Tlr7/8 antagonists and uses thereof

A method for inhibiting TLR7/8, or a mutant thereof, activity in a patient or in a biological sample, the method comprising:

• administering to said patient or contacting said biological sample with a compound of formula I-e,
• or a physiologically acceptable salt thereof, wherein:
• R1 is —CF3 or —CN;
• each R2 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R3 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —C(O)R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• R is C1-6 aliphatic, —C(O)R, —C(O)N(R)2, —C(NH)NR2, —NRC(O)R, —N(R)2:
• or 5-6 membered monocyclic heteroaryl rine having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• each R5 is independently C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R·—NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• or
• two R groups on the same atom are taken together with the atom to which they are attached to form a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur each of which is optionally substituted;
• k is 1;
• n is 0, 1, or 2;
• p is 0;
• r is 0;
• and
• t is or 2.

A method for treating a TLR7/8-mediated disorder in a patient in need thereof, the method comprising:

• administering to said patient a compound of formula I-e,
• or a physiologically acceptable salt thereof, wherein:
• R1 is —CF3 or —CN;
• each R2 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R3 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• R4 is C1-6 aliphatic, —C(O)R, —C(O)N(R)2, —C(NH)NR2, —NRC(O)R, —N(R)2;
• or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• each R5 is independently C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• or
• two R groups on the same atom are taken together with the atom to which they are attached to form a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur each of which is optionally substituted;
• k is 1;
• n is 0, 1, or 2;
• p is 0;
• r is 0;
• and
• t is 1 or 2.

A method for treating cancer in a subject, comprising the step of administering to said subject a compound of formula I-e,

• or a physiologically acceptable salt thereof, wherein:
• R1 is —CF3 or —CN;
• each R2 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R3 is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• R4 is C1-6 aliphatic, —C(O)R, —C(O)N(R)2, —C(NH)NR2, —NRC(O)R, —N(R)2;
• or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• each R is independently C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur each of which is optionally substituted;
• or
• two R groups on the same atom are taken together with the atom to which they are attached to form a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each of which is optionally substituted;
• k is 1;
• n is 0, 1, or 2;
• p is 0;
• r is 0, and
• t is 1 or 2.