A method of determining if a compound treats a poxvirus infection comprising administering to an animal that has been infected by a poxvirus an effective amount of a compound of formula (VIIIa):
- or a pharmaceutically acceptable salt thereof, wherein:
- stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
- Q is C(Rk);
- Ra is —OH;
- Rb is hydrogen, fluoro, or C1-4 aliphatic;
- Rc is hydrogen, —OH, or —OCH3;
- Rd is hydrogen;
- R8 is hydrogen or C1-4 aliphatic;
- Rk is hydrogen;
- each RP independently is fluoro;
- —OR5x;
- —N(R4x)(R4y);
- —CO2R5x;
- —C(O)N(R4x)(R4y);
- C1-4 aliphatic optionally substituted with —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
- or C1-4 fluoroaliphatic optionally substituted with —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
- each R8p independently is fluoro;
- —OR5x, —N(R4x)(R4y);
- —CO2R5x;
- —C(O)N(R4x)(R4y);
- C1-4 aliphatic optionally substituted with —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
- or C1-4 fluoroaliphatic optionally substituted with —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
- provided that when two R8p are attached to the same carbon atom, one must be selected from the group consisting of fluoro;
- —CO2R5x;
- —C(O)N(R4x)(R4y);
- C1-4 aliphatic optionally substituted with —OR5x, —N(R4x)(R4y), CO2R5x, or —C(O)N(R4x)(R4y);
- and C1-4 fluoroaliphatic optionally substituted with —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
- or two R8p on the same carbon atom together form ═O or ═C(R5x)2;
- R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4 )alkyl, the aryl portion of which is optionally substituted;
- R4y is hydrogen;
- C1-4 alkyl;
- C1-4 fluoroalkyl;
- C6-10 ar(C1-4)alkyl, the aryl portion of which is optionally substituted;
- optionally substituted 5- or 6-membered aryl;
- optionally substituted heteroaryl;
- or optionally substituted heterocyclyl ring;
- or
- R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from the group consisting of N, O, and S;
- each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl, or optionally substituted C6-10 ar(C1-4 )alkyl;
- wherein:
- in each recitation of optionally substituted aryl, the aryl group, when substituted, contains on one or more unsaturated carbon atoms a substituent independently selected from the group consisting of halo, —NO2, —CN, —R*, —C(R*)═C(R*)2, —C≡C—R*, —OR*, —SRo, —S(O)Ro, —SO2Ro, —SO2N(R+)2, —N(R+)2, —NR+C(O)R*, —NR+C(O)N(R+)2, —NR+CO2Ro, —O—CO2R*, —OC(O)N(R+)2, —O—C(O)R*, —CO2R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R+)2, —C(═NR+)—N(R+)2, —C(═NR+)—OR*, —N(R+)—N(R+)2, —N(R+)C(═NR+)—N(R+)2, —NR+SO2Ro, —NR+SO2N(R+)2, —P(O)(R*)2, —P(O)(OR*)2, —O—P(O)—OR*, and —P(O)(NR+)—N(R+)2;
- in each recitation of optionally substituted heteroaryl, the heteroaryl group, when substituted, if on an unsaturated carbon atom, contains on one or more unsaturated carbon atoms, a substituent independently selected from the group consisting of halo, —NO2, —CN, —R*, —C(R*)═C(R*)2, —C≡C—R*, —OR*, —SRo, —S(O)Ro, —SO2Ro, —SO2N(R+)2, —N(R+)2, —NR+C(O)R*, —NR+C(O)N(R+)2, —NR+CO2Ro, —O—CO2R*, —OC(O)N(R+)2, —O—C(O)R*, —CO2R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R+)2, —C(═NR+)—N(R+)2, —C(═NR+)—OR*, —N(R+)—N(R+)2, —N(R+)C(═NR+)—N(R+)2, —NR+SO2Ro, —NR+SO2N(R+)2, —P(O)(R*)2, —P(O)(OR*)2, —O—P(O)—OR*, and —P(O)(NR+)—N(R+)2, and, if on a substitutable nitrogen atom, contains on one or more substitutable nitrogen atoms, a substituent independently selected from the group consisting of —R*, —N(R*)2, —C(O)R*, —CO2R*, —C(O)—C(O)R*, —C(O)CH2C(O)R*, —SO2R*, —SO2N(R*)2, —C(═S)N(R*)2, —C(═NH)—N(R*)2, and —NR*SO2R*;
- and
- in each recitation of optionally substituted heterocyclyl, the heterocyclyl group, when substituted, if on a saturated carbon atom, contains on one or more saturated carbon atoms, a substituent independently selected from the group consisting of halo, —NO2, —CN, —R*, C(R*)═C(R*)2, —C≡—C—R*, —OR*, —SRo, —S(O)Ro, —SO2Ro, —SO2N(R+)2, —N(R+)2, —NR+C(O)R*, —NR+C(O)N(R+)2, —NR+CO2Ro, —O—CO2R*, —OC(O)N(R+)2, —O—C(O)R*, —CO2R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R+)2, —C(═NR+)—N(R+)2, —C(═NR+)—OR*, —N(R+)—N(R+)2, —N(R+)C(═NR+)—N(R+)2, —NR+SO2Ro, —NR+SO2N(R+)2, —P(O)(R*)2, —P(O)(OR*)2, —O—P(O)—OR*, and —P(O)(NR+)—N(R+)2, ═O, ═S, ═C(R*)2, ═N—N(R+)2, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO2Ro, ═N—NHSO2Ro, and ═N—R*, and, if on a substitutable nitrogen atom, contains on one or more substitutable nitrogen atoms, a substituent independently selected from the group consisting of —R*, —N(R*)2, —C(O)R*, —CO2R*, —C(O)—C(O)R*, —C(O)CH2C(O)R*, —SO2R*, —SO2N(R*)2, —C(═S)N(R*)2, —C(═NH)—N(R*)2, and —NR*SO2R*;
- wherein:
- each occurrence of Ro is independently an aliphatic or aryl group;
- each occurrence of R+ is independently hydrogen or an aliphatic, aryl, heteroaryl, or heterocyclyl group, or two R+ on the same nitrogen atom, taken together with the nitrogen atom, form a five to eight membered aromatic or non-aromatic ring having, in addition to the nitrogen atom, zero to two ring heteroatoms independently selected from the group consisting of N, O, and S;
- and
- each occurrence of R* is independently hydrogen, aliphatic, aryl, heteroaryl, or heterocyclyl group;
- s is 0, 1, or 2;
- and
- t is 0, 1, or 2.
- wherein the compound treats the poxvirus infection by accomplishing one or more of the following:
- reducing poxvirus-mediated degradation of PKR;
- increasing or improving the animal's immune response to the poxvirus;
- and reducing severity of one or more symptoms associated with a poxvirus infection in the animal.