Substituted quinolines as improved nf-kb-inducing kinase (nik) inhibitors

A compound of the following formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• ring A is an aromatic group selected from the groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), and (A-7):
• wherein the group (A-1) is phenyl or a 6-membered monocyclic heteroaryl, wherein said phenyl or said heteroaryl is substituted with a group RA1 and a group RA2 in the indicated positions, and is optionally further substituted with one or more groups RA3;
• wherein the groups (A-2) and (A-3) are each a 5-membered monocyclic heteroaryl which is substituted with a group RA1 and a group RA2 in the indicated positions, and is optionally further substituted with one or more groups RA3;
• wherein the group (A-4) is an 8-membered bicyclic heteroaryl which is substituted with a group RA2 in the indicated position and is optionally further substituted with one or more groups RA3;
• wherein the groups (A-5) and (A-6) are each a 9-membered bicyclic heteroaryl which is substituted with a group RA2 in the indicated position and is optionally further substituted with one or more groups RA3;
• and
• wherein the group (A-7) is naphthyl or a 10-membered bicyclic heteroaryl, wherein said naphthyl or said heteroaryl is substituted with a group RA2 in the indicated position and is optionally further substituted with one or more groups RA3;
• RA1 is selected from —O(C1-5 alkyl), —O(C2-5 alkenyl), C1-5 alkyl, C2-5 alkenyl, —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the cycloalkyl group in said —(C0-3 alkylene)-cycloalkyl and the heterocycloalkyl group in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-3 alkylene)-cycloalkyl or said —(C0-3 alkylene)-heterocycloalkyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• RA2 is selected from C1-12 alkyl, —(C1-12 alkylene)-OH, —(C0-5 alkylene)-O(C1-12 alkyl), —(C0-5 alkylene)-O(C1-12 haloalkyl), —(C0-5 alkylene)-O—(C1-12 alkylene)-OH, —(C0-5 alkylene)-O—(C1-5 alkylene)-O(C1-12 alkyl), —(C0-5 alkylene)-O—(C1-5 alkylene)-O(C1-12 haloalkyl), —CO(C1-12 alkyl), —CO(C1-12 haloalkyl), —SO2—(C1-12 alkyl), —SO2—(C1-12 haloalkyl), halogen, C1-5 haloalkyl, —(C0-5 alkylene)-carbocyclyl, and —(C0-5 alkylene)-heterocyclyl, wherein one or more —CH2— units in said C1-12 alkyl, said —(C1-12 alkylene)-OH, said —(C0-5 alkylene)-O(C1-12 alkyl), said —(C0-5 alkylene)-O(C1-12 haloalkyl), said —(C0-5 alkylene)-O—(C1-12 alkylene)-OH, said —(C0-5 alkylene)-O—(C1-5 alkylene)-O(C1-12 alkyl), said —(C0-5 alkylene)-O—(C1-5 alkylene)-O(C1-12 haloalkyl), said —CO(C1-12 alkyl), said —CO(C1-12 haloalkyl), said —SO2—(C1-12 alkyl) or said —SO2—(C1-12 haloalkyl) are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, and —CH═CH—, wherein the carbocyclyl group in said —(C0-5 alkylene)-carbocyclyl and the heterocyclyl group in said —(C0-5 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-5 alkylene)-carbocyclyl or said —(C0-5 alkylene)-heterocyclyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• each RA3, if present, is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-S(C1-5 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—COO(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-COO(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-carbocyclyl, —(C0-3 alkylene)-heterocyclyl, and —R6—R7, wherein the carbocyclyl group in said —(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said —(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-3 alkylene)-carbocyclyl or said —(C0-3 alkylene)-heterocyclyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• RN is selected from hydrogen, C1-5 alkyl, and —CO—(C1-5 alkyl);
• R1, R4 and R5 are each independently selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-S(C1-5 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—COO(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-COO(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-carbocyclyl, —(C0-3 alkylene)-heterocyclyl, and —R6—R7, wherein the carbocyclyl group in said —(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said —(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-3 alkylene)-carbocyclyl or said —(C0-3 alkylene)-heterocyclyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• R2 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-S(C1-5 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—COO(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-COO(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO—(C1-5 alkyl), —(C0-3 alkylene)-carbocyclyl, and —(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl group in said —(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said —(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-3 alkylene)-carbocyclyl or said —(C0-3 alkylene)-heterocyclyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, and —SO—;
• R3 is selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-S(C1-5 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-CHF2, —(C0-3 alkylene)-CH2F, —(C0-3 alkylene)-(C2-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—COO(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-COO(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-carbocyclyl, and —(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl group in said —(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said —(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc, and further wherein one or more —CH2— units comprised in the alkylene in said —(C0-3 alkylene)-carbocyclyl or said —(C0-3 alkylene)-heterocyclyl are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• provided that R3 is not morpholin-4-yl or —NH-phenyl, wherein the phenyl group in said —NH-phenyl is optionally substituted with one or more groups RCyc;
• each RCyc is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —O(C1-5 alkylene)-OH, —O(C1-5 alkylene)-O(C1-5 alkyl), —(C1-3 alkylene)-OH, —(C1-3 alkylene)-O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —S(C1-5 alkylene)-SH, —S(C1-5 alkylene)-S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —NH—OH, —N(C1-5 alkyl)-OH, —NH—O(C1-5 alkyl), —N(C1-5 alkyl)-O(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO(C1-5 alkyl), —COOH, —COO(C1-5 alkyl), —O—CO(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO(C1-5 alkyl), —N(C1-5 alkyl)-CO(C1-5 alkyl), —NH—COO(C1-5 alkyl), —N(C1-5 alkyl)-COO(C1-5 alkyl), —O—CO—NH(C1-5 alkyl), —O—CO—N(C1-5 alkyl)(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), —SO2—(C1-5 alkyl), —SO—(C1-5 alkyl), —(C0-3 alkylene)-cycloalkyl, —(C0-3 alkylene)-heterocycloalkyl, and —R6—R7, wherein the cycloalkyl group in said —(C0-3 alkylene)-cycloalkyl and the heterocycloalkyl group in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —CHO, —CO(C1-5 alkyl), —COOH, —COO(C1-5 alkyl), —O—CO(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO(C1-5 alkyl), —N(C1-5 alkyl)-CO(C1-5 alkyl), —NH—COO(C1-5 alkyl), —N(C1-5 alkyl)-COO(C1-5 alkyl), —O—CO—NH(C1-5 alkyl), —O—CO—N(C1-5 alkyl)(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), —SO2—(C1-5 alkyl), and —SO—(C1-5 alkyl);
• each R6 is independently selected from a covalent bond, C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl), and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-5 alkyl)-, —CO—, —S—, —SO—, and —SO2—;
• and
• each R7 is independently selected from —OH, —O(C1-5 alkyl), —O(C1-5 alkylene)-OH, —O(C1-5 alkylene)-O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —S(C1-5 alkylene)-SH, —S(C1-5 alkylene)-S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —NH—OH, —N(C1-5 alkyl)-OH, —NH—O(C1-5 alkyl), —N(C1-5 alkyl)-O(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO(C1-5 alkyl), —COOH, —COO(C1-5 alkyl), —O—CO(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO(C1-5 alkyl), —N(C1-5 alkyl)-CO(C1-5 alkyl), —NH—COO(C1-5 alkyl), —N(C1-5 alkyl)-COO(C1-5 alkyl), —O—CO—NH(C1-5 alkyl), —O—CO—N(C1-5 alkyl)(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), —SO2—(C1-5 alkyl), —SO—(C1-5 alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl).