Macrocycle kinase inhibitors

A compound of the formula I

• or a pharmaceutically acceptable salt thereof, wherein
• X1 and X2 are independently S, S(O), S(O)2, O or N(R10);
• R1 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, —C(O)OR8 or —C(O)NR8R9;
• wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, C3-C6 cycloalkyl and C6-C10 aryl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, —N(C1-C6 alkyl)C(O)C1-C6 alkyl, —NHC(O)NH2, —NHC(O)NHC1-C6 alkyl, —N(C1-C6 alkyl)C(O)NH2, —N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, —NHC(O)N(C1-C6 alkyl)2, N(C1C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)OC1-C6 alkyl, —N(C1-C6 alkyl)C(O)OC1-C6 alkyl, —NHS(O)(C1-C6 alkyl), —NHS(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)(C1-C6 alkyl), N(C1C6 alkyl)S(O)2(C1-C6 alkyl), —NHS(O)NH2, —NHS(O)2NH2, —N(C1-C6 alkyl)S(O)NH2, N(C1-C6 alkyl)S(O)2NH2, —NHS(O)NH(C1-C6 alkyl), —NHS(O)2NH(C1-C6 alkyl), NHS(O)N(C1-C6 alkyl)2, —NHS(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, —CO2H, —C(O)OC1-C6 alkyl, —C(O)NH2, —C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, SC1-C6 alkyl, —S(O)C1-C6 alkyl, —S(O)2C1-C6 alkyl, S(O)NH(C1-C6 alkyl), —S(O)2NH(C1-C6 alkyl), —S(O)N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, P(C1-C6 alkyl)2, —P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• each R2 and R3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, —C(O)OR8 or —C(O)NR8R9;
• wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C10 aryl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)C1-C6 alkyl, —N(C1-C6 alkyl)C(O)C1-C6 alkyl, —NHC(O)NH2, NHC(O)NHC1-C6 alkyl, —N(C1-C6 alkyl)C(O)NH2, —N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)OC1-C6 alkyl, N(C1C6 alkyl)C(O)OC1-C6 alkyl, —NHS(O)(C1-C6 alkyl), —NHS(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), —NHS(O)NH2, —NHS(O)2NH2, N(C1C6 alkyl)S(O)NH2, —N(C1-C6 alkyl)S(O)2NH2, —NHS(O)NH(C1-C6 alkyl), NHS(O)2NH(C1-C6 alkyl), —NHS(O)N(C1-C6 alkyl)2, —NHS(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)N(C1C6 alkyl)2, —N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, —CO2H, —C(O)OC1-C6 alkyl, C(O)NH2, C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —SC1-C6 alkyl, —S(O)C1-C6 alkyl, —S(O)2C1-C6 alkyl, —S(O)NH(C1-C6 alkyl), —S(O)2NH(C1-C6 alkyl), —S(O)N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —P(C1-C6 alkyl)2, —P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• or R2 and R3 taken together with the carbon atoms to which they are attached optionally form a C5-C7 cycloalkyl or a 5- to 7-membered heterocycloalkyl;
• or R2 and R6 taken together with the atoms to which they are attached optionally form a 5- to 7-membered heterocycloalkyl;
• R4 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —CN, —OC1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —CO2H, C(O)OC1C6 alkyl, —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;
• R5, R6 and R7 are each independently selected from the group consisting of H, fluoro, chloro, bromo, C1-C6 alkyl, —OH, —CN, OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C3-C6 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), 5- to 7 membered heteroaryl, C6-C10 aryl, and CF3;
• wherein each hydrogen atom in C1-C6 alkyl, OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C3-C6 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), 5- to 7 membered heteroaryl and C6-C10 aryl is independently optionally substituted by fluoro, chloro, bromo, —OH, CN, —OC1-C6 alkyl, —NH2, NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 7 membered heteroaryl, —CO2H, C(O)OC1C6 alkyl, C(O)NH2, —C(O)NH(C1-C6 alkyl) and —C(O)N(C1-C6 alkyl)2;
• each R8 and R9 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl or heteroaryl;
• each R10 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl;
• wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or —OR8;
• n is 1 or 2;
• and
• provided that at least one of R5 or R7 is not H, and provided that the compound is not of the formula