Pyridazinone macrocycles as IRAK inhibitors and uses thereof

A method for treating an IRAK 1- and/or IRAK 4-mediated disorder in a patient in need thereof, comprising:

• administering to said patient a compound of formula I,
• thereby inhibiting said IRAK 1 and/or IRAK 4 in said patient,
• wherein said disorder is Systemic Lupus Erythematosus, or Lupus nephritis,
• wherein:
• Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• which is optionally substituted;
• X is absent, C(O)—, —CO2—, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —(CRR)mC(O)—, —(CRR)mCO2—, —(CRR)mC(O)N(R)—, —(CRR)mOC(O)N(R)—, —(CRR)mNRC(O)—, or —(CRR)mNRC(O)N(R)—;
• Y is an optionally substituted C1-6 aliphatic;
• Z is —O—, a divalent C3-10 aryl, a divalent 3-8 membered saturated or partially unsaturated carbocyclic ring, a divalent 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is optionally substituted;
• W is CR or N;
• 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 heterocylic 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, and 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 C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic 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, and sulfur;
• each of which is optionally substituted;
• each R1 is independently —R, halogen, —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;
• R2 is —R, halogen, —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 —R, halogen, —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 m is independently 1 or 2;
• and
• n is 0, 1, 2, 3, 4, or 5;
• or a physiologically acceptable salt thereof.