Quinazolines useful as modulators of ion channels

A compound of formula IA-ii:

• wherein R1 and R2 are each independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• wherein R1 and R2, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• x is 0-4;
• y is 0-4;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• R5a is an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• and aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or R and R, two occurrences of R, 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 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are
• a. when x is 0, R1 is hydrogen, and R5a is Cl, Me, CF3, Br, or F, then R2 is not —(CH2)2-4-Cy1, —SO2CH2Cy1, or —CH2SO2Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• b. when x is 0, and R5a is Cl, Me, NO2, or OH, then:
• i. when R1 is hydrogen, R2 is not Me, iBu, nBu, —COCH3, —CH2COOEt, —CH2COOMe, —CH2CH2OH, iPr, —CH2-pyridyl, —CH2Ph, —(CH2)3NH2, —(CH2)2-moropholinyl, or —CH2CH2Ph;
• ii. R1 and R2 are not simultaneously Et or Me;
• and
• iii. when R1 is Et, then R2 is not 4-Me-phenyl, 4-OMe-phenyl, or 2-Me-phenyl;
• c. when x is 1 and R3 is 6—Cl, or 7—F, or x is 0 and R5a is —OPrn or Cl, then when R1 is hydrogen, R2is not —(CH2)2-morpholino, or —CH2(benzofuran);
• and
• d. when x is 2 and one occurrence of R3 is 6-OMe and the other occurrence of R3 is 7-OMe, and R5a is F, then when R1 is hydrogen, R2 is not —(CH2)3N(CH3)2;
• and provided that the following additional compounds are excluded:
• 2-(o-hydroxyphenyl)-4-bis(2-cyanoethyl)aminoquinazoline;
• 2-(o-hydroxyphenyl)-4-aminoquinazoline;
• 2-(o-hydroxyphenyl)-4-acetamidoquinazoline;
• 2-(o-hydroxyphenyl)-4-acrylamidoquinazoline;
• 2-(o-hydroxyphenyl)-4-[N-methyl-2-(N-methyl-methacrylamido)ethylamino]quinazoline;
• 2-(o-hydroxyphenyl)-4-dimethylamino-7-chloroquinazoline;
• and
• 2-(o-hydroxyphenyl)-4-dimethylamino-7-nitroquinazoline.

A compound of formula IA-i:

• or a pharmaceutically acceptable salt thereof,
• wherein R1 and R2 are each independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• wherein R1 and R2, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• x is 1 and R3 is substituted at either the 6- or 7-position of the quinazoline ring;
• y is 0-4;
• q is 0, 1 or 2;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• each occurrence of R5a is independently an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• and
• each occurrence of R is independently hydrogen or an optionally substituted C1-6aliphatic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6aliphatic 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 R and R′, two occurrences of R, 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;
• provided that:
• a) when R3 is at the 7-position of the quinazoline ring then:
• i) when R3 is Cl or Me, ring A is unsubstituted naphthyl, and R1 is hydrogen, then R2 is not —(CH2)3NMe2;
• ii) when R3 is Cl, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with Br, and R1 is hydrogen, then R2 is not Cy1, wherein Cy1 is bonded to the nitrogen atom through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• iii) when R3 is Cl or OMe, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with either OMe or Cl, and R1 is hydrogen, then R2 is not —CH(CH3)(CH2)3N(Et)2;
• iv) when R3 is Me, OMe, or NO2, and q and y are 0, then R1 and R2 are not both methyl;
• v) when R3 is OMe, q and y are 0, and R1 is hydrogen, then R2 is not —SO2(4-Me-phenyl);
• vi) when R3 is F, the sum of q and y is 1 and the phenyl ring is substituted at the 2-position with Cl, and R1 is hydrogen, then R2 is not —(CH2)morpholino;
• and
• b) when R3 is at the 6-position of the quinazoline ring then:
• i) when R3 is NH2, Me, Cl, Br, —NHAc, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with F, or ring A is naphthyl, and R1 is hydrogen, then R2 is not —(CH3)3-4N(R′)2;
• ii) when R3 is —OCH2Ph, or OH, and q and y are 0, then when R1 is hydrogen, R2 is not Me, nBu, or —(CH2)2morpholino, or R1 and R2 are not simultaneously Me or Et;
• iii) when R3 is Me or Cl, and the sum of q and y are 1, then the phenyl ring is not substituted in the 4-position with Br;
• iv) when R3 is Cl, q and y are 0, and R1 is hydrogen, then R2 is not —SO2(4-Me-phenyl);
• v) when R3 is OMe, and q and y are 0, and R1 is hydrogen, then R2 is not —CH2CH2OH or —CH2CH2pyrrolidinyl;
• vi) when R3 is Cl or Br, the sum of q and y is 1, and the phenyl ring is substituted in the 4-position with —CH2PO(OR′)2, then R1 is not hydrogen when R2 is -Me, or R1 and R2 are not simultaneously Me or Et;
• vii) when R is OH and q and y are 0, then R1 and R2 are not simultaneously —CH2CH2OMe;
• viii) when R3 is Cl, the sum of q and y is 1 and the phenyl ring is substituted in the 2-position with OnPr, and R1 is hydrogen, then R2 is not —CH2(1,3-benzodioxol);
• ix) when R3 is OMe, OH, Br, Cl, NO2, Me, and q and y are 0, then when R1 is hydrogen, R2 is not Me, —CH2CH2COOMe, —CH2COOMe, or —(CH2)3CH3, or R1 and R2 are not simultaneously Me;
• x) when R3 is Cl, the sum of q and y is 1 and the phenyl ring is substituted in the 4-position with Cl, then R1 and R2 are not simultaneously Me or iPr;
• c) when x, y, and q are 0, and R1 is hydrogen, then R2 is not phenyl, cyclohexyl, cyclopentyl, 2-ClPh, 3-ClPh, 4—ClPh, 3-NO2Ph, 3-(OMe)Ph, 3-(CO2Me)Ph, 4-(CO2Me)Ph, 3-pyridyl, 1-pyyrolyl, or 3-(5-Me-isoxazolyl);
• d) when x, y, and q are 0, R1 is hydrogen, and R2 is —CH2Cy1, then Cy1 is not phenyl, 2—ClPh, 3—ClPh, 4—ClPh, 3-NO2Ph, 2-thienyl, 2—Furyl, 2-pyridyl, 3-pyridyl, or 2-THF;
• and provided that the following additional compounds are excluded:
• Dimethyl-(2-phenyl-quinazolin-4-yl)-amine;
• Methyl-phenyl-(2-phenyl-quinazolin-4-yl)-amine;
• Benzyl-methyl-(2-phenyl-quinazolin-4-yl)-amine;
• Phenethyl-(2-phenyl-quinazolin-4-yl)-amine;
• 4-(2-Phenyl-quinazolin-4-ylamino)-butyric acid ethyl ester;
• (2-Phenyl-quinazolin-4-yl)-propyl-amine;
• 5-(4-{2-[methyl-(2-phenylquinazolin-4-yl)amino]-ethoxy}-benzyl)-thiazolidine-2,4-dione;
• 4-N-acetyl-N-[2-(4-morpholino)-ethyl]-amino-2-phenyl quinazoline;
• N,N-Diethyl-N′-(2-phenyl-quinazolin-4-yl)-ethane-1,2-diamine;
• (6-Methoxy-2-phenyl-quinazolin-4-yl)-(2-morpholin-4-yl-ethyl)-amine;
• N,N-Dimethyl-N′-(2-phenyl-quinazolin-4-yl)-ethane-1,2-diamine;
• (2-Phenyl-quinazolin-4-yl)-(2-piperidin-1-yl-ethyl)-amine;
• 4-(2-Morpholin-4-yl-ethylamino)-2-phenyl-quinazolin-6-ol;
• 7—Fluoro-4-N-[2-(4-morpholino)-ethyl]-amino-2-phenyl-quinazoline;
• 4-N-(2-N,N-di-n-propyl-amino-ethyl)-amino-2-phenyl-quinazoline;
• 4-N-[2-(4-morpholino)-ethyl]-amino-2-(3,4,5-trimethoxyphenyl)-quinazoline;
• 2-phenyl-4-N-[2-(1-piperazino)-ethyl]-aminoquinazoline;
• 6-benzyloxy-4-N-[2-(4-morpholino)-ethyl]amino-2-phenylquinazoline;
• 2-phenyl-4-N-[2-(1-pyrrolidino)-ethyl)-aminoquinazoline;
• 2-(2-chloro-phenyl)-7—Fluoro-4-N-[2-(4-morpholino)-ethyl]-aminoquinazoline;
• 4-N-[2-(4-morpholino)-ethyl]-amino-2-(2-thienyl)-quinazoline;
• 2-(4-chlorophenyl)-4-N-[2-(4-methyl-1-piperazino)-propyl]-aminoquinazoline;
• 7-methyl-2-phenyl-4-N-[2-(4-thiamorpholino)-ethyl]-aminoquinazoline;
• 6-fluoro-2-(4-methylphenyl)-4-N-methyl-N-[2-(1-pyrrolidino)-ethyl]-aminoquinazoline;
• 2-(2-chlorophenyl)-4-N-[2-(4-morpholino)-ethyl]-amino-quinazoline;
• 4-N-[2-(4-morpholino)-ethyl]-amino-2-phenyl-quinazoline;
• [4-(4-Methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(4-Ethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid dimethyl ester;
• [4-(6-Bromo-4-ethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid dimethyl ester;
• [4-(6-Bromo-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-ethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-butylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-cyclohexylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-hydrazino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-ethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diisopropyl ester;
• [4-(6-Bromo-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diisopropyl ester;
• [4-(6-Chloro-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6,7-Dimethoxy-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid diethyl ester;
• [4-(6-Bromo-4-methylamino-quinazolin-2-yl)-benzyl]-phosphonic acid monoethyl ester;
• [4-(6-Bromo-4-ethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid monoethyl ester;
• and
• [4-(6-Bromo-4-dimethylamino-quinazolin-2-yl)-benzyl]-phosphonic acid monoethyl ester.

A compound of formula V:

• wherein R1 and R2 are each independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• or R1 and R2, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
• wherein R1 and R2, or the ring formed by R1 and R2 taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• x is 0-4;
• y is 0-2;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• R5a is an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• and
• each occurrence of R is independently hydrogen or an optionally substituted C1-6aliphatic group;
• and each occurrence of R is independently hydrogen or an optionally substituted C1-6 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 R and R′, two occurrences of R, 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;
• provided that when x is 1 and R3 is 6-OMe, R1 is hydrogen, and y and q are both 0, then R2 is not —CH2CH2OCH2CH2OH or the monomethanesulfonate salt.

A compound of formula I-B-i:

• or a pharmaceutically acceptable salt thereof,
• wherein R1 is selected from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• wherein R1 is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• x is 0-4;
• y is 0-4;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• each occurrence of R5a is independently an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• and
• each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 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 R and R′, two occurrences of R, 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;
• provided that:
• a) when R5a is Me, Cl, or OMe, and x is 0, then R1 is not Et or Me;
• b) when R is Cl, x is 3, and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-Me, then R1 is not —(CH2)2piperidin-1-yl;
• c) when R5a is Me, x is 1 and R3 is NO2 or NH2, then R1 is not Et;
• d) when R5a is OH, NHMe, or N(NO)Me, and x is 0, then RI is not Et, Me or —CH2CH═CH2;
• e) when R5a is NH , and x is 0, then R1 is not —COCH3;
• f) when R5a is Cl or Me, and y is 0 or 1 and when y is 1, R5 is 4—Cl, and x is 0, then R1 is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO2-phenyl, —CH2CH2NHMe, Et, Me, 4-COOMe-phenyl, —CH2Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl, or —CH2CH═CH2;
• and
• provided that the following additional compounds are excluded:
• 2-(2-hydroxy-5-methylphenyl)-4-ethoxyquinazoline;
• 2-(2-hydroxy-5-methylphenyl)-4-butoxyquinazoline;
• 2-(o-hydroxyphenyl)-4-[2-hydroxyethoxy]quinazoline;
• 2-(o-hydroxyphenyl)-4-[2-dimethylaminoethoxy]quinazoline;
• 2-(o-hydroxyphenyl)-4-phenoxyquinazoline;
• 2-(o-hydroxyphenyl)-4-[p-cresyloxy]quinazoline;
• 2-(o-hydroxyphenyl)-4-[p-chlorophenoxy]quinazoline;
• and
• 2-(o-hydroxyphenyl)-4-(2-beta-acryloxyethyl)quinazoline.

A method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain comprising the step of administering to said patient an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or NR2;
• wherein R1 and R2 are each independently an optionally substituted group selected from hydrogen, C1-6aliphatic, or Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• or R1 and R2, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
• wherein R1 and R2, or the ring formed by R1 and R2 taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R5, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R5a, wherein q is 0-2;
• x is 0-4;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• each occurrence of R5a is independently an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or OPO(R′)2;
• and
• each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 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 R and R′, two occurrences of R, 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 provided that:
• i) when x is 1 and R3 is optionally substituted 6-phenyl or 6-pyridyl, and R1 is hydrogen, then R2 is not Cy1;
• and
• ii) Piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)-monohydrochloride and Piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)4[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]- are excluded.

A method of inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in:

• (a) a patient;
• or
• (b) a biological sample;
• which method comprises administering to said patient, or contacting said biological sample with a compound of formula I:
• or a pharmaceutically acceptable salt thereof, wherein:
• X is O or NR2;
• wherein R1 and R2 are each independently an optionally substituted group selected from hydrogen, C1-6aliphatic, or Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO2NR—, or —NRSO2—;
• or R1 and R2, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
• wherein R1 and R2, or the ring formed by R1 and R2 taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R5, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R5a, wherein q is 0-2;
• x is 0-4;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, ═O, ═NR′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• each occurrence of R5a is independently an optionally substituted C1-C6aliphatic group, halogen, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO2R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• and
• each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• and each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 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 R and R′, two occurrences of R, 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.