R¹ is hydrogen;

R² and R⁴ are each hydrogen;

R³ is independently hydrogen or halogen;

x is 1, 2 or 3;

each occurrence of R⁵ is independently halogen, CN, NO₂, or U—R′, wherein at least one R⁵ is other than H;

each U is independently a bond or an optionally substituted C₁-C₆ alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —NR′—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —CONR′—, —NR′CO—, —NR′CO₂—, —SO₂NR′—, —NR′SO₂—, —CONR′NR′—, —NR′CONR′—, —OCONR′—, —NR′NR′—, —NR′SO₂NR′—, —SO— or —SO₂—; and

each occurrence of R′ is independently hydrogen or an optionally substituted group selected from a C₁-C₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein an optional substituent on an unsaturated carbon atom of an aryl or heteroaryl group is selected from halogen; —R^o; —OR^o; —SR^o; phenyl (Ph) optionally substituted with R^o; —O(Ph) optionally substituted with R^o; —(CH₂)_1-2(Ph), optionally substituted with R^o; —CH═CH(Ph), optionally substituted with R^o; a 5-6 membered heteroaryl or heterocyclic ring optionally substituted with R^o; —NO₂; —CN; —N(R^o)₂; —NR^oC(O)R^o; —NR^oC(S)R^o; —NR^oC(O)N(R^o)₂; —NR^oC(S)N(R^o)₂; —NR^oCO₂R^o; —NR^oNR^oC(O)R^o; —NR^oNR^oC(O)N(R^o)₂; —NR^oNR^oCO₂R^o; —C(O)CH₂C(O)R^o; —CO₂R^o; —C(O)R^o; —C(S)R^o; —C(O)N(R^o)₂; —C(S)N(R^o)₂; —OC(O)N(R^o)₂; —OC(O)R^o; —C(O)N(OR^o)R^o; —C(NOR^o)R^o; —S(O)₂R^o; —S(O)₃R^o; —SO₂N(R^o)₂; —S(O)R^o; —NR^oSO₂N(R^o)₂; —NR^oSO₂R^o; —N(OR^o)R^o; —C(═NH)—N(R^o)₂; or —(CH₂)_0-2NHC(O)R^o; wherein each independent occurrence of R^o is selected from hydrogen, optionally substituted C_1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph), or, two independent occurrences of R^o, on the same substituent or different substituents, taken together with the atom(s) to which each R^o group is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein each optional substituent on the aliphatic group of R^o is selected from NH₂, NH(C_1-4 aliphatic), N(C_1-4 aliphatic)₂, halogen, C_1-4 aliphatic, OH, O(C_1-4 aliphatic), NO₂, CN, CO₂H, CO₂(C_1-4 aliphatic), O(haloC_1-4 aliphatic), or haloC_1-4 aliphatic, wherein each of the foregoing C_1-4aliphatic groups of R^o is unsubstituted;

wherein an optional substituent on a saturated carbon of an aliphatic or heteroaliphatic group, or on a saturated carbon of a non-aromatic heterocyclic ring is selected from halogen; —R^o; —OR^o; —SR^o; phenyl (Ph) optionally substituted with R^o; —O(Ph) optionally substituted with R^o; —(CH₂)_1-2(Ph), optionally substituted with R^o; —CH═CH(Ph), optionally substituted with R^o; a 5-6 membered heteroaryl or heterocyclic ring optionally substituted with R^o; —NO₂; —CN; —N(R^o)₂; —NR^oC(O)R^o; —NR^oC(S)R^o; —NR^oC(O)N(R^o)₂; —NR^oC(S)N(R^o)₂; —NR^oCO₂R^o; —NR^oNR^oC(O)R^o; —NR^oNR^oC(O)N(R^o)₂; —NR^oNR^oCO₂R^o; —C(O)CH₂C(O)R^o; —CO₂R^o; —C(O)R^o; —C(S)R^o; —C(O)N(R^o)₂; —C(S)N(R^o)₂; —OC(O)N(R^o)₂; —OC(O)R^o; —C(O)N(OR^o)R^o; —C(NOR^o)R^o; —S(O)₂R^o; —S(O)₃R^o; —SO₂N(R^o)₂; —S(O)R^o; —NR^oSO₂N(R^o)₂; —NR^oSO₂R^o; —N(OR^o)R^o; —C(═NH)—N(R^o)₂; or —(CH₂)_0-2NHC(O)R^o; ═O; ═S; ═NNHR*; ═NN(R*)₂; ═NNHC(O)R*; ═NNHCO₂(alkyl); ═NNHSO₂(alkyl); or ═NR*; where each R* is independently selected from hydrogen or a C_1-6 aliphatic group;

wherein an optional substituent on a nitrogen of a non-aromatic heterocyclic ring is selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C_1-6 aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH₂(Ph), optionally substituted —(CH₂)_1-2(Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur; or, two independent occurrences of R⁺, on the same substituent or different substituents, taken together with the atom(s) to which each R⁺ group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein an optional substituent on the aliphatic group or the phenyl ring of R⁺ is selected from —NH₂, —NH(C_1-4 aliphatic), —N(C_1-4 aliphatic)₂, halogen, C_1-4 aliphatic, —OH, —O(C_1-4 aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C_1-4 aliphatic), —O(halo C_1-4 aliphatic), or halo(C_1-4 aliphatic), wherein each of the foregoing C_1-4aliphatic groups of R⁺ is unsubstituted;

provided that:

if R³ is H and x is 1, then R⁵ is not —SMe, NH₂ or an optionally substituted NH-piperidine.