Heterocyclic rip1 kinase inhibitors

A method comprising administering to a subject a compound or pharmaceutical composition thereof, wherein the compound is:

• or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof, wherein:
• ring B is heteroaryl;
• each R1 independently is -linker-R6 group, wherein the linker is Ra, provided that Ra is not H or D, and R6 is heterocyclyl, Rb, —C(Rf)3, or —C(Rf)═C(Rf)2;
• R2 is Ra;
• R3 is Ra;
• R4 is C1-6 alkyl;
• if present, each R4 independently is Re;
• L is a heteroatom or Ra, provided that Ra is not H or D;
• X is CH2 or O;
• Z is heteroaryl;
• m is 1, 2, 3, or 4;
• n is 0, 1 or 2;
• Ra is independently for each occurrence H or D, except for embodiments where L is Ra, or is C1-10aliphatic, C1-10haloaliphatic, C5-10aromatic, C3-6heterocyclic, or C3-10spiroheterocyclic;
• Rb is independently for each occurrence —OH, —SH, —OR′, —SRc, —NRdRd, —Si(Ra)3, —C(O)OH, —C(O)ORc, —C(O)NRdRd, —OC(O)NRdRd, —OC(O)C1-10alkyl substituted with one or two NRdRd, carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH2;
• Rc is independently for each occurrence C1-10alkyl, which can be substituted with 1, 2 or 3 Re, C2-10alkenyl, which can be substituted with 1, 2 or 3 Re, C2-10alkynyl, which can be substituted with 1, 2 or 3 Re, C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re, or C5-10aromatic, which can be substituted with 1, 2 or 3 Re;
• Ra is independently for each occurrence H;
• C1-6alkyl, which can be substituted with 1, 2 or 3 Re or a C3-9heterocyclyl;
• C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re;
• C3-6heterocyclic, which can be substituted with 1, 2 or 3 Re;
• C5-10aryl, which can be substituted with 1, 2 or 3 Rb;
• C5-10heteroaryl, which can be substituted with 1, 2 or 3 Re;
• or two Ra groups together with the nitrogen bound thereto provide a C3-9heterocyclic, which can be substituted with one or more Re), or a C5-10heteroaryl, which can be substituted with one or more Re;
• Re is independently for each occurrence halogen, C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C5-10heteroaryl, or —ORa;
• and
• Rf is independently for each occurrence -alkyl-phosphate, Ra, Rb, or Re, or two Rf groups together with the carbon atom bound thereto provide a C2-6alkenyl group, a C3-6cycloalkyl group, which can be substituted with one or more Re, or a C3-10heterocyclic, which can be substituted with one or more Re or acyl.

A method comprising contacting a receptor-interacting protein-1 (RIP1) kinase with a compound or pharmaceutical composition thereof, wherein the compound is:

• or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof, wherein:
• ring B is heteroaryl;
• each R1 independently is -linker-R6 group, wherein the linker is Ra, provided that Ra is not H or D, and R6 is heterocyclyl, Rb, —C(Rf)3, or —C(Rf)═C(Rf)2;
• R2 is Ra;
• R3 is Ra;
• R4 is C1-6 alkyl;
• if present, each R4 independently is Re;
• L is a heteroatom or Ra, provided that Ra is not H or D;
• X is CH2 or O;
• Z is heteroaryl;
• m is 1, 2, 3, or 4;
• n is 0, 1 or 2;
• Ra is independently for each occurrence H or D, except for embodiments where L is Ra, or is C1-10aliphatic, C1-10haloaliphatic, C5-10aromatic, C3-6heterocyclic, or C3-10spiroheterocyclic;
• Rb is independently for each occurrence —OH, —SH, —ORe, —SRe, —NRdRd, —Si(Ra)3, —C(O)OH, —C(O)ORe, —C(O)NRdRd, —OC(O)NRdRd, —OC(O)C1-10alkyl substituted with one or two NRdRd, carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH2;
• Rc is independently for each occurrence C1-10alkyl, which can be substituted with 1, 2 or 3 Re, C2-10alkenyl, which can be substituted with 1, 2 or 3 Re, C2-10alkynyl, which can be substituted with 1, 2 or 3 Re, C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re, or C5-10aromatic, which can be substituted with 1, 2 or 3 Re;
• Ra is independently for each occurrence H;
• C1-6alkyl, which can be substituted with 1, 2 or 3 Re or a C3-9heterocyclyl;
• C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re;
• C3-6heterocyclic, which can be substituted with 1, 2 or 3 Re;
• C5-10aryl, which can be substituted with 1, 2 or 3 Rb;
• C5-10heteroaryl, which can be substituted with 1, 2 or 3 Re;
• or two Rd groups together with the nitrogen bound thereto provide a C3-9heterocyclic, which can be substituted with one or more Re), or a C5-10heteroaryl, which can be substituted with one or more Re;
• Re is independently for each occurrence halogen, C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C5-10heteroaryl, or —ORa;
• and
• Rf is independently for each occurrence -alkyl-phosphate, Ra, Rb, or Re, or two Rf groups together with the carbon atom bound thereto provide a C2-6alkenyl group, a C3-6cycloalkyl group, which can be substituted with one or more Re, or a C3-10heterocyclic, which can be substituted with one or more Re or acyl.

A method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof, or (ii) a therapeutically effective amount of a pharmaceutical composition of a compound;

• wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is a disease involving a receptor-interacting protein-1 (RIP1) kinase,
• wherein the compound is:
• wherein:
• ring B is heteroaryl;
• each R1 independently is -linker-R6 group, wherein the linker is Ra, provided that Ra is not H or D, and R6 is heterocyclyl, Rb, —C(Rf)3, or —C(Rf)═C(Rf)2;
• R2 is Ra;
• R3 is Ra;
• R4 is C1-6 alkyl;
• if present, each R4 independently is Re;
• L is a heteroatom or Ra, provided that Ra is not H or D;
• X is CH2 or O;
• Z is heteroaryl;
• m is 1, 2, 3, or 4;
• n is 0, 1 or 2;
• Ra is independently for each occurrence H or D, except for embodiments where L is Ra, or is C1-10aliphatic, C1-10haloaliphatic, C5-10aromatic, C3-6heterocyclic, or C3-10spiroheterocyclic;
• Rb is independently for each occurrence —OH, —SH, —ORc, —SRc, —NRdRd, —Si(Ra)3, —C(O)OH, —C(O)ORc, —C(O)NRdRd, —OC(O)NRdRd, —OC(O)C1-10alkyl substituted with one or two NRdRd, carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH2;
• Rc is independently for each occurrence C1-10alkyl, which can be substituted with 1, 2 or 3 Rc, C2-10alkenyl, which can be substituted with 1, 2 or 3 Rc, C2-10alkynyl, which can be substituted with 1, 2 or 3 Rc, C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Rc or C5-10aromatic, which can be substituted with 1, 2 or 3 Re;
• Rd is independently for each occurrence H;
• C1-6alkyl, which can be substituted with 1, 2 or 3 Re or a C3-9heterocyclyl;
• C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re;
• C3-6heterocyclic, which can be substituted with 1, 2 or 3 Re;
• C5-10aryl, which can be substituted with 1, 2 or 3 Rb;
• C5-10heteroaryl, which can be substituted with 1, 2 or 3 Re;
• or two Ra groups together with the nitrogen bound thereto provide a C3-9heterocyclic, which can be substituted with one or more Re), or a C5-10heteroaryl, which can be substituted with one or more Re;
• Re is independently for each occurrence halogen, C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C5-10heteroaryl, or —ORa;
• and
• Rf is independently for each occurrence -alkyl-phosphate, Ra, Rb, or Re, or two Rf groups together with the carbon atom bound thereto provide a C2-6alkenyl group, a C3-6cycloalkyl group, which can be substituted with one or more Re, or a C3-10heterocyclic, which can be substituted with one or more Re or acyl.