Irhom2 inhibitors and uses thereof

A method of inhibiting iRhom2/ADAM17 activity, said method comprising administering to a patient a compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• or C(C1-4alkyl)2;
• R2 is C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-10 cycloalkyl;
• wherein each R2 is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C0-4 alkyl(C3-6 cycloalkyl), C1-6 alkoxy, C0-6 alkyl(CN), C0-6 alkyl(OH), C0-6 alkyl(NO2), C0-6 alkyl(NH2), —C0-4 alkyl(NH(C1-4 alkyl)), —C0-4 alkyl(N(C1-4 alkyl)2), methylenedioxy, —C0-4 alkyl(S(C1-4 alkyl)), —C0-4 alkyl(C(O)(C1-4 alkyl)), —C0-4 alkyl(C(O)NH2), —C0-4 alkyl(C(O)NH(C1-4 alkyl)), —C0-4 alkyl(C(O)N(C1-4 alkyl)2), —C0-4 alkyl(C(O)O(C1-4 alkyl)), —C0-4 alkyl(OC(O)(C1-4 alkyl)), —C0-4 alkyl(OC(O)NH2), —C0-4 alkyl (OC(O)NH(C1-4 alkyl)), —C0-4 alkyl(OC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)(C1-4 alkyl)), —C0-4 alkyl(NHC(O)O(C1-4 alkyl)), —C0-4 alkyl(NHC(O)NH2), —C0-4 alkyl(NHC(O)NH(C1-4 alkyl)), —C0-4 alkyl(NHC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHS(O)(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2NH2), —C0-4 alkyl(NHS(O)2NH(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2N(C1-4 alkyl)2), —C0-4 alkyl(S(O)(C1-4 alkyl)), —C0-4 alkyl(S(O)NH2), —C0-4 alkyl(S(O)NH(C1-4 alkyl)), —C0-4 alkyl(S(O)N(C1-4 alkyl)2), —C0-4 alkyl(S(O)2(C1-4 alkyl)), —C0-4 alkyl(S(O)2NH2), —C0-4 alkyl(S(O)2NH(C1-4 alkyl)), —C0-4 alkyl(S(O)2N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)C6-10 aryl), —C0-4 alkyl(NHC(O)-(5-10 membered heteroaryl)), —C0-4 alkyl(NHC(O)C3-10 cycloalkyl), and —C0-4 alkyl(NHC(O)-(4-10 membered heterocycloalkyl)).

A method of inhibiting iRhom2/ADAM17 activity, said method comprising administering to a patient a compound of Formula (IV):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R4 is H, C1-4 haloalkyl, or C1-4 alkyl;
• R4a is —C0-6 alkyl(C6-10 aryl), —C0-6 alkyl(5-10 membered heteroaryl), —C0-6 alkyl(C3-10cycloalkyl), or —C0-6 alkyl(4-10 membered heterocycloalkyl);
• R4b is —C(O)—C0-4alkyl(C6-10 aryl), —C(O)—C0-4alkyl(5-10 membered heteroaryl), —C(O)—C0-4alkyl(C3-10 cycloalkyl), —C(O)—C0-4alkyl(4-10 membered heterocycloalkyl), —NHC(O)—C0-4alkyl(C6-10 aryl), —NHC(O)—C0-4alkyl(5-10 membered heteroaryl), —NHC(O)—C0-4alkyl(C3-10—C(O)OC0-4alkyl(5-10 membered heteroaryl), —C(O)OC0-4alkyl(C3-10 cycloalkyl), —C(O)OC0-4alkyl(4-10 membered heterocycloalkyl), —C(O)NH—C0-4alkyl(C6-10 aryl), —C(O)NH—C0-4alkyl(5-10 membered heteroaryl), —C(O)NH—C0-4alkyl(C3-10 cycloalkyl), —C(O)NH—C0-4alkyl(4-10 membered heterocycloalkyl), —C(O)N(C1-6 alkyl)(C0-4alkyl-C6-10 aryl), —C(O)N(C1-6 alkyl)(C0-4alkyl-(5-10 membered heteroaryl)), —C(O)N(C1-6 alkyl)(C0-4alkyl-C3-10 cycloalkyl), or —C(O)N(C1-6 alkyl)(C0-4alkyl-(4-10 membered heterocycloalkyl));
• wherein each R4a or R4b is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C0-4 alkyl(C3-6 cycloalkyl), C1-6 alkoxy, C0-6 alkyl(CN), C0-6 alkyl(OH), C0-6 alkyl(NO2), C0-6 alkyl(NH2), —C0-4 alkyl(NH(C1-4 alkyl)), —C0-4 alkyl(N(C1-4 alkyl)2), methylenedioxy, —C0-4 alkyl(S(C1-4 alkyl)), —C0-4 alkyl(C(O)(C1-4 alkyl)), —C0-4 alkyl(C(O)NH2), —C0-4 alkyl(C(O)NH(C1-4 alkyl)), —C0-4 alkyl(C(O)N(C1-4 alkyl)2), —C0-4 alkyl(C(O)O(C1-4 alkyl)), —C0-4 alkyl(OC(O)(C1-4 alkyl)), —C0-4 alkyl(OC(O)NH2), —C0-4 alkyl (OC(O)NH(C1-4 alkyl)), —C0-4 alkyl(OC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)(C1-4 alkyl)), —C0-4 alkyl(NHC(O)O(C1-4 alkyl)), —C0-4 alkyl(NHC(O)NH2), —C0-4 alkyl(NHC(O)NH(C1-4 alkyl)), —C0-4 alkyl(NHC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHS(O)(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2NH2), —C0-4 alkyl(NHS(O)2NH(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2N(C1-4 alkyl)2), —C0-4 alkyl(S(O)(C1-4 alkyl)), —C0-4 alkyl(S(O)NH2), —C0-4 alkyl(S(O)NH(C1-4 alkyl)), —C0-4 alkyl(S(O)N(C1-4 alkyl)2), —C0-4 alkyl(S(O)2(C1-4 alkyl)), —C0-4 alkyl(S(O)2NH2), —C0-4 alkyl(S(O)2NH(C1-4 alkyl)), —C0-4 alkyl(S(O)2N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)C6-10 aryl), —C0-4 alkyl(NHC(O)-(5-10 membered heteroaryl)), —C0-4 alkyl(NHC(O)C3-10 cycloalkyl), and —C0-4 alkyl(NHC(O)-(4-10 membered heterocycloalkyl)).

A method of treating a disease or disorder associated with inhibition of iRhom2/ADAM17 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• cycloalkyl;
• R1a is C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-10 cycloalkyl;
• wherein each R1 or R1a is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C0-4 alkyl(C3-6 cycloalkyl), C1-6 alkoxy, C0-6 alkyl(CN), C0-6 alkyl(OH), C0-6 alkyl(NO2), C0-6 alkyl(NH2), —C0-4 alkyl(NH(C1-4 alkyl)), —C0-4 alkyl(N(C1-4 alkyl)2), methylenedioxy, —C0-4 alkyl(S(C1-4 alkyl)), —C0-4 alkyl(C(O)(C1-4 alkyl)), —C0-4 alkyl(C(O)NH2), —C0-4 alkyl(C(O)NH(C1-4 alkyl)), —C0-4 alkyl(C(O)N(C1-4 alkyl)2), —C0-4 alkyl(C(O)O(C1-4 alkyl)), —C0-4 alkyl(OC(O)(C1-4 alkyl)), —C0-4 alkyl(OC(O)NH2), —C0-4 alkyl (OC(O)NH(C1-4 alkyl)), —C0-4 alkyl(OC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)(C1-4 alkyl)), —C0-4 alkyl(NHC(O)O(C1-4 alkyl)), —C0-4 alkyl(NHC(O)NH2), —C0-4 alkyl(NHC(O)NH(C1-4 alkyl)), —C0-4 alkyl(NHC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHS(O)(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2NH2), —C0-4 alkyl(NHS(O)2NH(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2N(C1-4 alkyl)2), —C0-4 alkyl(S(O)(C1-4 alkyl)), —C0-4 alkyl(S(O)NH2), —C0-4 alkyl(S(O)NH(C1-4 alkyl)), —C0-4 alkyl(S(O)N(C1-4 alkyl)2), —C0-4 alkyl(S(O)2(C1-4 alkyl)), —C0-4 alkyl(S(O)2NH2), —C0-4 alkyl(S(O)2NH(C1-4 alkyl)), —C0-4 alkyl(S(O)2N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)C6-10 aryl), —C0-4 alkyl(NHC(O)-(5-10 membered heteroaryl)), —C0-4 alkyl(NHC(O)C3-10 cycloalkyl), and —C0-4 alkyl(NHC(O)-(4-10 membered heterocycloalkyl)).

A method of treating a disease or disorder associated with inhibition of iRhom2/ADAM17 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X is NH, N(C1-4alkyl), O, S, S(O), S(O)2, C(O), CH2, CH(halo), C(halo)2, CH(C1-4alkyl), or C(C1-4alkyl)2;
• R2 is C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-10 cycloalkyl;
• wherein each R2 is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C0-4 alkyl(C3-6 cycloalkyl), C1-6 alkoxy, C0-6 alkyl(N(C1-4 alkyl)2), methylenedioxy, —C0-4 alkyl(S(C1-4 alkyl)), —C0-4 alkyl(C(O)(C1-4 alkyl)), —C0-4 alkyl(C(O)NH2), —C0-4 alkyl(C(O)NH(C1-4 alkyl)), —C0-4 alkyl(C(O)N(C1-4 alkyl)2), —C0-4 alkyl(C(O)O(C1-4 alkyl)), —C0-4 alkyl(OC(O)(C1-4 alkyl)), —C0-4 alkyl(OC(O)NH2), —C0-4 alkyl (OC(O)NH(C1-4 alkyl)), —C0-4 alkyl(OC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)(C1-4 alkyl)), —C0-4 alkyl(NHC(O)O(C1-4 alkyl)), —C0-4 alkyl(NHC(O)NH2), —C0-4 alkyl(NHC(O)NH(C1-4 alkyl)), —C0-4 alkyl(NHC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHS(O)(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2NH2), —C0-4 alkyl(NHS(O)2NH(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2N(C1-4 alkyl)2), —C0-4 alkyl(S(O)(C1-4 alkyl)), —C0-4 alkyl(S(O)NH2), —C0-4 alkyl(S(O)NH(C1-4 alkyl)), —C0-4 alkyl(S(O)N(C1-4 alkyl)2), —C0-4 alkyl(S(O)2(C1-4 alkyl)), —C0-4 alkyl(S(O)2NH2), —C0-4 alkyl(S(O)2NH(C1-4 alkyl)), —C0-4 alkyl(S(O)2N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)C6-10 aryl), —C0-4 alkyl(NHC(O)-(5-10 membered heteroaryl)), —C0-4 alkyl(NHC(O)C3-10 cycloalkyl), and —C0-4 alkyl(NHC(O)-(4-10 membered heterocycloalkyl)).

A method of treating a disease or disorder associated with inhibition of iRhom2/ADAM17 activity, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IV):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R4 is H, C1-4 haloalkyl, or C1-4 alkyl;
• R4a is —C0-6 alkyl(C6-10 aryl), —C0-6 alkyl(5-10 membered heteroaryl), —C0-6 alkyl(C3-10cycloalkyl), or —C0-6 alkyl(4-10 membered heterocycloalkyl);
• R4b is —C(O)—C0-4alkyl(C6-10 aryl), —C(O)—C0-4alkyl(5-10 membered heteroaryl), —C(O)—C0-4alkyl(C3-10cycloalkyl), —C(O)—C0-4alkyl(4-10 membered heterocycloalkyl), —NHC(O)—C0-4alkyl(C6-10 aryl), —NHC(O)—C0-4alkyl(5-10 membered heteroaryl), —NHC(O)—C0-4alkyl(C3-10 cycloalkyl), —NHC(O)—C0-4alkyl(4-10 membered heterocycloalkyl), —C(O)OC0-4alkyl(C6-10 aryl), —C(O)OC0-4alkyl(5-10 membered heteroaryl), —C(O)OC0-4alkyl(C3-10 cycloalkyl), —C(O)OC0-4alkyl(4-10 membered heterocycloalkyl), —C(O)NH—C0-4alkyl(C6-10 aryl), —C(O)NH—C0-4alkyl(5-10 membered heteroaryl), —C(O)NH—C0-4alkyl(C3-10 cycloalkyl), —C(O)NH—C0-4alkyl(4-10 membered heterocycloalkyl), —C(O)N(C1-6 alkyl)(C0-4alkyl-C6-10 aryl), —C(O)N(C1-6 alkyl)(C0-4alkyl-(5-10 membered heteroaryl)), —C(O)N(C1-6 alkyl)(C0-4alkyl-C3-10cycloalkyl), or —C(O)N(C1-6 alkyl)(C0-4alkyl-(4-10 membered heterocycloalkyl));
• the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C0-4 alkyl(C3-6cycloalkyl), C1-6alkoxy, C0-6 alkyl(CN), C0-6 alkyl(OH), C0-6 alkyl(NO2), C0-6 alkyl(NH2), —C0-4 alkyl(NH(C1-4 alkyl)), —C0-4 alkyl(N(C1-4 alkyl)2), methylenedioxy, —C0-4 alkyl(S(C1-4 alkyl)), —C0-4 alkyl(C(O)(C1-4 alkyl)), —C0-4 alkyl(C(O)NH2), —C0-4 alkyl(C(O)NH(C1-4 alkyl)), —C0-4 alkyl(C(O)N(C1-4 alkyl)2), —C0-4 alkyl(C(O)O(C1-4 alkyl)), —C0-4 alkyl(OC(O)(C1-4 alkyl)), —C0-4 alkyl(OC(O)NH2), —C0-4 alkyl (OC(O)NH(C1-4 alkyl)), —C0-4 alkyl(OC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)(C1-4 alkyl)), —C0-4 alkyl(NHC(O)O(C1-4alkyl)), —C0-4 alkyl(NHC(O)NH2), —C0-4 alkyl(NHC(O)NH(C1-4alkyl)), —C0-4 alkyl(NHC(O)N(C1-4 alkyl)2), —C0-4 alkyl(NHS(O)(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2NH2), —C0-4 alkyl(NHS(O)2NH(C1-4 alkyl)), —C0-4 alkyl(NHS(O)2N(C1-4 alkyl)2), —C0-4 alkyl(S(O)(C1-4 alkyl)), —C0-4 alkyl(S(O)NH2), —C0-4 alkyl(S(O)NH(C1-4 alkyl)), —C0-4 alkyl(S(O)N(C1-4 alkyl)2), —C0-4 alkyl(S(O)2(C1-4 alkyl)), —C0-4 alkyl(S(O)2NH2), —C0-4 alkyl(S(O)2NH(C1-4 alkyl)), —C0-4 alkyl(S(O)2N(C1-4 alkyl)2), —C0-4 alkyl(NHC(O)C6-10 aryl), —C0-4 alkyl(NHC(O)-(5-10 membered heteroaryl)), —C0-4 alkyl(NHC(O)C3-10 cycloalkyl), and —C0-4 alkyl(NHC(O)-(4-10 membered heterocycloalkyl)).