R¹ is hydrogen or C_1-6 alkyl;

R² is Ar¹ or Cy¹, wherein Ar¹ is a group selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, thienyl pyrrolyl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl and Cy¹ is selected from cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrazolinyl, tetrahydropyranyl, or tetrahydrofuranyl; wherein each of Ar¹ and Cy¹ is optionally substituted with 0-5 independent occurrences of Q—R^X; wherein each independent occurrence of Q is a bond or is a C_1-6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; and each independent occurrence of R^X is independently selected from R′, halogen, NO₂, CN, OR′, SR′, N(R′)₂, NR′C(O)R′, NR′C(O)N(R′)₂, NR′CO₂R′, C(O)R′, CO₂R′, OC(O)R′, C(O)N(R′)₂, OC(O)N(R′)₂, SOR′, SO₂R′, SO₂N(R′)₂, NR′SO₂R′, NR′SO₂N(R′)₂, C(O)C(O)R′, or C(O)CH₂C(O)R′;

wherein R³ is Ar², wherein Ar² is an optionally substituted aryl group selected from pyridinyl or pyrimidinyl, optionally substituted with up to five substituents selected from Z-R^Y; wherein Z is a bond or is a C_1-6 alkylidene chain wherein up to two non-adjacent methylene units of Z are optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; and each occurrence of R^Y is independently selected from R′, halogen, NO₂, CN, OR′, SR′, N(R′)₂, NR′C(O)R′, NR′C(O)N(R′)₂, NR′CO₂R′, C(O)R′, CO₂R′, OC(O)R′, C(O)N(R′)₂, OC(O)N(R′)₂, SOR′, SO₂R′, SO₂N(R′)₂, NR′SO₂R′, NR′SO₂N(R′)₂, C(O)C(O)R′, or C(O)CH₂C(O)R′;

each occurrence of R is independently selected from hydrogen or an optionally substituted C_1-6 aliphatic group; and each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C_1-8 aliphatic, C_6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together, or two occurrences of R′ taken together, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of the optional substituents of said aryl or heteroaryl ring is selected from halogen; —R^o; —OR^o; —SR^o; 1,2-methylenedioxy; 1,2-ethylenedioxy; 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; —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)C(O)R^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; —C═(NH)—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, an optionally substituted C_1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(phenyl), or —CH₂(phenyl), wherein optional substituents on the aliphatic group of R^o are selected from NH₂, NH(C_1-4aliphatic), N(C_1-4aliphatic)₂, halogen, C_1-4aliphatic, OH, O(C_1-4aliphatic), NO₂, CN, CO₂H, CO₂(C_1-4aliphatic), O(haloC_1-4aliphatic), or haloC_1-4aliphatic, 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, form a 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of the optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from —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, 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 a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein optional substituents on the aliphatic group or the phenyl ring of R⁺ are 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_1-4 aliphatic groups of R⁺ is unsubstituted;

each of the optional substituents on said alkylidene chain, aliphatic, cycloalkyl, or heterocyclyl is selected from the list of optional substituents of optional substituents for aryl and heteroaryl rings and further comprise ═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; and

provided that when R³ is 4,6-dimethoxy 2-pyrimidinyl, and R¹ is hydrogen, then R² is not o-S(O)Me phenyl.