Back to results
US 2022/0017566 A1Published application
Terpinoid derivatives and uses thereof
AssigneeSichuan Haisco Pharmaceutical Co., Ltd.
InventorsBohan JIN, Qing DONG, Gene HUNG, Stephen W. KALDOR
Life of this patent
Estimating the term…
Abstract
Described herein are terpinoid derivatives as NRF2 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of inflammatory diseases.
Claims60
A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
- wherein:
- R1 is hydrogen, deuterium, halogen, —CN, —ORb, —NRcRd, —NRbS (═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- R3 is N-linked heterocycloalkyl, N-linked heteroaryl, —P(═O)(R4)2, —P(═O)(OR5)2, —B(OR5)2, —S(═O)R4, —S(═O)2R4, —NR5C(═NRx)R5, —NR5C(═NRx)NR6R7, —S(═O)(═NRx)R5, —S(═O)(═NRx)NR6R7, —NR5S(═O)2NR5C(═O)R5, —NR5S (═O) (═NRx) R5, —Z—O-cycloalkyl, —Z—O- heterocycloalkyl, —Z—O-aryl, —Z—O-heteroaryl, —Z—NR5-cycloalkyl, —Z—NR5-heterocycloalkyl, —Z—NR5-aryl, —Z—NR5-heteroaryl, —Y(C1-C6alkylene)S(═O)R4, —Y(C1-C6alkylene)S(═O)R4, —Y(C1-C6alkylene)P(═O)(R4)2, —Y(C1-C6alkylene)P(═O)(OR5)2, —Y(C1-C6alkylene)B(OR5)2, —Y(C1-C6alkylene)NR5C(═NRx)R5, —Y(C1-C6alkylene)NR5C(═NRx)NR6R7, —Y(C1-C6alkylene)S(═O)(═NRx)R5, —Y(C1-C6alkylene)S(═O)(═NRx)NR6R7, —Y(C1-C6alkylene)NR5S(═O)2NR5C(═O)R5, —NR5C(═O)(C1-C6alkylene)S(═NRx)NR6R7, —NR5C(═O)(C1-C6alkylene)S(═NRx)R5, —Y(C1-C6alkylene)NR5S(═O)(═NRx)R5, —Y(C2-C6alkenylene)S(═O)2R4, —Y(C2-C6alkenylene)P(═O)(R4)2, —Y(C2-C6alkenylene)P(═O)(OR5)2, —Y(C2-C6alkenylene)B(OR5)2, —Y(C2-C6alkenylene)NR5C(═NRx)R5, —Y(C2-C6alkenylene)NR5C(═NRx)NR6R7, —Y(C2-C6alkenylene)S(═O)(═NRx)R5, —Y(C2-C6alkenylene)S(═O)(═NRx)NR6R7, —Y(C2-C6alkenylene)NR5S(═O)2NR5C(═O)R5, —Y(C2-C6alkenylene)NR5S(═O)(═NRx)R5, —Y(C2-C6alkenylene)cycloalkyl, —Y(C2-C6alkenylene)heterocycloalkyl, —Y(C2-C6alkenylene)aryl, —Y(C2-C6alkenylene)heteroaryl, —(C1-C6alkylene)OP(═O)(OR5)2, —(C1-C6alkylene)O(C1-C6alkylene)OP(═O)(OR5)2, or —(C1-C6alkylene)OP(═O)(OR5)[N(R5)2];
- wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R3a;
- each R3a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- Y is a bond, —O—, —S—, or —NRb—;
- Z is a bond or C1-C6alkylene;
- Rx is hydrogen, —NO2, —CN, or —S(═O)2Ra;
- each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a;
- each R4a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a;
- or two R5 are taken together to form an optionally substituted heterocycloalkyl;
- each R5a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a;
- each R6a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b;
- each R6b is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R8 is hydrogen, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R11 is hydrogen, deuterium, halogen, or —ORb;
- or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
- R12 and R13 are independently hydrogen, —ORb, —NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl;
- each substituted with 0-6 R14;
- each R14 is independently deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R15 and R16 are independently hydrogen, —ORb, —NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl;
- each substituted with 0-6 R2;
- each R2 is independently deuterium, halogen, —CN, —ORb, −NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl;
- each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, —OH, —NH2, or C1-C6 alkyl;
- and
- each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl;
- or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl.
38 more elements
A compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
- wherein:
- R1 is hydrogen, deuterium, halogen, —CN, —ORb, —NRcRd, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- R3 is halogen, —CN, —S(═O)R4, —S(═O)2R4, —NO2, —NR6R7, —S(═O)2NR6R7, —C(═O)R4, —OC(═O)R4, —C(═O)OR5, —OC(═O)OR5, —C(═O)NR6R7, -OC(═O)NR6R7, —NR5C(═O)NR6R7, —NR5C(═O)OR5, —NR5S(═O)2NR6R7, —NR5S(═O)2R4, —NR5C(═O)R4, —P(═O)(R4)2, —P(═O)(OR5)2, —B(OR5)2, —NR5C(═NRx)R5, —NR5C(═NRx)NR6R7, —S(═O)(═NRx)R5, —S(═O)(═NRx)NR6R7, —NR5S(═O)2NR5C(═O)R5, —NR5S(═O)(═NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a;
- each R3a is independently oxo, deuterium, halogen, —CN, -01V, —S(═O)R4, —S(═O)2R4, —NO2, —NR6R7, —S(═O)2NR6R7, —C(═O)R4, —OC(═O)R4, —C(═O)01e, —OC(═O)085, —C(═O)NR6R7, —OC(═O)NR6R7, —NR5C(═O)NR6R7, —NR5C(═O)OR5, —NR5S(═O)2NR6R7, —NR5S(═O)2R4, —NR5C(═O)R4, —P(═O)(R4)2, —P(═O)(OR5)2, —B(OR5)2, —NR5C(═NRx)R5, —NR5C(═NRx)NR6R7, —S(═O)(═NRx)R5, —S(═O)(═NRx)NR6R7, —NR5S(═O)2NR5C(═O)R5, —NR5S(═O)(═NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b;
- each R3b is independently deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- Rx is hydrogen, —NO2, —CN, or —S(═O)2Ra;
- each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a;
- each R4a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —NRbC(═NRx)Rb, —NRbC(═NRx)NRcRd, —S(═O)(═NRx)Rb, —S(═O)(═NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a;
- or two R5 are taken together to form an optionally substituted heterocycloalkyl;
- each R5a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —NRbC(═NRx)Rb, —NRbC(═NRx)NRcRd, —S(═O)(═NRx)Rb, —S(═O)(═NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a;
- each R6a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —NRbC(═NRx)Rb, —NRbC(═NRx)NRcRd, —S(═O)(═NRx)Rb, —S(═O)(═NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b;
- each R6b is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- Y1 and Y2 are independently hydrogen, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- R8 is hydrogen, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl;
- R11 is hydrogen, deuterium, halogen, or —ORb;
- or R3 and R4 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
- R12 is hydrogen, deuterium, —ORb, —NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R13 is —CN, —OR19, —S(═O)2NR20R21, —OC(═O)R18, —OC(═O)OR19, —OC(═O)NR20R21, —NR19C(═O)OR19, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —CH2(cycloalkyl), —CH2(heterocycloalkyl), —CH2(aryl), or —CH2(heteroaryl);
- wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a;
- each R13a is independently oxo, deuterium, halogen, —CN, —OR19, —SR19, —S(═O)R18, —S(═O)2R18, —NO2, —NR20R21, —S(═O)2NR20R21, —C(═O)R18, —OC(═O)R18, —C(═O)OR19, —OC(═O)OR19, —C(═O)NR20R21, —OC(═O)NR20R21, —NR19C(═O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a;
- each R18a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI—C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a;
- each R19a is independently oxo, deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a;
- each R20a is independently oxo, deuterium, halogen, —CN, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b;
- each R20b is independently oxo, deuterium, halogen, —CN, —ORb, 13 NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R15 and R16 are independently hydrogen, —ORb, —NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;
- or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl;
- each substituted with 0-6 R2;
- each R2 is independently deuterium, halogen, —CN, —ORb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl;
- each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, —OH, —NH2, or C1-C6 alkyl;
- and
- each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl;
- or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, —OH, —NH2, or C1-C6 alkyl.
50 more elements
Dependencies are inferred from the claim text.