Pfkfb3 inhibitors and their uses

A compound of Formula (0):

• or a pharmaceutically acceptable salt thereof, or N-oxide, or solvate, or tautomer, or stereoisomer, or racemate, including mixtures thereof in all ratios, wherein RG6 and RG5 is one of the following:
• A) RG6 and RG5 are taken together with the N to which they are attached to form a C2-C8 heterocycloalkyl optionally substituted with one or more substituents;
• RG1, RG3 and RG4 are independently selected from RM;
• RG2 is RL;
• RG5 is Z;
• RG6 is —C(═O)—;
• AG1 is —ArC—ArT;
• thus the Formula (0) can be represented as the Formula (I):
• wherein:
• Z is selected from —C(═O)— and —C(Ra)(Rb)—;
• Ra and Rb are independently selected from hydrogen, hydroxyl, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, and optionally substituted —O—C2-C8 heterocycloalkyl;
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and -O—C2-C8 heterocycloalkyl;
• Arc is selected from C3-C8 cycloalkenylene, C2-C8 heterocycloalkenylene, arylene, and heteroarylene;
• wherein Arc is substituted with one or more RC;
• each RC are independently selected from —CN, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted —O—C2-C8 heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, —C(═O)OH, —C(═O)OR3, —C(═O)NR4R5, —S(═O)2NR4R5, —NHC(═O)H, —NHC(═O)R6, —NHS(═O)2R6, and —C(═O)NHS(═O)2R6;
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)R6, —C(═O)NR1R2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR7R8;
• each R1 and R2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 cycloalkyl;
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and -O—C2-C8 heterocycloalkyl;
• or R1 and R2 are taken together with the N to which they are attached to form a C2-C8 heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy;
• each R3 is independently C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OH, optionally substituted —OC(═O)C1-C6alkyl, optionally substituted —C(═O)O—C1-C6 alkyl, C1-C6 alkoxy, —C(═O)OH, —NR1R2, —C(═O)NR1R2, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
• wherein the —OC(═O)C1-C6 alkyl and —C(═O)O—C1-C6 alkyl are optionally substituted with one or more substituents independently selected from halogen, —OH, and —NR7R8;
• and
• wherein the C2-C8 heterocycloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• or each R3 is independently C3-C8 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, optionally substituted —O(C═O)C1-C6 alkyl, optionally substituted —(C═O)OC1-C6 alkyl, C1-C6 alkoxy, —C(═O)OH, —NR1R2, —(C═O)NR1R2, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl, —OC(═O)C1-C6 alkyl and —C(═O)O—C1-C6 alkyl are optionally substituted with one or more substituent independently selected from halogen, —OH, and —NR7R8;
• and
• wherein the C2-C8 heterocycloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —(C═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• each R4 and R5 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• or R4 and R5 are taken together with the N to which they are attached to form a C2-C8 heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• each R7 and R8 is independently selected from hydrogen and C1-C6 alkyl;
• or R7 and R8 are taken together with the N to which they are attached to form a C2-C8 heterocycloalkyl optionally substituted with one or more C1-C6 alkyl substituents;
• ArT is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, and tetrazolyl, wherein ArT is optionally substituted by one or more substituents independently selected from halogen, —OH, —NR7R8, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C5 cycloalkyl, optionally substituted —O—C3-C8
• cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, and optionally substituted —O—C2-C8 heterocycloalkyl;
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and -O—C2-C8 heterocycloalkyl;
• each RM is independently selected from hydrogen, halogen, —OH, —CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—C3-C5 cycloalkyl, optionally substituted C2-C5 heterocycloalkyl, and optionally substituted —O—C2-C5 heterocycloalkyl;
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR7R8, —OH, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and -O—C2-C8 heterocycloalkyl;
• RL is selected from —OH, —CN, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted heteroaryl, —C(═O)OH, —C(═O)OR9, —C(═O)NR10R11, —S(═O)2NR10R11, —NHC(═O)H, —NHC(═O)R12, —NHS(═O)2R12 and —C(═O)NHS(═O)2R12;
• wherein the C1-C6 hydroxyalkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the heteroaryl is optionally substituted with one or more of —OH, —O—C(═O)C1-C6 alkyl, (C1-C4 alkylene)-O—C(═O)C1-C6 alkyl, C1-C6 alkyl-(aryl), C1-C6 alkyl-(heteroaryl), halogen, —C(═O)OR7, —C(═O)R12, —C(═O)NR1R2, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR1R2;
• R9 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OH, optionally substituted —OC(═O)C1-C6 alkyl, optionally substituted —C(═O)O—C1-C6 alkyl, C1-C6 alkoxy, —C(═O)OH, —NR1R2, —C(═O)NR1R2, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
• wherein the —OC(═O)C1-C6 alkyl and —C(═O)O—C1-C6 alkyl are optionally substituted with one or more substituents independently selected from halogen, —OH, and —NR7R8;
• and
• wherein the C2-C8 heterocycloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• or R9 is C3-C8 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, optionally substituted —O(C═O)C1-C6 alkyl, optionally substituted —(C═O)OC1-C6 alkyl, C1-C6 alkoxy, —C(═O)OH, —NR1R2, —(C═O)NR1R2, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl, —OC(═O)C1-C6 alkyl and —C(═O)O—C1-C6 alkyl are optionally substituted with one or more substituent independently selected from halogen, —OH, and —NR7R8;
• and
• wherein the C2-C8 heterocycloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —(C═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• each R10 and R11 is independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl (optionally substituted with —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, —NR7R8), and heteroaryl (optionally substituted with —OH, halogen, —C(═O)OR7, —C(═O)NR7R8, C1-C6 alkyl, C1-C6 alkoxy, —NR7R8, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, or —O—C2-C8 heterocycloalkyl);
• and
• wherein the C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR1R2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• or R10 and R11 are taken together with the N to which they are attached to form a C2-C8 heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy;
• R12 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, —C(═O)OR7, —C(═O)NR1R2, —OH, aryl, heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, and —O—C2-C8 heterocycloalkyl;
• and
• wherein the C3-C8 cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, halogen, —C(═O)OR7, —C(═O)NR1R2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, —O—C2-C8 heterocycloalkyl, and —NR7R8;
• provided that:
• (a) at least one of RC is not —NHCOR6 when RL is —NHCOR12 and ArC is heterocycloalkenylene or heteroarylene;
• or
• (b) at least one of RC is not -Me when RL is —OMe;
• or
• (c) at least one of RC is not —OEt when RL is —C(═O)OH;
• or
• (d) at least one of RC is not —OH when RL is —C(═O)OH;
• or
• (e) at least one of RC is not -Me when RL is —C(═O)OH;
• or
• (f) at least one of RC is not -Et when RL is —OMe;
• or
• (g) at least one of RC is not optionally substituted benzoxazolyl when RL is —C(═O)OH;
• or
• (h) at least one of RC is not optionally substituted isoindoline-1,3-dione when RL is —C(═O)OH;
• B) RG6 and RG5 do not form a C2-C8 heterocycloalkyl;
• RG1 is R5;
• RG2 is R1;
• RG3 is R6;
• RG4 is R20;
• RG5 is R4;
• RG6 is R10;
• AG1 is A;
• thus the Formula (0) can be represented as the Formula (VII):
• Formula (VII), or a pharmaceutically acceptable salt thereof, wherein:
• A is selected from:
• R1 is selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more halogens;
• each R2 and R3 is independently selected from hydrogen and C1-C6 alkyl,
• wherein the C1-C6 alkyl is optionally substituted with one or more halogens;
• or R2 and R3 are taken together with the N to which they are attached to form a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from C1-C6 alkyl;
• R4 is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogens;
• R8 is selected from —C(═O)OR15, —C(═O)NR2R3, —S(═O)2NR2R3, —C(═O)NHR15, —CH2OH, 3-hydroxyoxetan-3-yl, and —NH2;
• R6 is selected from hydrogen, halogen, hydroxyl, 5-membered heteroaryl, C1-C6 alkyl, —C(═O)OR15, —C(═O)R12, —C(═O)NHR15, and —C(═O)N═S(═X3)(CH3)2,
• wherein the C1-C6 alkyl are optionally substituted with one or more R9, and
• wherein 5-membered heteroaryl contains at least two heteroatoms and is optionally substituted with one or more substituents independently selected from R17;
• R7 is selected from hydrogen, —NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, —O—(3- to 10-membered heterocycloalkyl), aryl, and heteroaryl,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more halogens, and
• wherein C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, —O-(3- to 10-membered heterocycloalkyl), aryl and heteroaryl are optionally substituted with one or more R24;
• R8 is selected from hydrogen, —NO2, C1-C6 alkyl, aryl, and heteroaryl,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected at each occurrence from halogen;
• and
• wherein aryl and heteroaryl are optionally substituted with one or more substituents independently selected at each occurrence from R23;
• or R7 and R8 are taken together to form a C5-C10 carbocycle or 5- to 10-membered heterocycle,
• wherein C5-C10 carbocycle and 5- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, —NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, —O—(3- to 10-membered heterocycloalkyl), aryl, and heteroaryl,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more halogens, and
• wherein aryl, heteroaryl, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, and —O—(3- to 10-membered heterocycloalkyl) are optionally substituted with one or more R23;
• each R9 is independently selected from hydroxy and —COOH;
• R10 is selected from —C(═O)—X1—, —CH2—X1—, —X1—C(═O)—, and —X1-CH2—;
• R11 is selected from hydrogen, —NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, and —O—(3- to 10-membered heterocycloalkyl),
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more halogens, and
• wherein C3-C8 cycloalkyl, —O—C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, and —O—(3- to 10-membered heterocycloalkyl) are optionally substituted with one or more R23;
• R12 is selected from alanine, arginine, asparagine, aspartic acid, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, wherein the point of attachment of R12 is a nitrogen atom;
• R14 is selected from hydrogen, halogen, hydroxyl, nitrile, —C(═O)CR15 and —C(═O)OR15;
• each R15 is independently selected from hydrogen and C1-C6 alkyl, -heterocyclyl,
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from —C(═O)NR2R3, -heterocyclyl, —NR2R3;
• wherein the heterocyclyl is optionally substituted with one or more substituents independently selected at each occurrence from R2 and R3,
• R17 is selected from C1-C6 alkyl, aryl, and 6-membered heteroaryl,
• wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, and
• wherein aryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from halogen, —R2, and —OR2;
• R20 is selected from hydrogen, halogen, hydroxyl, —COOH, —NC(═O)R2, —OR2, 5-membered heteroaryl, C1-C6 alkyl, —C(═O)N═S(═X3)(CH3)2, —CH2(OH)CH2OH and —NH—SO2—R2,
• wherein the 5-membered heteroaryl contains at least two heteroatoms, and
• wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least two heteroatoms;
• R21 is selected from hydrogen and nitrile;
• R22 is selected from hydrogen and hydroxy;
• each R23 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy,
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogens;
• each R24 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, 5-membered heteroaryl
• wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from halogens;
• each X1 is independently selected from —NR2— and —CR2R3—;
• and
• each X3 is independently selected from NH and O.