 %) Purity: 98% by NMR, 100% by HPLC-MS.

Example 46

N-(2-(1H-indol-3-yl)ethyl)-2-hydroxybenzothioamide [Compound 00644]

(834) TABLE-US-00026 SM Scale Yield Conditions 78 4.14 g 6.22 g 78 CDI, DCM, 1 h, rt, (74%) then DIPEA and 60, overnight, rt. Purity: 98% by NMR, 96% by HPLC-MS. 85 6.22 g 1.24 g 85, toulene, Lawesson's reagent, (19%) reflux, 2 h. Purity: 97% by NMR, 100% by HPLC-MS.

Example 47

N-(2-(benzo[b]thiophen-3-yl)ethyl)-2-hydroxybenzothioamide [Compound 00672]

(835) TABLE-US-00027 0 SM Scale Yield Conditions 74 0.45 g 0.14 g LAH, ether, reflux. (31%) 74 1.00 g 0.90 g LAH, AlCl.sub.3, ether, 30 min, (88%) reflux. 75 0.50 g CDI, DCE rt.

Example 48

N-(Naphthalen-2-ylmethyl)-2-(2-thioxo-2,3-dihydrothiazol-4-yl)acetamide [Compound 00701]

(836) ##STR00971##

Example 49

Methyl 6-(1H-indol-3-yl)hexylcarbamodithioate [Compound 00027]

(837) TABLE-US-00028 Reaction Scale Yield Conditions 36 to 37 0.80 g 0.80 g LiAlH.sub.4 (6 equiv), dioxane, (Crude) reflux, 36 h; product consistent by ESI-MS analysis. 37 to 38 0.80 g 0.09 g Et.sub.3N (1.1 equiv), CS.sub.2 (8%) (1.2 equiv), MeI (1.2 equiv), pyridine, 0 C. to r.t., 15 h; product consistent by ESI-MS and .sup.1H NMR analysis

Example 50

Methyl 1-(1H-indol-3-yl)-2-methylpropan-2-ylcarbamodithioate [Compound 00028]

(838) TABLE-US-00029 Scale Yield Conditions 260 mg 0.30 g 21, CS.sub.2 (1.2 equiv), NEt.sub.3 (1.3 equiv), pyridine, (71%) MeI (1.2 equiv), 0 C. to r.t., overnight; consistent by ESI-MS and .sup.1H NMR analysis

Example 51

Methyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamodithioate [Compound 00032]

(839) TABLE-US-00030 Reaction Scale Yield Conditions 25 to 30 100 mg 126 mg 25, CS.sub.2 (1.2 equiv), NEt.sub.3 (85%) (1.3 equiv), pyridine, MeI (1.2 equiv), 0 C. to r.t., overnight; product consistent by ESI-MS and .sup.1H NMR analysis. 27 to 32 500 mg 499 mg 27, CS.sub.2 (1.2 equiv), (74%) NEt.sub.3 (1.5 equiv), pyridine, MeI (1.2 equiv), 0 C. to r.t., overnight; consistent by ESI- MS and .sup.1H NMR analysis.

Example 52

Naphthalen-2-ylmethyl 2-(benzofuran-3-yl)ethylcarbamodithioate [Compound 00057]

(840) TABLE-US-00031 0 Reaction Scale Yield Conditions 49 to 51 0.10 g 0.19 g Et.sub.3N (1.1 equiv), CS.sub.2 (1.2 equiv), (82%) 50 (1.2 equiv), pyridine, 0 C. to r.t., 15 h; product consistent by ESI-MS and .sup.1H NMR analysis.

Example 53

N-(2-aminophenyl)-3-phenylpropanamide [Compound 00581]

(841) TABLE-US-00032 SM Scale Yield Conditions 41 1.00 g 0.345 g 38 (3 equiv), DCE, 41, rt, 10 min. Chromatographic (24%) purification. 95% pure by HPLC, MS, NMR.

Example 54

N-(2-aminophenyl)-4-(1H-indol-3-yl)butanamide [Compound 00588]

(842) TABLE-US-00033 SM Scale Yield Conditions 45 1.00 g 0.751 g (52%) purity: 98% by HPLC-MS.

Example 55

N-(2-aminophenyl)-3-(benzo[b]thiophen-3-yl)propanamide [Compound 00739]

(843) TABLE-US-00034 0 SM Scale Yield Conditions 59 1.00 g 1.00 g 59, Meldrum's acid, triethylamine formate, (79 %) 100 C., 2 h. HPLC: 94%, NMR: 95%. 61 0.50 g 0.13 g 61, CDI, DCE, rt, 1 h. 62, rt, (18%) 16 h. LCMS, NMR.

Example 56

N-hydroxy-2-(naphthalen-2-yl)acetamide [Compound 00827]

(844) TABLE-US-00035 Reaction Scale Yield 15 to 16 0.100 g 0.035 g (31%)

Example 57

5-((1H-indol-3-yl)methyl)quinolin-8-ol [Compound 00655]

(845) TABLE-US-00036 SM Scale Yield Conditions 121 2.00 g Ethanol, cat. piperidine acetate, reflux, 16 h. crude: 15% product by HPLC, after chrom. 29%.

Example 58

5-Benzylquionolin-8-ol [Compound 00664]

(846) TABLE-US-00037 SM Scale Yield Comments 107 5.00 g 5.00 g 65% HNO.sub.3(aq.), acetic acid, 12-15 C., (80%) 0.5 h. HPLC 97%, NMR. 108 2.29 g 1.80 g 20% HCl-solution, Sn powder (3.1 equiv.), (90%) reflux, 2 h. LC-MS: 96%, NMR. 109 0.50 g 0.135 g 109 (0.57 equiv.), glycerol (5.5 equiv.), (14%) acetic acid (80% aq. solution), sulfuric acid; 150-160 C., 1.5 h; NMR, 100% pure by HPLC.

Example 59

General Method for Synthesis of Hydroxylamine Compounds

(847) Alcohol (1.0 equiv.), N-hydroxypthalimide (1.1 equiv.) and triphenylphosphine (1.1 equiv.) were dissolved in dichloromethane (6 mL). Diethyl azodicarboxylate (DEAD) (1.1 equiv.) was added dropwise while stirring to the solution and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL). The combined dichloromethane was washed with 10% NaOH (215 mL), water (215 mL) and brine (15 mL). The solvent was removed under reduced pressure and the crude product was used for the next step. The crude product was dissolved in ethanol (8 mL) and hydrazine monohydrate (2.0 equiv.) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel.

(848) The following compounds (Table A) were prepared essentially according to the preceding example with the proper substitution of starting materials:

(849) TABLE-US-00038 TABLE A Yield .sup.1H NMR (CDCl.sub.3 unless otherwise noted): Compound (%) (ppm) O-(3- 53 4.75 (s, 2 H), 5.53 (br s, 2 H), 7.48-7.54 (m, 1 H), Nitrobenzyl)hydroxylamine 7.66 (d, 1 H, J = 10 Hz), 8.13 (d, 1 H, J = 11 Hz), 8.20 (s, 1 H) O-(Pyridin-2- 11 4.77 (s, 2 H), 5.58 (br s, 2 H), 7.16 (dd, 1 H, J = 4.8, ylmethyl)hydroxylamine 6.8 Hz), 7.32 (d, 1 H, J = 7.6 Hz), 7.64 (dt, 1 H, J = 2, 8 Hz), 8.54 (d, 1 H, J = 4.8 Hz) O-(Pyridin-3- 10 4.66 (s, 2 H), 5.44 (br s, 2 H), 7.23-7.27 (m, 1 H), ylmethyl)hydroxylamine 7.65 (d, 1 H, J = 8 Hz), 8.53 (d, 1 H, J = 4.4 Hz), 8.58 (s, 1 H) O-(Pyridin-4- 37 4.64 (s, 2 H), 5.53 (br s, 2 H), 7.20 (dd, 2 H, J = 1.6, ylmethyl)hydroxylamine 4.4 Hz), 8.53 (dd, 2 H, J = 1.6, 4.4 Hz) O-(Benzo[d][1,3]dioxol-5- 48 4.56 (s, 2 H), 5.35 (br s, 2 H), 5.94 (s, 2 H), ylmethyl)hydroxylamine 6.76-6.85 (m, 3 H) O-((5- 51 4.87 (s, 2 H), 5.44 (br s, 2 H), 7.30 (dd, 2 H, J = 2, Chlorobenzo[b]thiophen-3- 8.8 Hz), 7.45 (s, 1 H), 7.74 (dd, 1 H, J = 0.4, 8.4 Hz), yl)methyl)hydroxylamine 7.87 (d, 1 H, J = 1.6 Hz) O-(Naphthalen-2- 61 4.84 (s, 2 H), 5.42 (br s, 2 H), 7.46-7.49 (m, 3 H), ylmethyl)hydroxylamine 7.80-7.85 (m, 4 H) O-(Quinolin-6- 55 4.79 (s, 2 H), 5.46 (br s, 2 H), 7.32 (dd, 1 H, J = 4.4, ylmethyl)hydroxylamine 8.4 Hz), 7.36-7.40 (m, 1 H), 7.65 (dd, 1 H, J = 1.6, 8.4 Hz), 7.71 (d, 1 H, J = 0.8 Hz), 8.03-8.07 (m, 2 H) O-((2,3- 61 4.20 (s, 4 H), 4.52 (s, 2 H), 5.32 (br s, 2 H), Dihydrobenzo[b][1,4]dioxin- 6.80-6.81 (m, 2 H), 6.85 (d, 1 H, J = 1.2 Hz). 6-yl)methyl)hydroxylamine O-(Chroman-2- 43 1.71-1.82 (m, 1 H), 1.95-1.99 (m, 1 H), ylmethyl)hydroxylamine 2.71-2.77 (m, 1 H), 2.81-2.90 (m, 1 H), 3.80-3.91 (m, 2 H), 4.25-4.31 (m, 1 H), 5.52 (br s, 2 H), 6.80-6.85 (m, 2 H), 7.01-7.08 (m, 1 H). O-(Benzo[d]thiazol-2- 39 5.05 (s, 2 H), 5.78 (br s, 2 H), 7.34-7.38 (m, 1 H), ylmethyl)hydroxylamine 7.43-7.47 (m, 1 H), 7.87 (dd, 1 H, J = 0.4, 7.6 Hz), 7.99 (d, 1 H, J = 8 Hz). O-((4-Methyl-2- 53 2.59 (s, 3 H), 4.69 (s, 2 H), 5.47 (br s, 2 H), phenylpyrimidin-5- 7.44-7.45 (m, 3 H), 8.40-8.43 (m, 2 H), 8.59 (s, 1 H). yl)methyl)hydroxylamine O-(Benzofuran-2- 28 4.76 (s, 2 H), 5.55 (br s, 2 H), 6.72 (s, 1 H), ylmethyl)hydroxylamine 7.18-7.29 (m, 2 H), 7.47 (d, 1 H, J = 8 Hz), 7.54 (d, 1 H, J = 7.6 Hz). O-(3- 42 4.65 (s, 2 H), 5.42 (br s, 2 H), 6.95-7.11 (m, 3 H), Fluorobenzyl)hydroxylamine 7.23-7.29 (m, 1 H). O-(3,5- 47 4.63 (s, 2 H), 5.47 (br s, 2 H), 6.69-6.72 (m, 1 H), Difluorobenzyl)hydroxylamine 6.84-6.86 (m, 2 H). O-(3- 57 4.71 (s, 2 H), 5.45 (br s, 2 H), 7.46-7.56 (m, 3 H), (Trifluoromethyl)benzyl)hydroxylamine 7.61 (s, 1 H). O-(3,5- 44 4.63 (s, 2 H), 5.50 (br s, 2 H), 7.25-7.27 (m, 2 H), Dichlorobenzyl)hydroxylamine 7.30 (d, 1 H, J = 1.8 Hz). O-(3- 58 4.62 (s, 2 H), 5.42 (br s, 2 H), 7.18-7.26 (m, 2 H), Bromobenzyl)hydroxylamine 7.40-7.43 (m, 1 H), 7.50 (s, 1 H). O-(2,5- 49 3.78 (s, 3 H), 3.80 (s, 3 H), 4.74 (s, 2 H), 5.44 (br s, Dimethoxybenzyl)hydroxylamine 2 H), 6.82 (d, 2 H, J = 2 Hz), 6.95 (s, 1 H). O-(4- 54 4.72 (s, 2 H), 5.45 (br s, 2 H), 7.45 (d, 2 H, J = 8 Hz), (Trifluoromethyl)benzyl)hydroxylamine 7.60 (d, 2 H, J = 8 Hz). O-(4- 57 4.61 (s, 2 H), 5.38 (br s, 2 H), 6.99-7.03 (m, 2 H), Fluorobenzyl)hydroxylamine 7.28-7.31 (m, 2 H). O-(2-Chloro-4- 48 4.74 (s, 2 H), 5.46 (br s, 2 H), 6.97 (dt, 1 H, J = 2.4, fluorobenzyl)hydroxylamine 8.4 Hz), 7.11 (dd, 1 H, J = 2.4, 8.4 Hz), 7.39 (dd, 1 H, J = 6.4, 8.4 Hz). O-(2-Chloro-6- 39 4.86 (s, 2 H), 5.47 (br s, 2 H), 6.96-7.01 (m, 1 H), fluorobenzyl)hydroxylamine 7.17-7.25 (m, 2 H). O-(2- 56 4.78 (s, 2 H), 5.49 (br s, 2 H), 7.15 (dt, 1 H, J = 1.6, Bromobenzyl)hydroxylamine 7.6 Hz), 7.29 (dt, 1 H, J = 1.2, 7.6 Hz), 7.41 (dd, 1 H, J = 1.2, 7.6 Hz), 7.54 (dd, 1 H, J = 1.2, 7.6 Hz). O-(3- 58 2.34 (s, 3 H), 4.64 (s, 2 H), 5.36 (br s, 2 H), Methylbenzyl)hydroxylamine 7.10-7.16 (m, 3 H), 7.21-7.25 (m, 1 H). Methyl 4- 35 3.89 (s, 3 H), 4.72 (s, 2 H), 5.44 (br s, 2 H), 7.38 (d, (aminooxymethyl)benzoate 2 H, J = 7.6 Hz), 7.99 (d, 2 H, J = 6.8 Hz). O-(3-Chloro-4- 42 4.59 (s, 2 H), 5.41 (br s, 2 H), 7.07-7.12 (m, 1 H), fluorobenzyl)hydroxylamine 7.18-7.19 (m, 1 H), 7.40 (dd, 1 H, J = 1.6, 6.8 Hz). O-(2- 48 3.82 (s, 3 H), 4.74 (s, 2 H), 5.39 (br s, 2 H), 6.87 (d, Methoxybenzyl)hydroxylamine 1 H, J = 8 Hz), 6.93 (t, 1 H, J = 7.6 Hz), 7.25-7.32 (m, 2 H). O-(2- 52 4.91 (s, 2 H), 5.54 (br s, 2 H), 7.39-7.43 (m, 1 H), (Trifluoromethyl)benzyl)hydroxylamine 7.55-7.62 (m, 3 H). O-(2- 39 5.05 (s, 2 H), 5.54 (br s, 2 H), 7.41-7.44 (m, 1 H), Nitrobenzyl)hydroxylamine 7.61-7.63 (m, 2 H), 7.99-8.01 (m, 1 H). O-(3-Chloro-5- 35 4.61 (s, 2 H), 5.47 (br s, 2 H), 6.94-6.97 (m, 1 H), fluorobenzyl)hydroxylamine 7.01 (td, 1 H, J = 2, 8.4 Hz), 7.12 (s, 1 H). O- 30 4.77 (s, 2 H), 5.51 (br s, 2 H). (Perfluorobenzyl)hydroxylamine O-(3- 47 2.97 (t, 2 H, J = 6.8 Hz), 3.88 (t, 2 H, J = 6.8 Hz), Nitrophenethyl)hydroxylamine 5.40 (br s, 2 H), 7.40-7.43 (m, 1 H), 7.51-7.53 (m, 1 H), 8.01-8.05 (m, 2 H). O-(4- 49 3.80 (s, 3 H), 4.62 (s, 2 H), 5.33 (br s, 2 H), 6.89 (d, Methoxybenzyl)hydroxylamine 2 H, J = 8.4 Hz), 7.29 (d, 2 H, J = 8.4 Hz). O-(4- 52 4.59 (s, 2 H), 5.38 (br s, 2 H), 7.08 (d, 2 H, J = 7.6 Hz), Iodobenzyl)hydroxylamine 7.66 (d, 2 H, J = 7.6 Hz). O-(3- 61 4.59 (s, 2 H), 5.41 (br s, 2 H), 7.07 (t, 1 H, J = 7.6 Hz), Iodobenzyl)hydroxylamine 7.29 (d, 1 H, J = 7.2 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.70 (s, 1 H). O-(2- 57 4.71 (s, 2 H), 5.49 (br s, 2 H), 6.95-7.00 (m, 1 H), Iodobenzyl)hydroxylamine 7.30-7.38 (m, 2 H), 7.82 (d, 1 H, J = 8 Hz). 2-(aminooxymethyl)-N- 32 4.72 (s, 2 H), 5.35 (br s, 2 H), 6.88-6.92 (m, 2 H), phenylaniline 7.04-7.06 (m, 2 H), 7.22-7.27 (m, 4 H), 7.37-7.39 (d, 1 H, J = 8 Hz) 2-(aminooxymethyl)-N- 28 4.37 (s, 2 H), 4.73 (s, 2 H), 5.30 (br s, 3 H), benzylaniline 6.61-6.69 (m, 2 H), 7.11-7.13 (dd, 1 H, J = 1.6, 7.6 Hz), 7.16-7.20 (dt, 1 H, J = 1.6, 8.4 Hz), 7.23-7.27 (m, 1 H), 7.30-7.35 (m, 4 H) 3-(aminooxymethyl)-N- 39 (CD.sub.3OD) 4.59 (s, 2 H), 5.06 (s, 2 H), 7.38-7.40 (m, benzylaniline 6 H), 7.48-7.56 (m, 3 H) O-benzhydrylhydroxylamine 65 5.30 (br s, 2 H), 5.64 (s, 1 H), 7.23-7.35 (m, 10 H) O- 57 0.81-1.25 (m, 6 H), 1.55-1.60 (m, 2 H), 1.71 (d, 1 H, (cyclohexyl(phenyl)methyl)hydroxylamine J = 12.4 Hz), 2.00 (d, 1 H, J = 12.8 Hz), 4.17 (d, 1H, J = 8 Hz), 5.10 (br s, 2 H), 7.23-7.32 (m, 5 H) O-(3-morpholino-1- 52 1.64-1.65 (m, 1 H), 1.89-1.93 (m, 1 H), phenylpropyl)hydroxylamine 2.21-2.28 (m, 6 H), 3.56-3.57 (m, 4 H), 4.45-4.46 (m, 1 H), 5.09 (br s, 2 H), 7.20-7.25 (m, 5 H) O-(1,2- 58 2.86-2.91 (dd, 1 H, J = 5.6, 13.6 Hz), 3.10-3.15 (dd, diphenylethyl)hydroxylamine 1 H, J = 7.6, 13.6 Hz). 4.71-4.74 (dd, 1 H, J = 6, 7.6 Hz), 5.18 (br s, 2 H), 7.12 (d, 1 H, J = 6.8 Hz), 7.16-7.30 (m, 8 H) O-(2-morpholino-1- 64 2.35-2.39 (dd, 1 H, J = 3.2, 13.6 Hz), 2.48-2.58 (m, phenylethyl)hydroxylamine 4 H), 2.73-2.78 (dd, 1 H, J = 9.6, 13.6 Hz), 3.67-3.76 (m, 4 H), 4.74-4.77 (dd, 1 H, J = 3.2, 9.2 Hz), 5.24 (br s, 2 H), 7.27-7.36 (m, 5 H) 4-(aminooxy)-N-methyl-4- 41 1.98-2.11 (m, 2 H), 2.17-2.21 (m, 2 H), 2.75 (d, 3 H, phenylbutanamide J = 4 Hz), 4.48-4.51 (dd, 1 H, J = 5.6, 7.6 Hz), 5.20 (br s, 2 H), 5.56 (br s, 1 H), 7.24-7.32 (m, 5 H) 4-(aminooxy)-N-cyclohexyl- 38 1.05-1.18 (m, 2 H), 1.26-1.41 (m, 2 H), 4-phenylbutanamide 1.62-1.74 (m, 4 H), 1.88-1.97 (m, 2 H), 1.99-2.21 (m, 4 H), 3.71-3.77 (m, 1 H), 4.50-4.55 (dd, 1 H, J = 7.6, 10 Hz), 5.22 (br s, 2 H), 5.35 (d, 1 H, J = 10 Hz), 7.27-7.39 (m, 5 H) methyl 4-(aminooxy)-4- 49 1.95-1.99 (m, 1 H), 2.06-2.11 (m, 1 H), phenylbutanoate 2.34-2.38 (dd, 2 H, J = 1.2, 8.4 Hz), 3.63 (s, 3 H), 4.49-4.52 (dd, 1 H, J = 5.6, 7.6 Hz), 5.22 (br s, 2 H), 7.26-7.36 (m, 5 H) 2-(aminooxy)-2- 52 (CD.sub.3OD) 3.22-3.71 (m, 2 H), 5.31-5.34 (m, 1 H), phenylethanamine 7.41-7.45 (m, 5 H) 3-(aminooxy)-3- 45 1.78-1.85 (m, 1 H), 1.87-1.94 (m, 1 H), phenylpropan-1-amine 3.13-3.24 (m, 2 H), 4.52-4.55 (m, 1 H), 4.76 (br s, 2 H), 5.22 (br s, 2 H), 7.23-7.32 (m, 5 H) O-((3,4-dichlorobiphenyl-2- 33 4.56 (s, 2H), 5.45 (br s, 2H), 7.19-7.23 (m, 2H), yl)methyl)hydroxylammonium 7.33-7.36 (m, 4H), 7.54 (d, 1H, J = 1.5 Hz) chloride O-((3,4,4-trichlorobiphenyl- 62 4.54 (s, 2H), 5.46 (br s, 2H), 7.18-7.21 (m, 2H), 2- 7.33-7.36 (dd, 1H, J = 1.5, 4.5 Hz), 7.47-7.49 (m, yl)methyl)hydroxylammonium 2H), 7.54 (s, 1H) chloride O-((4-chloro-4- 31 4.54 (s, 2H), 5.46 (br s, 2H), 7.21 (d, 1H, J = 6.30 Hz), (trifluoromethyl)biphenyl-2- 7.36 (d, 1H, J = 4.8 Hz), 7.47 (d, 2H, J = 6.0 Hz), yl)methyl)hydroxylamine 7.56 (d, 1H, J = 1.5 Hz), 7.68 (d, 2H, J = 6.0 Hz) O-(5-chloro-2-(pyrimidin-5- 45 4.52 (s, 2H), 5.48 (br s, 2H), 7.18-7.24 (m, 1H), yl)benzyl)hydroxylamine 7.39 (d, 1H, J = 4.8 Hz), 7.57 (s, 1H), 8.75-8.82 (m, 2H), 9.21 (s, 1H) O-(5-chloro-2-(thiophen-3- 62 4.64 (s, 2H), 5.42 (br s, 2H), 7.17 (dd, 1H, J = 1.32, yl)benzyl)hydroxylamine 3.54 Hz), 7.31-7.39 (m, 4H), 7.53 (s, 1H) O-(5-chloro-2-(thiophen-2- 36 4.71 (s, 2H), 5.30 (br s, 2H), 7.08-7.13 (m, 2H), yl)benzyl)hydroxylamine 7.25-7.41 (m, 3H), 7.53 (d, 1H, J = 1.83 Hz) O-((4-chlorobiphenyl-2- 67 4.58 (s, 2H), 4.36 (s, 2H), 7.23-7.27 (m, 1H), yl)methyl)hydroxylamine 7.30-7.33 (dd, 2H, J = 2, 6.6 Hz), 7.35-7.40 (m, 4H), 7.51-7.53 (m, 1H) O-((4-chlorobiphenyl-3- 78 DMSO-d6 5.10 (s, 2H), 7.43-7.45 (d, 1H, J = 7.6 Hz), yl)methyl)hydroxylamine 7.51-7.64 (m, 4H), 7.71-7.73 (m, 3H), 11.02 (br hydrochloride s, 3H) O-((4-methylbiphenyl-3- 65 2.68 (s, 3H), 4.73 (s, 2H), 5.41 (s, 2H), 7.22-7.24 (d, yl)methyl)hydroxylamine 2H, 7.9 Hz), 7.30-7.32 (d, 1H, J = 7.5 Hz), 7.39-7.42 (t, 1H, J = 7.6 Hz), 7.48-7.53 (m, 3H), 7.57 (s, 1H) O-((4-methoxybiphenyl-3- 62 3.84 (s, 3H), 4.74 (s, 2H), 5.43 (br s, 2H), yl)methyl)hydroxylamine 6.96-6.98 (dd, 2H, J = 1.8, 6.9 Hz), 7.29-7.31 (d, 1H, J = 7.5 Hz), 7.39-7.42 (t, 1H, J = 7.5 Hz), 7.49-7.55 (m, 4H) O-(3-(pyridin-4- 49 4.77 (s, 2H), 5.51 (br s, 2H), 7.43-7.53 (m, 4H), yl)benzyl)hydroxylamine 7.58-7.60 (d, 2H, J = 7.6 Hz), 7.64 (s, 1H), 8.65-8.67 (dd, 2H, J = 1.6, 4.5 Hz) O-(2-(pyridin-4- 50 4.60 (s, 2H), 5.42 (br s, 2H), 7.28-7.31 (dd, 1H, J = 1.9, yl)benzyl)hydroxylamine 7.8 Hz), 7.34-7.36 (dd, 2H, J = 1.4, 4.5 Hz), 7.40-7.47 (m, 2H), 7.55-7.58 (dd, 1H, J = 2.0, 7.8 Hz), 8.65-8.66 (d, 2H, J = 5.9 Hz) 2-(aminooxy)-N-methyl-2- 44 2.79-2.81 (d, 3H, J = 5.0 Hz), 5.00 (s, 1H), 5.66 (br phenylacetamide s, 2H), 6.68 (br s, 1H), 7.31-7.39 (m, 5H) tert-butyl 2-(aminooxy)-2- 70 1.42 (s, 9H), 2.85 (s, 3H), 3.28-3.33 (dd, 1H, J = 7.7, phenylethyl(methyl)carbamate 14.5 Hz), 3.44-3.49 (dd, 1H, J = 4.5, 14.8 Hz), 4.74-4.79 (m, 1H), 5.21 (br s, 2H), 7.28-7.36 (m, 5H) O-(naphthalen-1- 90 5.13 (s, 2H), 5.40 (br s, 2H), 7.40-7.54 (m, 4H), ylmethyl)hydroxylamine 7.80-7.86 (m, 2H), 8.14 (d, 1H, J = 6.18 Hz) O-((4,4-dichlorobiphenyl-2- 85 4.55 (s, 2H), 5.43 (br s, 2H), 7.19 (d, 1H, J = 6.18 Hz), yl)methyl)hydroxylamine 7.25-7.40 (m, 5H), 7.54 (d, 1H, J = 1.47 Hz) O-((4,5-dichlorobiphenyl-3- 75 4.70 (s, 2H), 5.49 (br s, 2H), 7.34 (s, 1H), yl)methyl)hydroxylamine 7.39-7.49 (m, 6 H) 2-(aminooxy)-N-methyl-2- 70 DMSO-d6 2.61 (s, 3H), 3.21 (dd, 1H, J = 2.5, 11.3 Hz), phenylethanamine 3.43 (dd, 1H, J = 9.74, 3.78 Hz), 5.60 (d, 1H, J = 7.3 Hz), dihydrochloride 7.46 (s, 5H), 10.06 (br s, 3H) O-((4-chlorobiphenyl-2- 62 4.58 (s, 2H), 5.41 (br s, 2H), 7.22 (d, 1H, J = 6.2 Hz), yl)methyl)hydroxylamine 7.31-7.43 (m, 6H), 7.54 (d, 1H, J = 1.5 Hz) O-((4-chloro-4- 57 3.85 (s, 3H), 4.58 (s, 2H), 5.42 (br s, 2H), 6.94 (d, methoxybiphenyl-2- 2H, J = 6.5 Hz), 7.19-7.32 (m, 4H), 7.52 (d, 1H, 1.6 Hz), yl)methyl)hydroxylamine O-((2,4-dichlorobiphenyl-2- 10 4.40 (d, 1H, J = 9.45 Hz), 4.53 (d, 1H, J = 9.5 Hz), yl)methyl)hydroxylamine 5.35 (br s, 2H), 7.13 (d, 1H, J = 6.2 Hz), 7.22-7.35 (m, 4H), 7.45-7.47 (m, 1H), 7.54 (d, 1H, J = 1.4 Hz) O-(5-chloro-2-(1H-indol-5- 82 4.64 (s, 2H), 5.38 (br s, 2H), 6.56 (s, 1H), 7.13 (dd, yl)benzyl)hydroxylamine 1H, J = 1.1, 5.2 Hz), 7.21-7.39 (m, 4H), 7.54-7.56 (m, 2H), 8.30 (br s, 1H) 2-(aminooxymethyl)-4- 71 2.99 (s, 6H), 4.63 (s, 2H), 5.40 (br s, 2H), 6.76 (d, chloro-N,N-dimethylbiphenyl- 2H, J = 6.72 Hz), 7.20-7.30 (m, 4H), 7.51 (s, 1H) 4-amine methyl 2-(aminooxymethyl)- 83 3.95 (s, 3H), 4.56 (s, 2H), 5.44 (br s, 2H), 4-chlorobiphenyl-4- 7.22-7.24 (d, 1H, J = 8.2 Hz), 7.34-7.37 (dd, 1H, J = 2.2, 8.2 Hz), carboxylate 7.41-7.43 (d, 2H, J = 8.4 Hz), 7.55-7.56 (d, 1H, J = 2.1 Hz), 8.08-8.10 (d, 2H, J = 8.3 Hz) O-(biphenyl-3- 47 4.75 (s, 2 H), 5.43 (br s, 2 H), 7.33-7.36 (m, 2 H), ylmethyl)hydroxylamine 7.41-7.45 (m, 3 H), 7.54 (d, 1 H, J = 8 Hz), 7.59-7.61 (m, 3 H). O-(biphenyl-2- 28 4.64 (s, 2 H), 5.36 (br s, 2 H), 7.30-7.45 (m, 8 H), ylmethyl)hydroxylamine 7.53-7.56 (m, 1 H). (S)O-(3-(tert- 28 0.01 (s, 3 H), 0.02 (s, 3 H), 0.08 (s, 9 H), butyldimethylsilyloxy)-1- 1.75-1.82 (m, 1 H), 1.93-2.06 (m, 1 H), 3.52-3.54 (m, 1 H), phenylpropyl)hydroxylamine 3.68-3.75 (m, 1 H), 4.63-4.65 (m, 1 H), 5.14 (br s, 2 H), 7.23-7.33 (m, 5 H). O-(4- 61 4.67 (s, 2 H), 5.48 (br s, 2 H), 7.39 (d, 2 H, J = 8.0 Hz), cyanobenzyl)hydroxylamine 7.57 (d, 2 H, J = 8.0 Hz) O-(1,2,3,4- 23 1.66-1.84 (m, 3 H), 2.29-2.32 (m, 1 H), tetrahydronaphthalen-1- 2.58-2.77 (m, 2 H), 5.33-5.35 (m, 1 H), 7.11 (d, 1 H, J = 7.6 Hz), yl)hydroxylammonium 7.16-7.26 (m, 2 H), 7.41 (d, 1 H, J = 7.6 Hz), chloride 11.10 (s, 3 H) O-(2-cyclohexyl-1- 37 0.79-1.25 (m, 5 H), 1.35-1.82 (m, 6 H), phenylethyl)hydroxylammonium 2.38-2.46 (m, 2 H), 7.34-7.39 (m, 5 H), 10.75 (s, 3 H) chloride O-(2-phenoxy-1- 47 4.18-4.22 (m, 1 H), 4.29-4.40 (m, 1 H), phenylethyl)hydroxylammonium 5.41-5.51 (m, 1 H), 6.89-6.94 (m, 3 H), 7.23-7.27 (m, 2 H), chloride 7.38-7.44 (m, 3 H), 7.46-7.52 (m, 2 H), 11.02 (br. s, 3 H) O-(2-(benzyloxy)-1- 52 3.58-3.62 (m, 1 H), 3.75-3.82 (m, 1 H), phenylethyl)hydroxylammonium 4.48-4.57 (m, 2 H), 5.33-5.38 (m, 1 H), 7.16-7.35 (m, 5 H), chloride 7.36-7.41 (m, 5 H), 10.98 (br. s, 3 H) O-(1,3- 73 1.96-2.01 (m, 1 H), 2.15-2.28 (m, 1 H), diphenylpropyl)hydroxylammonium 2.33-2.65 (m, 2 H), 5.00-5.15 (m, 1 H), 7.10-7.18 (m, 3 H), chloride 7.19-7.27 (m, 2 H), 7.32-7.45 (m, 5 H), 11.00 (br. s, 3 H) O-(3-cyclohexyl-1- 42 0.93-1.25 (m, 7 H), 1.56-1.86 (m, 8 H), phenylpropyl)hydroxylammonium 4.98-5.10 (m, 1 H), 7.15-7.39 (m, 5 H), 10.81 (br. s, 3 H) chloride

Example 60

General Method for Synthesis of bis(hydroxylamine) Compounds

(850) Alcohol (1.0 equiv.), N-hydroxypthalimide (2.2 equiv.) and triphenylphosphine (2.2 equiv.) were dissolved in dichloromethane (6 mL). Diethyl azodicarboxylate (DEAD) (2.2 equiv.) was added dropwise while stirring to the solution and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL). The combined dichloromethane was washed with 10% NaOH (215 mL), water (215 mL) and brine (15 mL). The solvent was removed under reduced pressure and the crude product was used for the next step. The crude product was dissolved in ethanol (8 mL) and hydrazine monohydrate (4.0 equiv.) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel.

(851) The following compounds (Table B) were prepared essentially according to the preceding example with the proper substitution of starting materials:

(852) TABLE-US-00039 TABLE B Yield .sup.1H NMR (CDCl.sub.3 unless otherwise Compound (%) noted): (ppm) O,O-(1,3- 28 4.67 (s, 4 H), 5.42 (br s, 4 H), phenylenebis(methylene))- 7.28-7.33 (m, 4 H). bis(hydroxylamine) O,O-(1,2- 36 4.80 (s, 4 H), 5.42 (br s, 4 H), phenylenebis(methylene))- 7.30-7.40 (m, 4 H). bis(hydroxylamine) O,O-(1,4- 32 4.67 (s, 4 H), 5.40 (br s, 4 H), phenylenebis(methylene))- 7.34-7.36 (m, 4 H). bis(hydroxylamine)

Example 61

Synthesis of O-(1-(3-Nitrophenyl)but-3-enyl)hydroxylamine

(853) 3-Nitrobenzaldehyde (296 mg, 1.96 mmol) was dissolved in THF (4 mL) and cooled to 78 C. Allyl magnesium bromide (1 M in butyl ether, 2.4 mL, 2.35 mmol) was added dropwise and the reaction mixture was stirred at 78 C. for 1 h. It was then quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography on silica gel using 25% EtOAc/hexanes as eluent to yield the desired product as yellow oil which was used in the next step. 1-(3-Nitrophenyl)but-3-en-1-ol (139 mg, 0.720), N-hydroxyphthalimide (129 mg, 0.792 mmol) and triphenylphosphine (208 mg, 0.792 mmol) were dissolved in dichloromethane (6 mL). Diethyl azodicarboxylate (DEAD) (0.13 mL, 0.792 mmol) was added dropwise while stirring to the solution and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL). The combined dichloromethane was washed with 10% NaOH (215 mL), water (215 mL) and brine (15 mL). The solvent was removed under reduced pressure and the crude product was used for the next step. The crude product was dissolved in ethanol (6 mL) and hydrazine monohydrate (0.16 mL, 3.22 mmol) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 20%-35% EtOAc/hexanes as eluent to yield the desired product as colorless oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 2.38-2.43 (m, 1H), 2.53-2.59 (m, 1H), 4.67 (t, 1H, J=6.8 Hz), 5.00-5.04 (m, 2H), 5.35 (br s, 2H), 5.67-5.74 (m, 2H), 7.49-7.53 (m, 1H), 7.62 (d, 1H, J=7.6 Hz), 8.11-8.16 (m, 2H).

Example 62

Synthesis of N-Boc-Indole-3-carbinol

(854) To a solution of indole-3-carbinol (250 mg, 1.70 mmol) and (Boc).sub.2O (371 mg, 1.70 mmol) in dichloromethane (6 mL) was added triethylamine (0.47 mL, 3.40 mmol) followed by DMAP (21 mg, 0.170 mmol). The reaction mixture was stirred at room temperature for 1 h and poured into water. The dichloromethane layer was separated, dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography on silica gel using 20%-30% EtOAc/hexanes as eluent to afford Boc protected indole as solid (60 mg, 0.243 mmol, 15%). .sup.1H NMR (CDCl.sub.3, 300 MHz): (ppm) 1.66 (s, 9H), 1.84 (br s, 1H), 4.82 (s, 2H), 7.22-7.36 (m, 2H), 7.57 (s, 1H), 7.64 (dd, 1H, J=0.6, 7.5 Hz), 8.14 (d, 1H, J=8.1 Hz).

Example 63

Synthesis of O-((1H-Indol-3-yl)methyl)hydroxylamine hydrochloride

(855) N-Boc-Indole-3-carbinol (120 mg, 0.486 mmol), N-hydroxyphthalimide (87 mg, 0.534 mmol) and triphenylphosphine (140 mg, 0.534 mmol) were dissolved in dichloromethane (6 mL). Diethyl azodicarboxylate (DEAD) (0.08 mL, 0.534 mmol) was added dropwise while stirring to the solution and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL). The combined dichloromethane was washed with 10% NaOH (215 mL), water (215 mL) and brine (15 mL). The solvent was removed under reduced pressure and the crude product was used for the next step. The crude product was dissolved in ethanol (5 mL) and hydrazine monohydrate (0.07 mL, 1.42 mmol) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 20%-35% EtOAc/hexanes as eluent to yield the desired product as colorless oil. The product was dissolved in dioxane (1 mL) and HCl (4M in dioxane, 2 mL) was added. The reaction was stirred at room temperature for 20 h and concentrated. The crude product was triturated with 20% EtOAc/hexanes and dried to afford the final product as hydrochloride salt (34 mg, 0.171, 35% over two steps). .sup.1H NMR (CD.sub.3OD, 400 MHz): (ppm) 3.62 (s, 2H), 7.27-7.36 (m, 2H), 7.67-7.69 (m, 1H), 7.87 (s, 1H), 8.17 (d, 1H, J=8.4 Hz).

Example 64

General Method for the Synthesis of Sulfonamides

(856) To a solution of O-(3-nitrobenzyl)hydroxylamine (1.0 equiv.) in dichloromethane (2 mL) was sequentially added pyridine (2.0 equiv.) and sulfonylchloride (1.2 equiv.). The reaction mixture was stirred at room temperature for 18 h and then poured into water (5 mL). The aqueous layer was extracted with dichloromethane (215 mL). The combined organic layers were concentrated and the crude product was purified by flash column chromatography on silica gel using 10%-27% EtOAc/hexanes as eluent.

(857) The following compounds (Table C) were prepared essentially according to the preceding example with the proper substitution of starting materials:

(858) TABLE-US-00040 TABLE C Yield .sup.1H NMR (CDCl.sub.3 unless otherwise Compound (%) noted): (ppm) 4-Methyl-N-(3- 62 2.41 (s, 3 H), 5.03 (d, 2 H), 7.17 (s, 1 nitrobenzyloxy)- H), 7.31 (d, 2 H, J = 8 Hz), benzenesulfonamide 7.47-7.51 (m, 1 H), 7.63 (d, 1 H, J = 7.6 Hz), 7.78 (d, 2 H, J = 8 Hz), 8.13-8.15 (m, 2 H). N-(3-Nitrobenzyloxy)- 71 3.08 (s, 3 H), 5.09 (s, 2 H), 6.93 (s, 1 methanesulfonamide H), 7.55 (t, 1 H, J = 7.6 Hz), 7.70 (d, 1 H, J = 7.6 Hz), 8.20-8.24 (m, 2 H). 2-Methyl-5-nitro-N-(3- 65 2.73 (s, 3 H), 5.02 (s, 2 H), 7.40 (s, 1 nitrobenzyloxy)- H), 7.50-7.53 (m, 1 H), 7.64 (d, 1 H, benzenesulfonamide J = 7.6 Hz), 8.09 (s, 1 H), 8.14-8.16 (m, 1 H), 8.31 (dd, 1 H, J = 2.4, 8.4 Hz), 8.82 (d, 1 H, J = 2.4 Hz).

Example 65

Synthesis of (3-(aminooxymethyl)phenyl)methanamine

(859) 3-Cyanobenzyl alcohol (308 mg, 2.32 mmol), N-hydroxyphthalimide (416 mg, 2.55 mmol) and triphenylphosphine (668 mg, 2.55 mmol) were dissolved in THF (8 mL). Diethyl azodicarboxylate (DEAD) (0.40 mL, 2.55 mmol) was added dropwise while stirring to the solution and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the residue washed with THF (4 mL) and dried under high vacuum. The crude product (1.24 g, 4.46 mmol) was dissolved in ethanol (8 mL) and hydrazine monohydrate (0.43 mL, 8.92 mmol) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure and the residue suspended in ethyl ether. The ethyl ether layer was washed with 3% Na.sub.2CO.sub.3 (210 mL), brine (10 mL) and concentrated. The crude product (830 mg, 5.61 mmol) was dissolved in THF (15 mL) and cooled to 0 C. Lithium aluminum hydride (1 M in THF, 11.2 mL, 11.2 mmol) was added dropwise and the reaction was stirred overnight at room temperature. It was then quenched with methanol (10 mL) and water (2 mL). The mixture for stirred for a further 30 min. The salts were filtered off and the solvent removed by evaporation in vacuo. The crude product was purified by silica gel flash column chromatography using 20% MeOH/dichloromethane as eluent to afford the desired product as white solid (59 mg, 0.388 mmol, 17% over 3 steps). .sup.1H NMR (CDCl.sub.3, 300 MHz): (ppm) 4.07 (s, 2H), 4.63 (s, 2H), 5.18 (s, 4H), 7.36-7.44 (m, 4H).

Example 66

General Procedure for Suzuki Reaction

(860) To a degassed solution of appropriate halo-substituted benzyl alcohol (1.5 mmol), aryl boronic acid (1.5 equiv), and sodium carbonate (2.0 equiv) in DME/water (6 mL/3 mL) was added Pd(PPh.sub.3).sub.4 (2 mol %). The mixture was heated to 85 C. until the reaction was complete as indicated by TLC. The mixture was allowed to cool to room temperature, and then partition between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (220 mL) and the combined organic layers were washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel flash column chromatography.

(861) The following compounds (Table D) were prepared essentially according to the preceding example with the proper substitution of starting materials:

(862) TABLE-US-00041 TABLE D Yield Compound (%) .sup.1H NMR (CDCl.sub.3 unless otherwise noted): (ppm) (3-(pyridin-4- 91 4.22 (br s, 1H), 4.78 (s, 2H), 7.44-7.52 (m, 5H), yl)phenyl)methanol 7.63 (s, 1H), 8.53-8.54 (dd, 2H, J = 4.8 Hz) (2-(pyridin-4- 40 4.56 (s, 2H), 4.68 (br s, 1H), 7.20-7.23 (dd, 1H, J = 1.6, yl)phenyl)methanol 7.4 Hz), 7.30-7.32 (dd, 2H, J = 1.6, 4.5 Hz), 7.34-7.43 (m, 2H), 7.58-7.61 (dd, 1H, J = 1.1, 7.9 Hz), 8.45-8.47 (dd, 2H, J = 1.6, 4.5 Hz) (4-chlorobiphenyl-3- 67 2.51 (br s, 1H), 4.66 (s, 2H), 7.27-7.28 (d, 1H, J = 7.1 Hz), yl)methanol 7.33-7.38 (dt, 3H, J = 1.9, 6.6 Hz), 7.41-7.45 (m, 3H), 7.48 (s, 1H) (4-chlorobiphenyl-2- 75 2.08 (br s, 1H), 4.51 (s, 2H), 7.21-7.23 (m, 1H), yl)methanol 7.26-7.27 (t, 1H, J = 2.2 Hz), 7.28-7.29 (t, 1H, J = 2.2 Hz), 7.31-7.39 (m, 4H), 7.49-7.51 (dd, 1H, J = 1.6, 7.4 Hz) (4,4-dichlorobiphenyl-2- 89 1.73-1.75 (t, 1H, J = 5.7 Hz), 4.55-4.56 (d, 2H, J = 5.7 Hz), yl)methanol 7.16-7.18 (d, 1H, J = 8.1 Hz) 7.25-7.27 (d, 2H, J = 8.3 Hz), 7.31-7.33 (dd, 1H, J = 2.1, 8.2 Hz), 7.39-7.40 (d, 2H, J = 8.3 Hz), 7.56-7.57 (d, 1H, J = 2.0 Hz) (4-chlorobiphenyl-2- 91 2.02 (br s, 1H), 4.53 (s, 2H), 7.16-7.19 (d, 1H, J = 8.2 Hz), yl)methanol 7.26-7.43 (m, 6H), 7.54-7.55 (d, 1H, J = 2.9 Hz) (4-chloro-4- 98 2.31 (br s, 1H), 3.82 (s, 3H), 4.52 (s, 2H), methoxybiphenyl-2- 6.89-6.94 (td, 2H, J = 2.2, 8.7 Hz), 7.13-7.28 (m 4H), yl)methanol 7.50-7.51 (d, 1H, J = 2.1 Hz) (2,4-dichlorobiphenyl-2- 96 1.77-1.80 (t, 1H, J = 5.8 Hz), 4.35-4.40 (dd, 1H, J = 5.9, yl)methanol 13.5 Hz), 4.45-4.50 (dd, 1H, J = 5.1, 13.4 Hz), 7.09-7.11 (d, 1H, J = 8.0 Hz), 7.20-7.22 (m, 1H), 7.31-7.36 (m, 3H), 7.45-7.48 (m, 1H), 7.60-7.61 (d, 1H, J = 1.8 Hz) methyl 4-chloro-2- 92 1.73 (br s, 1H), 3.95 (s, 3H), 4.57 (s, 2H), (hydroxymethyl)biphenyl- 7.20-7.22 (d, 1H, 8.2 Hz), 7.33-7.36 (dd, 1H, J = 2.1, 8.2 Hz), 4-carboxylate 7.39-7.42 (d, 2H, J = 8.4 Hz), 7.61-7.62 (d, 1H, J = 1.8 Hz), 7.08-8.11 (d, 2H, J = 8.4 Hz) (4,5-dichlorobiphenyl-3- 95 2.01 (br s, 1H), 4.72 (s, 2H), 7.34 (s, 1H), yl)methanol 7.39-7.48 (m, 6H) (5-chloro-2-(1H-indol-5- 97 1.72 (br s, 1H), 7.62 (s, 2H), 6.56-6.58 (m, 1H), yl)phenyl)methanol 7.10-7.13 (dd, 1H, J = 1.5, 8.4 Hz), 7.21-7.26 (m, 2H merged with CDCl.sub.3), 7.29-7.32 (dd, 1H, J = 2.2, 8.2 Hz), 7.39-7.42 (d, 1H, J = 8.3 Hz), 7.55 (s, 2H), 8.29 (br s, 1H) (4-chloro-4- 37 1.25 (br s, 1H), 2.96 (s, 6H), 4.60 (s, 2H), (dimethylamino)biphenyl- 6.75-6.77 (d, 2H, J = 8.4 Hz), 7.17-7.28 (m, 4H), 7.51-7.52 (d, 2-yl)methanol 1H, J = 2.0 Hz) (3,4-dichlorobiphenyl-2- 88 1.77 (br s, 1H), 4.56 (d, 2H, J = 3.3 Hz), yl)methanol 7.16-7.57 (m, 6H), 7.58 (s, 1H) (4-chloro-4- 78 1.68 (t, 1H, J = 3.9 HZ), 4.56 (d, 2H, J = 3.9 HZ), (trifluoromethyl)biphenyl- 7.19 (d, 1H, J = 6.3 Hz), 7.34-7.36 (m, 1H), 7.46 (d, 2-yl)methanol 2H, J = 6.3 Hz), 7.60 (d, 1H, J = 1.5 Hz), 7.68 (d, 2H, J = 6.3 Hz) (3,4,4-trichlorobiphenyl- 83 1.73 (t, 1H, J = 4.2 Hz), 4.56 (d, 2H, J = 4.2 Hz), 2-yl)methanol 7.16-7.19 (m, 2H), 7.32-7.57 (m, 3H), 7.58 (s, 1H) (5-chloro-2-(thiophen-3- 87 1.67 (s, 1H), 4.64 (s, 2H), 7.13 (d, 1H, J = 0.9 Hz), yl)phenyl)methanol 7.15-7.39 (m, 4H), 7.52 (s, 1H) (5-chloro-2-(thiophen-2- 62 1.96 (s, 1H), 4.69 (s, 2H), 7.06-7.09 (m, 2H), yl)phenyl)methanol 7.23-7.35 (m, 3H), 7.55 (d, 1H, J = 1.5 Hz) (5-chloro-2-(pyrimidin-5- 88 2.46 (br s, 1H), 4.56 (s, 2H), 7.21 (d, 1H, J = 8.19 Hz), yl)phenyl)methanol 7.39-7.65 (m, 2H), 8.78 (s, 2H), 9.21 (s, 1H)

Example 67

Synthesis of (3-(phenylamino)phenyl)methanol

(863) To a degassed solution of racemic-BINAP (67 mg, 0.107 mmol) in toluene (6 mL) was added palladium (II) acetate (36 mg, 0.054 mmol) and stirred at room temperature for 10 min. 3-Bromobenzyl alcohol (200 mg, 1.07 mmol) and aniline (149 mg, 1.60 mmol) were added and stirred for 5 min, cesium carbonate (522 mg, 1.60 mmol) was then added and stirred for 5 min. The mixture was then heated at 90 C. for 16 h diluted with ether (containing 1% triethylamine) and filtered. The solvent was removed under reduced pressure and the crude product was purified by silica gel flash column chromatography using 15-30% EtOAc/hexanes as eluent to afford the desired product as yellow oil (67 mg, 0.337 mmol, 32%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 1.74 (br s, 1H), 4.61 (s, 2H), 5.72 (br s, 1H), 6.87-7.07 (m, 6H), 7.21-7.28 (m, 3H).

Example 68

Synthesis of 3-(aminooxymethyl)-N-phenylaniline

(864) (3-(Phenylamino)phenyl)methanol (67 mg, 0.337 mmol), N-hydroxyphthalimide (66 mg, 0.404 mmol) and triphenylphosphine (106 mg, 0.404 mmol) were dissolved in THF (4 mL). Diethyl azodicarboxylate (DEAD) (0.07 mL, 0.404 mmol) was added dropwise while stirring to the solution and the reaction mixture was stirred at room temperature for 2 h. THF was evaporated under reduced pressure and the residue dissolved in dichloromethane (20 mL). The dichloromethane solution was washed with 10% NaOH (215 mL), water (215 mL) and brine (15 mL). The solvent was removed under reduced pressure and the crude product was used for the next step. The crude product (267 mg, 0.778 mmol) was dissolved in ethanol (4 mL) and hydrazine monohydrate (0.08 mL, 1.56 mmol) was added. The reaction was refluxed for 2 h and filtered. Ethanol was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 20%-40% EtOAc/hexanes as eluent to yield the desired product as white solid (50 mg, 0.234 mmol, 69% over 2 steps). .sup.1H NMR (CDCl.sub.3, 300 MHz): (ppm) 4.65 (s, 2H), 5.41 (br s, 2H), 5.74 (br s, 1H), 6.90-7.09 (m, 5H), 7.22-7.30 (m, 4H).

Example 69

Synthesis of 2-(aminooxy)-2-phenylethanol

(865) Methyl 2-aminooxy-2-phenylacetate (35 mg, 0.193 mmol) was dissolved in ether (3 mL) and LAH (1 M in THF, 0.39 mL, 0.387 mmol) was added at 0 C. The mixture was allowed to warm to room temperature over 2 h, and then quenched with water (0.3 mL) and 10% NaOH (0.3 mL) and additional water (1 mL). The product was extracted with ethyl acetate and the organic phase was washed with brine, dried and evaporated. The crude product was purified by silica gel flash column chromatography using 48% EtOAc/hexanes as eluent to yield the desired alcohol as clear oil (15 mg, 0.098 mmol, 51%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 2.38 (br s, 1H), 2.82 (br s, 2H), 3.62-3.67 (dd, 1H, J=8, 11.2 Hz), 3.73-3.76 (dd, 1H, J=3.6, 11.6 Hz), 4.79-4.82 (dd, 1H, J=3.2, 8 Hz), 7.25-7.36 (m, 5H).

Example 70

Synthesis of 4-(aminooxy)-4-phenylbutan-1-ol

(866) Methyl 4-(aminooxy)-4-phenylbutanoate (45 mg, 0.215 mmol) was dissolved in ether (3 mL) and LAH (1 M in THF, 0.4 mL, 0.431 mmol) was added at 0 C. The mixture was allowed to warm to room temperature over 2 h, and then quenched with water (0.3 mL) and 10% NaOH (0.3 mL) and additional water (1 mL). The product was extracted with ethyl acetate and the organic phase was washed with brine, dried and evaporated. The crude product was purified by silica gel flash column chromatography using 48% EtOAc/hexanes as eluent to yield the desired alcohol as clear oil (18 mg, 0.099 mmol, 46%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 1.62-1.68 (m, 2H), 1.80-1.87 (m, 2H), 2.68 (br s, 2H), 3.62-3.67 (m, 2H), 4.68-4.72 (m, 1H), 7.24-7.33 (m, 5H).

Example 71

Synthesis of (S)-3-(aminooxy)-3-phenylpropan-1-ol

(867) A solution of TBS protected (R)-1-phenyl-1-aminooxy-3-propanol (199 mg, 0.708 mmol) in THF (3 mL) at was cooled to 0 C. TBAF (1 M in THF, 1.4 mL, 1.42 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 h and concentrated. The residue was dissolved in EtOAc (40 mL), washed with 3% sodium carbonate (10 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel flash column chromatography using 25%-40% EtOAc/hexanes as eluent to afford the desired alcohol as colorless oil (75 mg, 0.449 mmol, 63%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (ppm) 1.82-1.88 (m, 2H), 2.02-2.09 (m, 2H), 2.28 (br s, 1H), 3.69-3.77 (m, 2H), 4.70-4.73 (dd, 1H, J=4.4, 8.8 Hz), 5.27 (br s, 2H), 7.27-7.38 (m, 5H).

Example 72

General Method for the Synthesis of Aryl Hydroxylamine Compounds

(868) In a 20 mL vial containing N-hydroxypthalamide (1 equiv), CuCl (1 equiv), freshly activated 4 molecular sieves (500 mg), and 1-naphthaleneboronic acid (2 equiv). The 1,2-dichloroethane solvent (5 mL) was added followed by pyridine (1.1 equiv), resulting in a light brown suspension. The cap was loosely applied such that the reaction was open to the atmosphere. Reaction progress was followed by TLC and was complete in 48 h. The reaction mixture became green as the reaction proceeded. The reaction products were adsorbed to SiO2 and the solvent was removed under reduced pressure. Chromatography of the reaction mixture (hexanes followed by DCM) afforded product as a light brown liquid. To the solution of phthalimide protected hydroxylamine and ethanol at room temperature, hydrazine hydrate (2 equiv) was added drop wise. The reaction was allowed to run for 1 hour at 50 C. The solution was filtered to remove the white precipitate and was concentrated under reduced pressure. To the concentrated mixture ethyl ether was added and the resulting solution was filtered and dried in to give pure product.

(869) The following compounds (Table E) were prepared essentially according to the preceding example with the proper substitution of starting materials:

(870) TABLE-US-00042 TABLE E Yield .sup.1H NMR (CDCl.sub.3 unless otherwise Compound (%) noted): (ppm) O-phenylhydroxylamine 43 6.84-6.89 (m, 1 H), 7.03-7.09 (m, 2 H), 7.19-7.25 (m, 2 H) O-(naphthalen-1- 35 7.16 (dd, 1 H, J = 9 Hz), 7.24-7.32 yl)hydroxylamine (m, 1 H), 7.35-7.42 (m, 1 H), 7.55 (d, 1 H, J = 2 Hz), 7.67-7.76 (m, 3 H)

Example 73

Synthesis of 2-(benzyloxy)-1-phenylethanol

(871) A solution of benzoyloxyacetaldehyde (350 mg, 2.33 mmol) and THF (10 mL) was flushed with nitrogen and cooled to 0 C. and phenylmagnesium bromide (2.6 mL, 2.6 mmol, 1M in THF) was added drop wise. The resulting solution was allowed to stir for additional 12 hours at room temperature. After reaction was finished the reaction mixture was cooled to 0 C. and 1 mL of water was added drop wise. The mixture was concentrated in vacuum and diluted with DCM washed with NaHCO.sub.3 solution, water, and brine respectively. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography using hexanes and EtOAc (10:1) as eluent. The pure product was obtained as colorless oil in 83% yield. .sup.1H NMR (DMSO-d6, 400 MHz): 3.36-3.50 (m, 2H), 4.65 (s, 2H), 4.69-4.73 (m, 1H), 5.37 (d, 1H, J=4.4 Hz), 5.20-5.33 (m, 1H), 7.18-7.32 (m, 10H).

Example 74

Synthesis of 1,3-diphenylpropan-1-ol

(872) Solution of hydrocinnamaldehyde (540 mg, 4.0 mmol) and THF was flushed with nitrogen and cooled to 0 C. and Phenylmagnesium bromide (4.4 mL, 1M in THF) was added dropwise. The resulting solution was allowed to stir for additional 12 hours at room temperature. After reaction was finished the reaction mixture was cooled to 0 C. and 1 mL of water was added dropwise. The mixture was concentrated in vacuum and diluted with DCM washed with NaHCO.sub.3 solution, water, and brine respectively. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography using hexanes and EtOAc (10:1) as eluent. The product was obtained as pale yellow oil in 58% yield. .sup.1H NMR (DMSO-d6, 400 MHz): 1.80-1.87 (m, 2H), 2.52-2.62 (m, 2H), 4.46-4-51 (m, 1H), 5.24 (d, 1H, J=4.8 Hz), 7.09-7.14 (m, 3H), 7.16-7.25 (m, 3H) 7.27-7.31 (m, 4H).

Example 75

Synthesis of 3-cyclohexyl-1-phenylpropan-1-ol

(873) To the stirred solution of CuI and THF (5 mL) at 78 C. and under nitrogen cyclohexylmethyl magnesium bromide (7.2 mL, 3.6 mmol, 0.5 M in THF) was added. This mixture was allowed to stir for additional 10 minutes and styrene oxide (360.5 mg, 3 mmol) dissolved in 1 mL of THF was added. The resulting mixture was stir overnight at room temperature. After the reaction was over water 5 mL was added. The mixture was concentrated in vacuum and diluted with DCM washed with NaHCO.sub.3 solution, water, and brine respectively. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated. The crude mixture was purified by column chromatography using EtOAc/Hexanes (1:10) to give the desired product as colorless liquid in 17% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 0.71-0.90 (m, 2H), 1.08-1.34 (m, 6H), 1.60-1.82 (m, 7H), 1.90 (br. s, 1H), 4.58-5.59 (m, 1H), 7.31-7.34 (m, 1H) 7.23-7.28 (m, 4H).

Example 76

Synthesis of tert-Butyl 2-hydroxy-2-phenylethylcarbamate

(874) To a solution of 2-amino-1-phenylethanol (685 mg, 5.0 mmol) in dichloromethane (20 mL), triethylamine (1.04 mL, 7.5 mmol) followed by di-tert-butyl dicarbonate (1.14 mL, 5.0 mmol) were added. The reaction mixture was stirred overnight at room temperature then saturated ammonium chloride solution added. The phases were separated and the aqueous layer extracted with dichloromethane (230 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography using EtOAc/hexanes (1:2) as eluent to give desired product as white solid in 83% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 1.45 (s, 9H); 3.0 (s, 1H), 3.27-3.47 (m, 2H), 4.84 (m, 1H), 4.91 (br. s, 1H), 7.28-7.37 (m, 5H).

Example 77

Synthesis of tert-Butyl 2-(1,3-dioxoisoindolin-2-yloxy)-2-phenylethylcarbamate

(875) To the solution of tert-Butyl 2-hydroxy-2-phenylethylcarbamate (878.0 mg, 3.6 mmol), N-hydroxyphthalimide (664.2 mg, 4.06 mmol), and triphenylphosphine (1067.6 mg, 4.06 mmol) in THF (16 mL), Diethyl azodicarboxylate (DEAD) (1.66 mL, 4.06 mmol, 40 wt % in toluene) was added dropwise. The solution was allowed to stir at 50 C. for 12 h. Water (5 mL) was added after the reaction was over. The organic layer was extracted in DCM and was dried over sodium sulfate. After concentrating in vacuum the crude product was purified by silica gel flash column chromatography using EtOAc/hexanes (1:2) as eluent to give desired product as off white solid in 69% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 1.42 (s, 9H); 3.52-3.68 (m, 2H), 5.25-5.50 (m, 1H), 5.56 (br. s, 1H), 7.25-7.40 (m, 3H), 7.41-7.59 (m, 2H), 7.72-7.82 (m, 4H).

Example 78

Synthesis of 2-(2-amino-1-phenylethoxy)isoindoline-1,3-dione

(876) To a solution of tert-Butyl 2-aminooxy-2-phenylethylcarbamate (554.4 mg, 2.2 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to yield the desired crude product as clear oil. The crude product was then purified by column chromatography using MeOH/DCM (10:90) as an eluent to give the product as colorless oil in 72% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 3.40-3.51 (m, 1H); 3.57-3.66 (m, 1H); 5.50-5.52 (m, 1H), 7.32-7.45 (m, 3H), 7.46-7.51 (m, 2H), 7.57-7.62 (m, 4H). 8.61 (br, s, 2H).

Example 79

Synthesis of N-(2-(1,3-dioxoisoindolin-2-yloxy)-2-phenylethyl)acetamide

(877) To a solution of 2-amino-1-phenylethanol (400.0 mg, 1.41 mmol) in THF (5 mL) was added NaHCO.sub.3 (238 mg, 2.83 mmol) and cooled to 0 C. Acetyl chloride (0.11 mL, 1.56 mmol) was added and the reaction mixture stirred at room temperature for 4 h. The THF was removed under reduced pressure and 5 mL of water was added to the remaining solution. The aqueous layer was extracted with dichloromethane (310 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography using ethyl acetate as an eluent to give the product as colorless oil in 71% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 2.06 (s, 3H); 3.63-3.68 (m, 1H); 3.82-3.88 (m, 1H), 5.17-5.20 (m, 1H), 6.82 (br, s, 1H), 7.15-7.42 (m, 3H), 7.45-7.50 (m, 2H), 7.67-7.91 (m, 4H).

Example 80

Synthesis of N-(2-(aminooxy)-2-phenylethyl)acetamide

(878) To the solution of N-(2-(1,3-dioxoisoindolin-2-yloxy)-2-phenylethyl)acetamide (83 mg, 0.25 mmol) and ethanol (3 mL), methyl hydrazine (0.25 mL, 1M solution in Ethanol) was added drop wise. The reaction was allowed to run for 1 hour at room temperature. The solution was filtered to remove the white precipitate and was concentrated. Ethyl ether was added and the resulting solution was filtered and dried in vacuum to give the desired product as white solid in 51% yield. .sup.1H NMR (DMSO, 400 MHz): 1.75 (s, 3H); 3.22-3.32 (m, 1H), 4.43-4.62 (m, 1H), 5.89 (br, s, 2H), 7.03-7.25 (m, 3H), 7.26-7.34 (m, 2H), 7.89 (br, s, 1H).

Example 81

Synthesis of tert-Butyl 3-hydroxy-3-phenylpropyl(methyl)carbamate

(879) To a solution of 3-(methylamino)-1-phenylpropan-1-ol (495 mg, 3 mmol) in dichloromethane (8 mL), triethylamine (0.62 mL, 4.5 mmol), followed by di-tert-butyl dicarbonate (0.68 mL, 3 mmol) were added. The reaction mixture was stirred overnight at room temperature then saturated ammonium chloride solution added. The phases were separated and the aqueous layer extracted with dichloromethane (230 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated and purified by column chromatography using EtOAc/hexanes (1:5) as an eluent to give the product as colorless oil in 67% yield. .sup.1H NMR (300 MHz, CDCl.sub.3): 1.46 (s, 9H), 1.86-2.02 (m, 2H), 2.86 (s, 3H), 3.08 (br, s, 1H), 3.86 (br, s, 1H), 4.59 (d, 1H, J=7.7 Hz), 7.35-7.23 (m, 5H).

Example 82

Synthesis of tert-Butyl 3-(1,3-dioxoisoindolin-2-yloxy)-3-phenylpropyl(methyl)carbamate

(880) To the solution of tert-Butyl 2-hydroxy-2-phenylethylcarbamate (785.0 mg, 3.0 mmol), N-hydroxyphthalimide (579.0 mg, 3.55 mmol), and triphenylphosphine (930.1 mg, 3.55 mmol) in THF (12 mL), Diethyl azodicarboxylate (DEAD) (1.50 mL, 3.55 mmol, 40 wt % in toluene) was added dropwise. The solution was allowed to stir at 50 C. for 12 h. Water (5 mL) was added after the reaction was over. The organic layer was extracted in DCM and was dried over sodium sulfate. After concentrating in vacuum the crude product was purified by silica gel flash column chromatography using EtOAc/hexanes (1:2) as eluent to give desired product as off white solid in 69% yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 1.38 (s, 9H); 1.98-2.2 (m, 1H), 2.30-2.42 (m, 1H), 2.85 (s, 3H), 3.25-3.44 (m, 2H), 5.25-5.32 (m, 1H), 7.22-7.35 (m, 3H), 7.38-7.47 (m, 2H), 7.55-7.72 (m, 4H).

Example 83

Synthesis of 3-(Ammoniooxy)-N-methyl-3-phenylpropan-1-aminium chloride

(881) To the solution of tert-butyl 3-(1,3-dioxoisoindolin-2-yloxy)-3-phenylpropyl(methyl)carbamate (410 mg, 1 mmol) and ethanol (3 mL) at room temperature Hydrazine Hydrate (3 mL, 1M solution in Ethanol) was added drop wise. The reaction was allowed to run for 1 hour. The solution was filtered to remove the white precipitate and was concentrated. Ethyl ether was added and the resulting solution was filtered and dried in vacuum. Resulting solid was dissolved in 2 mL of dioxane and solution of HCl (2 mL, 4M in Dioxane) was added drop wise. The resulting solution was allowed to stir for 24 h at room temperature. The white precipitate was collected by filtration and dried in vacuum to give the desired product in 83% overall yield. .sup.1H NMR (CDCl.sub.3, 400 MHz): 2.0-2.10 (m, 1H), 2.14-2.32 (m, 1H), 2.46 (s, 3H), 2.64-3.00 (m, 2H), 5.20-5.33 (m, 1H), 7.31-7.48 (m, 5H), 9.21 (br, s, 2H), 11.05 (br, s, 3H).

Example 84

Virtual Screening of IDO Inhibitors and Molecular Docking

(882) The published crystal structure of human IDO complexed with cyanide (pdb code:2D01) or with the IDO inhibitor 4-phenylimidazole (pdb code:2D0T) has been published by Sugimoto et al. (Sugimoto et at 2006, Proc. Natl. Acad. Sci. USA, 103(8) 2611-2616). Additionally, site directed mutagenesis and comparison with the mouse IDO aminoacid sequence identified aminoacids important for catalysis and substrate binding.

(883) All molecular modeling studies including docking were carried out using GLIDE v4.0 (SCHRODINGER L.L.C, New York). The published X-ray crystal structure of the human IDO complexed with 4-phenylimidazole provided the structural framework for molecular docking studies.

(884) A database with a library of 400,000 compounds was obtained from Albany Molecular Research Inc (Albany, N.Y.). Glide scores were obtained for known IDO inhibitors and used as reference to evaluate the results for other series of compounds. The known IDO inhibitors docked were: a) 1-methyl-tryptophan (Docking Score: 9.31), b) 4-phenylimidazole (Docking Score: 7.96), c) brassinin (Docking Score: 5.07) and d) 3-butyl-b-carboline (a non-competitive inhibitor, docking score: N/A). The more negative the value of the docking score, the better the result for the respective compounds. The calculations for known reference competitive inhibitors of IDO suggested that values between 7 kcal/mol and 10 kcal/mol would indicate compounds that are likely inhibitors of IDO. The library of 400,000 compounds was docked at the active site of IDO, yielding 852 structures with acceptable binding. The top 10% of these structures (88 compounds) were selected and used as a query in a 2D similarity search on a more extensive library of compounds (ACD). This broadened the diversity set of compounds to 30000 structures, which were subsequently docked using more stringent docking parameters (fine tuning of structures), yielding 800 structures with good docking scores (shown in Tables 1-11).

(885) In addition to compounds identified via virtual screening, several rationally designed IDO inhibitors were docked to IDO to evaluate their potential as good IDO inhibitors. Such compounds belong to families of known IDO inhibitors such as derivatives of brassinin, analogs of tryptophan, indole derivatives, known metal chelators, naphtoquinones, and compounds that mimic the transition state of tryptophan dioxygenation. The whole focused set of compounds was re-docked, yielding 1200 compounds with favorable docking scores (shown in Tables 1-11 of the present application). Docking scores for the compounds in Tables 1-12 are report in Table 13.

(886) TABLE-US-00043 TABLE 13 Docking Score Cmpd # (kcal/mol) 00001 8.56 00002 7.98 00003 8.71 00004 8.25 00006 8.24 00007 8.8 00008 8.91 00009 7.24 00010 7.83 00012 8.6 00020 6.56 00021 8.07 00027 8.5 00028 7.61 00030 8.61 00047 6.1 00053 8.58 00062 8.18 00063 7.62 00064 7.28 00077 6.04 00078 8.13 00079 7.23 00080 8.24 00081 7.6 00138 9.56 00140 9.05 00141 7.36 00142 7 00144 6.73 00145 6.84 00146 6.62 00147 6.95 00148 6.03 00149 5.25 00150 6.63 00151 7.35 00152 5.6 00154 6.64 00155 6.73 00157 5.93 00167 6.48 00168 7.75 00209 6.69 00210 9.02 00214 7.58 00215 8.4 00216 6.17 00217 7.27 00218 6.57 00219 7.73 00220 7 00221 6.4 00222 7.49 00224 6.14 00225 7.6 00226 7.64 00228 7.09 00230 8.61 00233 7.24 00239 7.9 00240 8.6 00252 7.06 00254 8.31 00256 8.65 00261 8 00262 7.39 00267 8.27 00268 6.56 00271 7.65 00272 6.37 00281 6.3 00282 8.22 00288 8.8 00289 5.52 00291 5.65 00292 8.32 00293 8.08 00300 8.62 00305 6.9 00307 7.65 00309 6.08 00310 8.44 00311 6.97 00312 7.84 00313 8.24 00317 8.06 00319 8.03 00320 6.2 00324 6.77 00325 8.82 00327 8.78 00332 7.66 00334 6.05 00335 9.29 00337 6.49 00342 6.78 00343 8.63 00345 6.81 00346 7.18 00347 8.11 00348 6.75 00352 9.49 00356 6.91 00360 7.44 00363 6.97 00364 6.31 00366 7.53 00367 7.43 00368 8.02 00378 7.53 00379 8.44 00380 6.79 00382 5.85 00385 7.62 00386 9.31 00388 9.05 00389 8.63 00390 8.94 00391 5.82 00392 5.93 00394 7.85 00396 7.84 00398 6.07 00464 6.29 00477 6.12 00507 6.55 00515 5.22 00516 4.69 00523 3.79 00525 4.28 00526 7.67 00527 6.32 00528 6.41 00530 5.91 00531 4.57 00532 5.24 00533 6.16 00535 6.64 00539 6.2 00541 5.54 00545 6.99 00546 6.97 00549 6.44 00550 6.87 00552 9.11 00553 9.64 00554 8.12 00555 8.23 00561 10.64 00562 10.44 00563 10.3 00564 10.27 00565 10.22 00566 10.17 00567 10.11 00568 9.96 00571 9.87 00572 9.83 00577 9.72 00578 9.65 00586 9.49 00587 9.46 00588 9.45 00589 9.45 00590 9.42 00591 9.38 00592 9.35 00593 9.32 00596 9.29 00599 9.21 00601 9.19 00602 9.18 00603 9.14 00604 9.14 00605 9.13 00606 9.11 00607 9.11 00608 9.1 00610 9.09 00611 9.08 00613 9.04 00616 9 00620 8.97 00621 8.97 00622 8.97 00623 8.95 00627 8.92 00628 8.92 00630 8.89 00632 8.88 00634 8.86 00636 8.85 00637 8.84 00644 8.8 00645 8.79 00646 8.78 00649 8.76 00650 8.75 00655 8.71 00656 8.71 00657 8.7 00658 8.69 00660 8.68 00662 8.67 00663 8.66 00664 8.65 00665 8.64 00667 8.64 00668 8.63 00669 8.61 00670 8.61 00671 8.61 00672 8.58 00673 8.58 00674 8.57 00675 8.57 00678 8.56 00681 8.53 00682 8.53 00683 8.53 00685 8.52 00686 8.5 00687 8.49 00688 8.49 00689 8.49 00690 8.48 00691 8.48 00692 8.47 00695 8.46 00697 8.46 00698 8.45 00699 8.44 00700 8.44 00701 8.44 00705 8.43 00707 8.42 00711 8.4 00714 8.4 00716 8.39 00717 8.39 00718 8.38 00720 8.37 00721 8.36 00722 8.36 00724 8.36 00725 8.36 00727 8.35 00729 8.34 00732 8.34 00737 8.31 00738 8.3 00739 8.3 00740 8.29 00741 8.29 00744 8.28 00745 8.26 00746 8.26 00748 8.26 00749 8.25 00750 8.25 00751 8.62 00752 8.25 00753 8.25 00755 8.23 00757 8.21 00758 8.21 00759 8.21 00760 8.2 00761 8.2 00762 8.2 00764 8.18 00766 8.17 00767 8.16 00768 8.15 00770 8.15 00772 8.15 00773 8.14 00774 8.14 00775 8.14 00777 8.14 00778 8.13 00781 8.12 00782 8.11 00783 8.11 00784 8.09 00786 8.08 00787 8.07 00788 8.07 00789 8.06 00791 8.04 00793 8.03 00796 8 00797 8 00799 8 00801 8 00803 7.99 00805 7.99 00806 7.99 00807 7.98 00808 7.98 00809 7.97 00810 7.97 00811 7.97 00812 7.96 00813 7.96 00814 7.96 00815 7.96 00819 7.95 00820 7.95 00821 7.94 00822 7.94 00824 7.94 00827 7.94 00828 7.92 00830 7.92 00834 7.91 00835 7.9 00836 7.9 00837 7.89 00840 7.89 00843 7.88 00848 7.87 00849 7.86 00850 7.86 00852 7.85 00855 7.84 00856 7.84 00857 7.83 00858 7.83 00861 7.81 00862 7.81 00864 7.81 00867 7.79 00868 7.79 00869 7.78 00870 7.77 00871 7.77 00872 7.77 00874 7.76 00875 7.76 00877 7.76 00880 7.74 00881 7.74 00882 7.74 00883 7.73 00886 7.72 00887 7.72 00888 7.71 00889 7.71 00890 7.71 00891 7.68 00892 7.68 00894 7.67 00895 7.67 00896 7.67 00897 7.66 00898 7.66 00899 7.66 00900 7.65 00901 7.65 00902 7.65 00903 7.64 00905 7.62 00906 7.62 00909 8 00910 7.61 00912 7.61 00913 7.6 00914 7.59 00915 7.59 00916 7.59 00917 7.59 00918 7.59 00919 7.59 00920 7.58 00921 7.57 00922 7.57 00924 7.57 00927 7.56 00929 7.52 00930 7.52 00931 7.52 00932 7.51 00934 7.5 00935 7.5 00938 7.48 00939 7.47 00940 7.47 00943 7.46 00944 7.45 00945 7.45 00946 7.45 00947 7.45 00949 7.45 00950 7.45 00951 7.45 00952 7.44 00953 7.44 00954 7.44 00955 7.44 00957 7.43 00958 7.43 00959 7.43 00960 7.42 00961 7.42 00963 7.42 00964 7.41 00965 7.41 00966 7.4 00967 7.4 00969 7.39 00970 7.39 00973 7.37 00974 7.35 00975 7.35 00976 7.35 00977 7.35 00978 7.35 00979 7.35 00980 7.34 00981 7.34 00982 7.34 00983 7.33 00984 7.33 00985 7.33 00988 7.31 00989 7.31 00990 7.31 00991 7.3 00993 7.29 00994 7.29 00995 7.29 00996 7.28 00997 7.28 00998 7.27 00999 7.27 01000 7.27 01001 7.26 01003 7.26 01004 7.26 01007 7.24 01008 7.24 01009 7.24 01010 7.24 01011 7.24 01012 7.24 01013 7.23 01014 7.23 01015 7.22 01016 7.22 01017 7.21 01018 7.21 01019 7.2 01020 7.2 01021 7.2 01022 7.19 01024 7.18 01026 7.17 01027 7.16 01028 7.16 01029 7.16 01030 7.16 01031 7.15 01033 7.15 01034 7.15 01036 7.14 01037 7.14 01038 7.13 01039 7.11 01040 7.11 01041 7.11 01042 7.1 01043 7.1 01044 7.09 01045 7.07 01046 7.07 01048 7.04 01051 7.04 01052 7.03 01056 7.01 01057 7 01058 7 01059 6.99 01060 6.97 01061 6.97 01062 6.97 01063 6.97 01064 6.96 01065 6.96 01066 6.94 01067 6.94 01068 6.94 01069 6.92 01070 6.92 01071 6.92 01072 6.92 01073 6.91 01074 6.91 01075 6.91 01076 6.91 01077 6.91 01078 6.9 01079 6.9 01080 6.89 01081 6.89 01082 6.89 01083 6.88 01087 6.86 01088 6.86 01089 6.85 01090 6.85 01091 6.85 01092 6.84 01093 6.84 01094 6.83 01096 6.82 01098 6.81 01099 6.81 01100 6.81 01101 6.81 01104 6.79 01105 6.79 01106 6.78 01107 6.78 01108 6.78 01109 6.78 01110 6.77 01111 6.76 01113 6.74 01114 6.74 01115 6.73 01116 6.72 01118 6.72 01119 6.7 01120 6.7 01121 6.7 01123 6.69 01124 6.68 01125 6.68 01126 6.66 01127 6.64 01128 6.64 01129 6.63 01130 6.63 01131 6.63 01133 6.61 01134 6.6 01135 6.59 01137 6.58 01138 6.57 01139 6.57 01140 6.56 01141 6.56 01142 6.56 01143 6.55 01144 6.54 01145 6.52 01146 6.52 01147 6.51 01148 6.51 01149 6.51 01150 6.49 01151 6.48 01152 6.46 01153 6.46 01154 6.46 01156 6.44 01158 6.43 01159 6.43 01160 6.42 01161 6.42 01163 6.4 01164 6.4 01165 6.39 01167 6.39 01168 6.38 01169 6.38 01170 6.38 01171 6.35 01173 6.33 01174 6.32 01175 6.32 01177 6.29 01178 6.29 01179 6.26 01180 6.26 01181 6.26 01182 6.25 01183 6.24 01184 6.23 01185 6.21 01187 6.21 01188 6.19 01189 6.19 01190 6.19 01191 6.16 01192 6.16 01194 6.13 01195 6.11 01196 6.1 01197 6.1 01198 6.07 01199 6.05 01200 6.03 01202 6.01 01204 6 01205 6 01206 5.98 01207 5.97 01209 5.95 01210 5.95 01212 5.92 01213 5.92 01214 5.91 01215 5.9 01217 5.88 01218 5.88 01219 5.86 01220 5.84 01222 5.8 01224 5.75 01225 5.74 01226 5.66 01228 5.6 01229 5.6 01230 5.56 01231 5.54 01232 5.51 01233 5.49 01234 5.48 01235 5.47 01236 5.42 01237 5.42 01238 5.34 01239 5.33 01240 5.26 01241 5.19 01242 5.14 01243 5.14 01244 5.1 01245 5.09 01246 5.03 01247 5.01 01248 4.91 01249 4.87 01250 4.86 01251 4.82 01252 4.82 01253 4.8 01254 4.67 01255 4.66 01256 4.52 01257 3.63 01258 3.5 01259 3.43 01260 8.06 01261 8.68 01262 9.34 01263 7.45 01264 7.51 01265 6.92 01266 7.48 01267 7.87 01268 8.81 01269 8.32 01270 8.9 01271 9.3 01272 8.3 01273 8.75 01274 8.41 01275 8.54 01276 9 01277 8.11 01278 8.88 01279 8.71 01280 8.61 01281 8.29 01282 7.3 01283 9.08 01284 6.02 01285 8.67 01286 8.42 01287 8.11 01288 7.4 01289 7.76 01290 7.47 01291 8.03 01292 6.99 01293 8.52 01294 7.91 01295 7.17 01296 6.95 01298 7.27 01299 8.39 01300 8.57 01301 8.72 01302 8.12 01305 9.18 01306 8.99 01307 8.93 01308 9.24 01309 8.99 01310 9.21 01311 5.72 01360 8.27 01361 8.01 01362 6.42 01363 6.38 01364 6.77 01365 8.65 01366 5.7 01367 8.92 01368 8.89 01369 8.57 01370 7.91 01371 7.65 01372 7.96 01373 6.63 01374 8.06 01375 7.4 01376 5.83 01377 6.24 01378 7.85 01379 7.04 01380 7.8 01381 7.7 01382 7.91 01383 6.63 01384 6.69 01385 6.81 01386 3.58 01387 10.21 01388 5.56 01389 6.8 01390 5.2 01391 9.34 01392 8.41 01393 6.19 01394 3.58 01395 4.35 01396 4.24 01397 6.7 01398 7.22 01399 7.35 01400 4.29 01401 5.75 01402 6.96 01403 8.93 01404 7.78 01406 8.09 01407 5.12 01408 5.23 01409 4.43 01410 5.44 01410 5.44 01411 4.19 01412 7.09 01413 6.52 01414 7.71 01415 6.1 01416 5.18 01417 6.51 01418 5.29 01419 5.33 01420 8.16 01421 7.05 01422 7.38 01423 6.99 01424 7.05 01425 6.76 01427 4.02 01429 7.11 01430 5.3 01431 7.11 01432 5.86 01433 6.42 01434 6.1 01435 7.28 01436 8.59 01438 6.91 01439 5.89 01440 9.26 01442 9.3 01443 8.26 01444 9.85 01445 9.38 01446 8.11 01447 8.13 01448 8.52 01449 6.89 01450 4.88 01451 6.51 01452 4.98 01453 6.97 01454 4.33 01455 5.72 01456 5.63 01457 5.72 01458 8.89 01459 5.73 01460 5.42 01461 6.68 01462 6.51 01463 6.02 01464 6.15 01465 6.55 01467 5.56 01469 5.9 01470 6.25 01471 4.97 01472 5.25 01473 6.81 01474 6.22 01475 6.86 01476 6.96 01478 8.09 01479 8.31 01480 5.93 01481 6.41 01482 6.83 01483 5.77 01484 5.96 01485 5.34 01486 5.61 01487 5.34 01488 7.08 01489 6.71 01490 6.47 01491 6.95

Example 85

Human IDO Protein Cloning, Expression and Purification

(887) Expression vectors for human indoleamine-2,3-dioxygenase (IDO) protein were prepared by amplification of a 1219 bp fragment of the sequence present in vector phIDO6His cDNA with primers 5-ggagcatgctaATGGCACACGCTATGGAAAAC-3 and 5-gagagatctACCTTCCTTCAAAAGGGATTTC-3 and cloning the SphI-BglII 1213 bp fragment into pQE70 (Qiagen), to yield vector pQE70-hIDO. This construct adds 2 extra amino acids and a 6-Histidine tag to the C-terminus of the natural human IDO protein while preserving intact the natural start codon and N-terminus amino acid sequence. The amplified allele of human IDO shows two polymorphisms with respect to the sequence deposited in accession file P14902 of SwissProt database. These polymorphisms result in a P110S and E119G amino acid changes.

(888) Plasmid pQE70-hIDO was transformed into M15(pREP4) cells (Qiagen) and clones were selected in LB-agar plates supplemented with carbenicillin 50 g/mL and kanamycin 30 g/mL. Protein expression was carried out by growing an overnight culture of the M15pREP4/pQE70-hIDO clone in 100 mL LB supplemented with 100 g/mL carbenicillin, 50 g/mL kanamycin and 50 g/mL of L-tryptophan (LBCKT medium). 40 mL of this culture were inoculated into 750 mL of LBCKT for 4 hours at 37 C. This culture was diluted 1:10 into LBCKT medium and cultured for another 2 hours at 37 C. until OD600 was higher than 0.8. At this point the cultures were inoculated with Hemin to 7 M and L-Tryptophan to 75 g/mL and incubated at 37 C. for 2 h. Induction of protein expression was carried out by supplementing the cultures with IPTG to 1 mM, PMSF to 200 M, EDTA to 1 mM and L-tryptophan to 50 g/mL. Incubation was continued for additional 16 h at 25 C. Cells were collected by centrifugation, and the cell pellets were washed with PBS buffer supplemented with 200 M PMSF and 1 mM EDTA and stored at 80 C. until protein purification.

(889) The equivalent of 16 L of culture were processed in one batch of purification. Cell pellets were thawed, resuspended in 50 mM potassium phosphate buffer pH 7.0, 200 M PMSF, 1 mM EDTA, 1 mg/mL lysozyme to 10 mL per liter of bacterial culture and incubated 30 minutes on ice. Cells were then lysed by sonication. Cell lysates were centrifuged 20 min at 20000 g and the supernatant was filtered through 0.45 m filters. The filtered supernatant was loaded onto a 60 mL phosphocellulose column equilibrated with 50 mM potassium phosphate buffer pH 6.5 (KPB) at 1-3 mL/min. The column was washed with 3 volumes of 50 mM KPB, 3 volumes of 100 mM KPB and the protein was eluted with 15 volumes of a linear gradient of 100-500 mM KPB. Fractions were collected and IDO activity assay was performed by measuring kynurenine production. This was carried out by mixing 50 L of each fraction with 100 L of reaction mix to yield a final concentration of 50 mM KPB buffer, 20 mM ascorbic acid, 200 g/mL catalase, 20 M methylene blue and 400 M L-tryptophan. Fractions demonstrating IDO activity were loaded onto a Ni-NTA purification column (15 mL). This affinity purification column was washed with 10 volumes of 250 mM KPB, 150 mM NaCl, 50 mM imidazole pH 8, and eluted with 10 volumes of buffer containing 250 mM KPB, 150 mM NaCl and a 50 to 250 mM imidazole linear gradient. Collected fractions were assayed by IDO enzymatic assay described above and the positive fractions were pooled and concentrated by ultrafiltration and dialyzed against a buffer containing 250 mM KPB, 50% glycerol. This process yields 8-10 mg of pure protein (>98%) with a specific activity of 170 mol/h/mg.

Example 86

Testing of IDO Inhibitory Compounds by Enzymatic IDO Assay

(890) The IC.sub.50 values for each compound were determined by testing the activity of IDO in a mixture containing 50 mM potassium phosphate buffer at pH 6.5; 70 nM purified human IDO protein, 200 M L-tryptophan, 20 mM ascorbate, 20 M methylene blue, 0.1% DMSO. The inhibitors were initially diluted in DMSO at 100 mM and were diluted in potassium phosphate 50 mM, added to the reaction mixture at final concentrations raging from 1 mM to 5 nM and preincubated with the enzyme for 5 min at 25 C. The reaction was started by addition of L-tryptophan to 200 M and incubated 15 min at 37 C. The reaction was stopped by addition of 0.5 vol of 30% trichloroacetic acid and incubated 30 min at 60 C. to hydrolyze N-formylkynurenine to kynurenine. The reaction was centrifuged at 3400 g for 5 min to remove precipitated protein and the supernatant was reacted with 2% (w/v) of p-dimethylaminobenzaldehyde in acetic acid. The reaction was incubated 10 min at 25 C. and read at 480 nm in a spectrophotometer. Control samples with no IDO inhibitor, or with no IDO enzyme or with the reference inhibitors 1-methyl-tryptophan (200 M) and menadione (1.2 M) were used as controls to set the parameters for the non-linear regressions necessary for determination of the IC.sub.50 for each compound. Nonlinear regressions and determination of the IC.sub.50 values were performed using the GraphPad Prism 4 software. Compounds with an IC.sub.50 of less than 500 M were considered as active inhibitors in this assay.

Example 87

Determination of IDO Inhibitory Activity and Toxicity in Cell Based IDO/Kynurenine Assay

(891) 293-T-REx cells (Invitrogen) constitutively express a tet operator binding repressor protein and are maintained in DMEM, 10% FBS, 1 Penicillin+Streptomycin, 2 mM L-glutamine, 5 g/mL blasticidin at 37 C. with a 5% CO.sub.2 in air atmosphere and typically split prior to confluency. Cells were passed by splitting the culture 1/10by removing media by aspiration, washing 1 with PBS, incubating with 0.25% trypsin/EDTA until the cells detach, disbursing the cells in fresh growth media, and plating at 1/10 dilutions in fresh growth media. For long term cryopreservation, cells are detached from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium, 10% DMSO), stored in 1.8 mL cryopreservation vials (2510.sup.6 cells per vial), in liquid nitrogen vapor storage tanks.

(892) IDOLexpressing 293-T-Rex cell lines were generated by stable transfection of plasmid pcDNA-tetO-IDO expressing human IDO or murine IDO under the control of the doxycycline-inducible CMV-tet promoter. Transfected cells were selected in DBZ medium (DMEM, 10% FBS, 1 Penicillin+Streptomycin, 2 mM L-glutamine, 5 g/mL blasticidin and 25 g/ml Zeocin) at 37 C. with a 5% CO.sub.2 in air atmosphere. Individual clones were isolated by limiting dilution cloning from these populations. These clones were assayed for IDO activity and the clones that showed the highest levels of IDO activity inducible by doxycycline were used for subsequent cell based IDO assays.

(893) To setup an IDO cell based activity assay, IDO-293-T-Rex cells were harvested and resuspended in DBZ media at 10.sup.6 cells/mL, and split into poly-D-lysine coated 96-well plates at 100,000 cells per well. 100 L of Neutral medium (DBZ medium, 200 M L-tryptophan) or Induction media (Neutral medium supplemented with 5 M doxycycline) are added to the cells and incubated 28 h at 37 C. After the IDO induction period, medium is removed and replaced with Induction or Neutral medium containing different concentrations of each inhibitor (1 mM to 0.5 nM). The cells incubated in Neutral medium serve as negative control of the assay. The cells incubated in Induction medium and without inhibitor serve as the positive control of the assay. The incubation is carried out for 16 h at 37 C. in a cell culture incubator. 200 L of medium are transferred to U-bottom polypropylene 96-well plates containing 25 L of 30% TCA, incubated 30 minutes at 60 C. and centrifuged at 3400 g for 5 minutes. 150 L of the clear supernatant is transferred to a polystyrene 96-well plate containing 50 L of 4% (w/v) of p-dimethylaminobenzaldehyde in acetic acid, incubated for 10 min. Kynurenine concentration is determined by measuring the absorbance at 480 nm.

(894) To measure the toxicity of each compound after 16 h incubation with cells, cell viability is measured via a WST-1 assay (Roche) according to instructions from the manufacturer. Briefly, after the incubation with each compound, medium is aspirated and replaced with 100 mL of WST-1 reagent, and incubated 30 min at 37 C. Absorbance at 540 nm is correlated with the number of viable cells. Determination of IC.sub.50 (Kynurenine assay) or LD.sub.50 (WST-1 assay) is performed via non-linear regression analysis using GraphPad Prism software.

Example 88

Reversal of IDO-Mediated Suppression of T-Cell Proliferation by IDO Inhibitors

(895) Human monocytes were collected from peripheral mononuclear cells by leukoapheresis and cultured overnight at 10.sup.6 cells/well in a 96-well plate in RPMI 1640 medium supplemented with 10% fetal calf serum and 2 mM L-glutamine. Adherent cells were retained and cultured for 7 days with 200 ng/ml IL-4, 100 ng/ml GM-CSF. Cells were matured for 2 days with a cytokine cocktail containing TNF-, IL-, IL-6 and PGE2 for additional 2 days to induce dendritic cell maturation. At the end of maturation, loosely adherent cells were detached by gentle aspiration and plated in V-bottom 96 well plates, at 5000 cells/well. These cells are >80% IDO+ dendritic cells. Human allogeneic T cells (310.sup.5) from normal donors were resuspended in RPMI 1640 supplemented with 100-200 U/mL IL-2 and 100 ng/mL anti-CD3 antibody and added to the wells. Serial dilutions of IDO compounds dissolved in phenol red-free RPMI was added to yield a final concentration of IDOi between 500 and 1 M. After incubation for 2-4 days, T cell proliferation was measured by BrdU incorporation assay after an overnight pulse with BrdU labeling mix (Roche Molecular Biochemicals). At the en of the pulse, the cells were fixed and incubated with 100 L/well anti-BrdU-POD antibody following the instructions from the manufacturer. Plates were read in a microplate reader.

(896) Alternatively, testing of IDO inhibitors in an in vitro mouse model of IDO-mediated suppression of T cell proliferation is performed by the following procedure. C57b16 mice are inoculated with 110.sup.6 B78H1-GMCSF tumor cells in the right flank. After 10-12 days, tumor draining lymph nodes are collected and cells are stained with anti-CD11c and anti-B220 monoclonal antibodies. Cells are sorted by high-speed fluorescence activated cell sorting and the CD11c+/B220+ plasmacytoid dendritic cells are collected and seeded at 2000 cells/well in 96 well V-bottom plates. Splenocytes are collected from BM3 transgenic mice (in CBA background) and collected by nylon wool enrichment. BM3 T cells (10.sup.5 cells/well) are added to each well in 200 L of RPMI, 10% FCS, 50 M -mercaptoetanol. Alternatively, T cells are obtained from spleens of OT-I transgenic mice and added to the culture in combination with OVA peptide. IDO inhibitors are added dissolved in RPMI at final concentrations ranging from 1 mM to 10 nM. After 3 days of stimulation, cells are pulsed by 16 h with BrdU or .sup.3H-thymidine. Cells are collected, fixed and tested for BrdU incorporation following the instructions from the BrdU labeling kit manufacturer (Roche Diagnostics). If .sup.3H-tymidine is used to measure T cell proliferation, cells are harvested and dpm counts are measured in a scintillation counter following procedures widely known in the art. Control CD11c.sup.+ cells taken from the contralateral lymph node or CD11c.sup.+/B220.sup. cells (IDO.sup. population) from the TDLN are used as positive control for proliferation.

Example 89

In Vivo Testing of IDO Inhibitors for Antitumor Activity in Combination with Chemotherapeutic Agents

(897) In vivo anti-tumor efficacy can be tested using modified tumor allograft protocols. For instance, it has been described in the literature that IDO inhibition can syngerize with cytotoxic chemotherapy in immune-competent mice. Due to different susceptibilities of different tumor cell lines to chemotherapeutic drugs and to immune mediated rejection, each IDO inhibitor is tested alone and in combination with 2 different chemotherapeutic drugs in 4 different animal tumor models, represented by 4 different mouse tumor cell lines, of different tissue origin (colorectal, bladder, mammary and lung carcinoma), implanted subcutaneously in syngeneic strains of mice. These cell lines have been selected based on their known susceptibility to chemotherapeutic drugs, their partial response to IDO inhibitors as single agents, their presumed pattern of IDO expression according to their tissue of origin, and their ability to elicit an immune reaction.

(898) For every animal tumor model, 2 different chemotherapeutic drugs are tested in separate groups of mice according to the following list: 1] LLC tumor: cyclophosphamide and paclitaxel; 2] EMT6 tumor: cyclophosphamide and paclitaxel; 3] CT26 tumor: cyclophosphamide and doxorubicin; and 4] MB49 tumor: cyclophosphamide and gemcitabine.

(899) The following chemotherapeutic drugs are used, at the indicated doses. The maximum tolerated dose for the following chemotherapeutic agents in mice depends on the formulation, concentration, frequency of administration, route of administration and number of doses. The chemotherapeutic drugs administered in conjunction with each IDO inhibitor drug are: 1] Paclitaxel: 20 mg/kg/day i.p, every 4 days, 4 times (q4d4) (in Cremophor); 2] Doxorubicin: mg/kg, once a week for 3 weeks (q7d3); 3] Cyclophosphamide: 100 mg/kg, I.P., every 4 days, 4 times (q4d4); 4] Gemcitabine: 80 mg/kg every 4 days, 4 times, i.p. (q4d4).

(900) All animals receive a subcutaneous injection of a tumor forming dose of live tumor cells (50000-1000000 cells) suspended in 0.1 mL of PBS or saline on day 1. Subcutaneous injection forms a localized tumor that allows monitoring tumor growth over time.

(901) To mimic the effect of IDO inhibitor drugs as therapeutic compositions, administration of IDO inhibitor drugs begins at day 5-8 after tumor inoculation. Dosing, route of administration, dosing frequency varies depending on the toxicity and pharmacokinetics profile of each drug. Duration of the treatment is 2 weeks. Most preferably, drug is administered continuously via oral gavage or dissolution in the drinking water. Alternatively, subcutaneous slow release pellets containing 100 mg of each drug are implanted under the skin by surgical procedure. IDO inhibitor drug are administered at the maximum tolerated dose or at a concentration corresponding to the LD.sub.10.

Example 90

Pharmacological Values

(902) Tables 14-16 report pharmacological values for compounds tested according to one or more of the preceding examples, including,

(903) Human IDO IC.sub.50: this is the concentration of the compound at which we observe 50% of enzymatic activity using recombinant human IDO under the assay conditions described in one of the examples;

(904) Human IDO EC.sub.50: This is the concentration of the compound at which we observe 50% of kynurenine production in a cell based assay using a 293T cell lines stably transfected with an expression cassette expressing human IDO. The conditions of the assay were as described in the examples.

(905) Human IDO LD.sub.50: This is the concentration of the compound at which we observe 50% of cell viability loss in the IDO cell based assay. Viability was measure by the WST assay as described in one of the examples.

(906) In Table 14, values are reported in ranges: A: 1-10 mM; B: 0.1-1 mM; C: 20-100 M; D: <20 M.

(907) TABLE-US-00044 TABLE 14 hIDO hIDO hIDO Cmpd # IC.sub.50 EC.sub.50 LD.sub.50 Docking_Score 1 B B B 8.56 2 B B B 7.98 3 B B B 8.71 4 B C B 8.25 6 B B B 8.24 7 B B B 8.8 8 B B B 8.91 9 B C B 7.24 10 B B B 7.83 12 B B B 8.6 13 B 7.88 14 B B B 7.19 20 B 6.56 21 B B B 8.07 23 B C C 4.45 27 B B B 8.5 28 B C A 7.61 30 B C B 8.61 32 B C B 7.57 38 B C C 6.22 40 B B B 8.29 42 B B B 6.13 43 B B B 6.31 44 B A A 5.34 45 B B B 7.39 47 B C C 6.1 50 C C C 8.92 52 C C B 9.51 53 B C C 8.58 57 D C B 8.73 58 B C C 7.84 60 C C B 8.04 63 C C B 7.62 64 B C B 7.28 65 C C B 8.57 66 B B B 6.05 69 B 7.19 77 B 6.04 78 B B A 8.13 79 C D A 7.23 81 B 7.6 138 B C C 9.56 140 B C C 9.05 142 D B A 7 148 B B B 6.03 149 B C B 5.25 150 B B C 6.63 151 B B B 7.35 152 C C A 5.6 162 D B B 6.26 163 D D D 5.85 167 D C B 6.48 168 B B A 7.75 209 B A B 6.69 222 B C B 7.49 252 B C A 7.06 261 B C B 8 267 B 8.27 280 B A A 8.02 282 B A A 8.22 289 B A A 5.52 307 D A B 7.65 309 C B B 6.08 312 D D A 7.84 313 B B A 8.24 317 D D A 8.06 320 D A A 6.2 321 B B B 8.37 325 B A A 8.82 352 B A A 9.49 463 C 5.49 464 C A A 6.29 477 D C A 6.12 525 B 4.28 552 B C A 9.11 561 B C A 10.64 565 B 10.22 568 B 9.96 581 B B A 9.6 588 B B B 9.45 591 B 9.38 592 B 9.35 606 B 9.11 607 C C B 9.11 634 B B A 8.86 644 B C B 8.8 656 B C C 8.71 664 B 8.65 672 B C B 8.58 673 B 8.58 682 B B A 8.53 701 B B A 8.44 707 B 8.42 739 B B A 8.3 786 B 8.08 827 B C B 7.94 830 C C A 7.92 889 B 7.71 1359 B C B 9.52

(908) In Tables 15 and 16, values are reported in ranges: A: <10 M; B: 10-100 M; C: 100-1000 M; D>1000 M.

(909) TABLE-US-00045 TABLE 15 Cpd hIDO mIDO # Structure Name IC.sub.50 EC.sub.50 LD.sub.50 EC.sub.50 LD.sub.50 1769 000 O-(3,5-dichlorobenzyl) hydroxylamine A A D A D 1914 001 O-((4-chloro-4- methoxybiphenyl-2- yl)methyl)hydroxylamine A A C B D 1935 002 methyl 2-(aminooxymethyl)-4- chlorobiphenyl-4-carboxylate A A C 1892 003 O-((4,4-dichlorobiphenyl-2- yl)methyl)hydroxylamine A A B A D 1932 004 O-(5-chloro-2-(thiophen-3- yl)benzyl)hydroxylamine A A D 1918 005 O-((3,4-dichlorobiphenyl-2- yl)methyl)hydroxylamine A A D B C 1916 006 O-((4-chlorobiphenyl-2- yl)methyl)hydroxylamine A A C B C 1937 007 O-(2-phenoxy-1- phenylethyl)hydroxylamine A A C 1825 008 O-(biphenyl-3- ylmethyl)hydroxylamine A A D B D 1879 009 O-((4-chlorobiphenyl-2- yl)methyl)hydroxylamine A A D B D 1931 010 O-(5-chloro-2-(thiophen-2- yl)benzyl)hydroxylamine A A D 1743 011 O-((5-chlorobenzo[b] thiophen-3- yl)methyl)hydroxylamine A A D B D 1880 012 methyl 4-(aminooxy)-4- phenylbutanoate A A D C D 1915 013 O-((2,4-dichlorobiphenyl-2- yl)methyl)hydroxylamine A B C C C 1749 014 O-(benzo[d]thiazol-2- ylmethyl)hydroxylamine A A D A D 1878 015 O-((4-chlorobiphenyl-3- yl)methyl)hydroxylamine A A D B D 1919 016 O-((3,4,4- trichlorobiphenyl-2- yl)methyl)hydroxylamine A A C B C 1923 017 O-(5-chloro-2-(pyrimidin-5- yl)benzyl)hydroxylamine A A C A D 1774 018 O-(benzofuran-2- ylmethyl)hydroxylamine A A D A D 1882 019 O-((4-methoxybiphenyl-3- yl)methyl)hydroxylamine A A D B D 1930 020 O-(5-chloro-2-(1H-indo1-5- yl)benzyl)hydroxylamine A A C 1873 021 3-(aminooxymethyl) benzonitrile A A D A D 2033 022 (S)-2-(aminooxy)-N-methyl-2- phenylacetamide A 1770 023 O-(3,5-difluorobenzyl) hydroxylamine A A D 2.3 D 1886 024 methyl 2-(aminooxy)- 2-phenylacetate A A D A D 1924 025 O-(1,3- diphenylpropyl)hydroxylamine A A C B C 1829 026 3-(aminooxymethyl)-N- phenylaniline A A D A C 1933 027 O-(2-(benzyloxy)-1- phenylethyl)hydroxylamine A A D 1827 028 O-(biphenyl-2- ylmethyl)hydroxylamine A A D B D 1660 029 O-(3-chloro-5- fluorobenzyl)hydroxylamine A A D A D 1903 030 O-(naphthalen-1-yl) hydroxylamine A B B B B 1893 031 O-((4,5-dichlorobiphenyl-3- yl)methyl)hydroxylamine A A D B D 1662 032 2-(aminooxymethyl)-N- benzylaniline A A D C D 1771 033 O-(2,5- dimethoxybenzyl) hydroxylamine A A D A D 1938 034 O-(3-cyclohexyl-1- phenylpropyl)hydroxylamine A A C 1871 035 2-(aminooxymethyl)-N- phenylaniline A A D B D 1736 036 O-(naphthalen-2- ylmethyl)hydroxylamine A A D A D 1920 037 O- (cyclohexyl(phenyl)methyl) hydroxylamine A A D B B 1917 038 O-((4-chloro-4- (trifluoromethyl)biphenyl-2- yl)methyl)hydroxylamine A A C B C 1744 039 O-(benzo[d][1,3]dioxol-5- ylmethyl)hydroxylamine A A D B D 1897 040 2-(aminooxy)-N-methyl-2- phenylacetamide A A D A D 1921 041 O-(1,2-diphenylethyl) hydroxylamine A A C B D 1895 042 O-(1,2,3,4- tetrahydronaphthalen-1- yl)hydroxylamine A A D B D 1676 043 O-(2-chloro-4- fluorobenzyl)hydroxylamine A A D B D 1896 044 4-(aminooxymethyl) benzonitrile A A D B D 1768 045 O-(chroman-2- ylmethyl)hydroxylamine A A D A D 1872 046 3-(aminooxymethyl)-N- benzylaniline A A D A D 1934 047 2-(aminooxymethyl)-4- chloro-N,N- dimethylbiphenyl-4-amine A A D 1739 048 O-(pyridin-2-ylmethyl) hydroxylamine B A D A D 1674 049 O-(2-chloro-6- fluorobenzyl)hydroxylamine B A D B D 1889 050 O-(2-(pyridin-4- yl)benzyl)hydroxylamine B A D C D 1742 051 O-((1H-indol-3- yl)methyl)hydroxylamine B A D A D 1737 052 O-(pyridin-4-ylmethyl) hydroxylamine B A D A D 1738 053 O-(pyridin-3-ylmethyl) hydroxylamine B A D B D 1888 054 O-(3-(pyridin-4- yl)benzyl)hydroxylamine B A D C D 1750 055 O-((2,3-dihydrobenzo[b] [1,4]dioxin- 6-yl)methyl)hydroxylamine B A D B B 1824 056 3-(aminooxymethyl)aniline B A D B D 1741 057 O-(quinolin-6- ylmethyl)hydroxylamine B A D A D 1925 058 O-(2-cyclohexyl-1- phenylethyl)hydroxylamine B A C B C 1881 059 O-((4-methylbiphenyl-3- yl)methyl)hydroxylamine B A D B D 1898 060 4-(aminooxy)-N-methyl-4- phenylbutanamide B A D B B 1875 061 2-(aminooxy)-2- phenylethanamine B D D 1877 062 3-(aminooxy)-3- phenylpropan-1- amine B 1936 063 O-(2-morpholino-1- phenylethyl)hydroxylamine B 1740 064 O-((4-methyl-2- phenylpyrimidin-5- yl)methyl)hydroxylamine B A D A D 1828 065 3-(aminooxymethyl)-N- benzylaniline C B D C C 1902 066 2-(aminooxy)-N-methyl-2- phenylethanamine C 1901 067 4-(aminooxy)-N-cyclohexyl-4- phenylbutanamide C 1876 068 tert-butyl 2-(aminooxy)-2- phenylethylcarbamate C 2034 069 (R)-2-(aminooxy)-N-methyl-2- phenylacetamide C 1904 070 3-(aminooxy)-N-methyl-3- phenylpropan-1-amine C 1899 071 N-(2-(aminooxy)-2- phenylethyl)acetamide C 1929 072 O-(3-morpholino-1- phenylpropyl)hydroxylamine C 1883 073 (S)-3-(aminooxy)- 3-phenylpropan-1-ol C

(910) TABLE-US-00046 TABLE 16 Cpd hIDO mIDO # Structure Name IC50 EC50 LD50 EC50 LD50 1656 074 O-(3-bromobenzyl) hydroxylamine A A D A D 1672 075 O-(3-chlorobenzyl) hydroxylamine A A D A D 1775 076 O-(3-(trifluoromethyl) benzyl)hydroxylamine A A D A D 1816 077 O-(3-iodobenzyl) hydroxylamine A A D B D 317 078 O-(3-nitrobenzyl) hydroxylamine A A D A D 762 079 O-(3-fluorobenzyl) hydroxylamine A A D A D 1817 080 O-(2-iodobenzyl) hydroxylamine A A D B D 1657 081 O-(3,5-dinitrobenzyl) hydroxylamine A A D A D 1767 082 O-(naphthalen-1-ylmethyl) hydroxylamine A A D B D 1922 083 O-benzhydrylhydroxylamine A A C A C 1666 084 O-benzylhydroxylamine A A D A D 774 085 O-(4-fluorobenzyl) hydroxylamine A A D A D 1677 086 O-(2-(trifluoromethyl)benzyl) hydroxylamine A A D B D 1818 087 O-(4-iodobenzyl)hydroxylamine A A D B D 934 088 O-(4-(trifluoromethyl)benzyl) hydroxylamine A A D A D 1679 089 O-(2-phenoxyethyl) hydroxylamine A A D A D 1682 090 O-(3-methoxybenzyl) hydroxylamine A A D A D 1752 091 O-(3-nitrophenethyl) hydroxylamine A A D A D 1675 092 O-(2-bromobenzyl) hydroxylamine A A D A D 1755 093 O-(1-(3-nitrophenyl)but-3-enyl) hydroxylamine A A D A D 1684 094 methyl 4-(aminooxymethyl) benzoate A A D B D 811 095 O-(2-nitrobenzyl) hydroxylamine A A D B D 1669 096 O-(tetrahydro-2H-pyran-2-yl) hydroxylamine B A D A D 1692 097 O-(3-methylbenzyl) hydroxylamine B A D B D 1822 098 O,O-(1,2- phenylenebis(methylene)) bis(hydroxylamine) B B D B D 1667 099 O-(perfluorobenzyl) hydroxylamine B A D B D 1823 00 O,O-(1,3- phenylenebis(methylene)) bis(hydroxylamine) B B D A D 1678 01 O-(2-methoxybenzyl) hydroxylamine B A D B D 1492 02 O,O-(1,4- phenylenebis(methylene)) bis(hydroxylamine) B A D B C 1815 03 O-(4-methoxybenzyl) hydroxylamine B A D B C 1014 04 O-(4-nitrobenzyl) hydroxylamine B A D B D 1900 05 O-phenylhydroxylamine B 1693 06 O-(3-phenylpropyl) hydroxylamine B A D B D 1673 07 O-(3-chloro-4-fluorobenzyl) hydroxylamine C A C D DS 1690 08 (R)-2-(aminooxy)-3- phenylpropanoic acid C