Beta-lactam derivatives for the treatment of diseases

Abstract

Provided herein are compounds and methods for modulating or inhibiting glutaminyl-peptide cyclotransferase-like protein (QPCTL).In one embodiment, described herein are compounds of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba) and (IIbb), stereoisomers thereof, or salts or solvates thereof.Further provided herein is a method for treating disease or condition, comprising administering a compound of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba) or (IIbb), stereoisomers thereof, or salts or solvates thereof. TIFF2024523552000361.tif10089

Description

[Technical Field]

[0001] Cross-referencing related passwords

[0001] This application claims the benefit of PCT / CN2021 / 102061 filed on June 24, 2021, PCT / CN2021 / 107806 filed on July 22, 2021, and PCT / CN2021 / 142624 filed on December 29, 2021, each of which is incorporated by reference in its entirety into this specification.

[0002] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE

[0002] This disclosure relates to beta-lactam derivatives that function as inhibitors of glutaminyl-peptide cyclotransferase-like proteins (QPCTLs). [Background technology]

[0003] Glutaminyl-peptide cyclotransferase (GC), also known as glutaminyl cyclase (GC), catalyzes the conversion of N-terminal L-glutaminyl residues of peptides to pyroglutamyl groups. This enzyme belongs to the family of transferases, particularly aminoacyltransferases, and is present in the pituitary and adrenal glands, where it is important for the generation of N-terminal pyroglutamyl groups in peptide hormones such as neurotensin and thyrotropin-releasing hormone. Glutaminyl cyclase also catalyzes the conversion of N-terminal L-glutamyl residues to pyroglutamyl residues. This activity contributes to the formation of several amyloid-associated plaque-forming peptides and may contribute to the pathology of Alzheimer's disease. Glutaminyl cyclase is also considered a diagnostic marker for thyroid tumors. Summary of the Invention

[0004]

[0004] The present disclosure addresses the above needs and provides further advantages.

[0005] In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0005] [ka]

[0006] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each of R is independently selected from H and halogen; 3 -OR11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0007] In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0008] [ka]

[0009] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each is independently selected from H and halogen; R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR21 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-C6 alkynyl, a substituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0010] In some embodiments, the present disclosure provides a compound represented by formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0011] [ka]

[0012] In some embodiments, the present disclosure provides a compound represented by formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0013] [ka]

[0014] In some embodiments, the present disclosure provides a compound represented by formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:

[0015] [ka]

[0016] In some embodiments, the present disclosure provides a compound represented by formula (Iab), or a pharmaceutically acceptable salt or solvate thereof:

[0017] [ka]

[0018] In some embodiments, the present disclosure provides a compound represented by formula (Iba), or a pharmaceutically acceptable salt or solvate thereof:

[0019] [ka]

[0020] In some embodiments, the present disclosure provides a compound represented by formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof:

[0021] [ka]

[0022] In another aspect, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0023] [ka]

[0024] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0025] In some embodiments, the compound of formula (II) has the structure of formula (IIa), a pharmaceutically acceptable salt or solvate thereof:

[0026] [ka]

[0027] In some embodiments, the compound of formula (II) has the structure of formula (IIb), a pharmaceutically acceptable salt or solvate thereof:

[0028] [ka]

[0029] In some embodiments, the compound of formula (II) has the structure of formula (IIaa), a pharmaceutically acceptable salt or solvate thereof:

[0030] [ka]

[0031] In some embodiments, the compound of formula (II) has the structure of formula (IIab), a pharmaceutically acceptable salt or solvate thereof:

[0032] [ka]

[0033] In some embodiments, the compound of formula (II) has the structure of formula (IIba), a pharmaceutically acceptable salt or solvate thereof:

[0034] [ka]

[0035] In some embodiments, the compound of formula (II) has the structure of formula (IIbb), a pharmaceutically acceptable salt or solvate thereof:

[0036] [ka]

[0037] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is halogen, -OH, -SR 10a , -CN, amino, -NR 22 R 23 , -OR 10a , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 -OH, -OR 10a , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 HA-OR 10a and R 10a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1is a substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is halogen, -OH, amino, cyano, oxime, oxo, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R is C1-C6 alkyl optionally substituted with 1 to 5 substituents selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 1 are -CH3, -CHF2, -CF3,

[0038] [ka]

[0039] , -CHOH, -CHCH, -CHCHCH, -CHCHCH, or benzyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is a substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 teeth,

[0040] [ka]

[0041] In some embodiments, R 1 is H. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 2 is H, halogen, —OH, or substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is H. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is -CH3.

[0042] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 and R 2 are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered cyclic or heterocyclic ring. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2 Let's get together and 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12b is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12bis hydrogen or phenyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12b is hydrogen.

[0043] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 5 is H, F, Cl, or Br. In some embodiments, R 5 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 is H, F, Cl, or Br. In some embodiments, R 7 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 is H, F, Cl, or Br. In some embodiments, R 4 is H. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 is H, F, Cl, or Br. In some embodiments, R 6 is H.

[0044] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted 5-membered monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted bicyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a fused bicyclic heteroaryl having 8 to 10 ring atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, and S. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3is a substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a monocyclic 5- or 6-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is phenyl or naphthyl, each of which is optionally substituted. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is one or more R 31 and each R 31 are independently cyano, oxime, oxo, halogen, hydroxy, amino, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl and substituted or unsubstituted C 1~6 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21, halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 -OR 11 , -SR 11 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 HA-OR 11 is.

[0045] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is a substituted C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is cyano, oxime, oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, S(=O)2(C1-C4 alkyl), mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl and substituted or unsubstituted C 1~6In some embodiments, R is substituted with one or more substituents selected from alkoxy-heteroaryl. 11 is substituted with one or more substituents selected from halogen, —OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is substituted with one or more substituents selected from halogen, —OH, and C-C cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is substituted with one or more F's.

[0046] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR22 R 23 , -NR 22 C(=O)R 21 or -NR 22 C(=O)OR 21 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 21 , R 22 and R 23 are each independently selected from hydrogen and C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted C1-C8 alkyl, a substituted C2-C8 alkenyl, a substituted C2-C8 alkynyl, or a substituted C1-C8 heteroalkyl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 -OR 11 or -SR 11 and R 11is substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0047]

[0027] In some embodiments, provided herein are stereoisomers of compounds of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb).

[0048] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of Table 3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of Formula (Iaa). In some embodiments, the compound is a compound of Formula (IIaa).

[0049] In some embodiments, the compound has a brain / blood AUC of at most about 0.0001, 0.001, 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 5, or 10.

[0050] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound described herein and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, or subcutaneous administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

[0051]

[0031] In another aspect, the present disclosure provides a method for modulating glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In another aspect, the present disclosure provides a method for inhibiting glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In another aspect, the present disclosure provides a method for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or condition is associated with aberrant glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity. In some embodiments, the disease or condition associated with aberrant QPCTL activity is cancer. In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0052] In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the cancer is AML. In some embodiments, the cancer is a solid cancer or metastatic cancer. In some embodiments, the cancer is skin cancer, eye cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.

[0053]

[0033] In one aspect, described herein are methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, wherein the disease or condition is a disease involving the innate immune system. In some embodiments, the disease is atherosclerosis, a fibrotic disease, ischemia-reperfusion injury, or an infection caused by a pathogen. In some embodiments, the disease is a fibrotic disease selected from liver fibrosis, pulmonary fibrosis, renal fibrosis, and scleroderma. In some embodiments, the disease is chronic kidney disease, including diabetic nephropathy and focal segmental glomerulosclerosis (FSGS).

[0054] In one aspect, described herein is a method of treating a disease or condition in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, wherein the disease or condition is selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infection, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathogenic psychiatric states, and the like. , schizophrenia, infertility, neoplasms, inflammatory host response, cancer, psoriasis, humoral and cell-mediated immune response disorders, endothelial leukocyte adhesion and migration processes, food intake disorders, sleep-wake disorders, homeostatic dysregulation of energy metabolism, autonomic dysfunction, hormone balance disorders or fluid regulation disorders, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, familial British dementia, familial Danish dementia, neurodegeneration in Down syndrome, Huntington's disease, rheumatoid arthritis, pancreatitis, and restenosis. In some embodiments, the method includes administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a monoclonal antibody. In some embodiments, the monoclonal antibody is selected from edrecolomab, rituximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab, cetuximab, bevacizumab, and trastuzumab. In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or cemiplimab.

[0055]

[0035] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0056] Incorporation by Reference

[0036] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, this specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION OF THE INVENTION

[0057] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be utilized.

[0058] A.Definition

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referenced herein are incorporated by reference.

[0059] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having 1 to 15 carbon atoms (i.e., C1 to C 15Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (i.e., C1 to C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (i.e., C5-C6 alkyl). 15In other embodiments, an alkyl contains 5 to 8 carbon atoms (i.e., a C5-C8 alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (i.e., a C2-C5 alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (i.e., a C3-C5 alkyl). In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0060] When used with a chemical moiety such as alkyl, alkenyl, or alkynyl, the term "C x~y " is intended to include groups containing x to y carbons in the chain. For example, "C 1~6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, containing 1 to 6 carbons. x~y Alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1~6Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -C x~y Alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbon atoms in the chain. For example, -C 2~6 Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any one of which is optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond within the alkynylene chain.

[0061]

[0041] "Alkoxy" refers to a radical attached through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0062] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms (i.e., C2 to C6 12Alkenyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Alkenyls are attached to the remainder of the molecule by a single bond, e.g., ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless stated otherwise specifically in the specification, alkenyl groups can be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0063] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms (i.e., C2-C 12Alkynyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Alkynyl is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0064] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, e.g., methylene, ethylene, propylene, n-butylene, etc., consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having 1 to 12 carbon atoms, connecting the rest of the molecule to a radical group. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe.In some embodiments, the alkylene is optionally substituted with halogen.

[0065] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkenylene contains from 2 to 10 carbon atoms (i.e., C2 to C6). 10alkenylene). In certain embodiments, alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenylene is optionally substituted with halogen.

[0066] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkynylene contains from 2 to 10 carbon atoms (i.e., C2 to C6). 10alkynylene). In certain embodiments, alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkynylene is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, an alkynylene is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, an alkynylene is optionally substituted with halogen.

[0067] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system may contain only hydrogen and carbon and 5 to 18 carbon atoms, where at least one ring in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified specifically in the specification, aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0068] "Aralkyl" refers to a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. "Aralkenyl" refers to a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. "Aralkynyl" refers to a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above.

[0069] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, where valences permit, is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specified specifically in the specification, carbocycles may be optionally substituted.

[0070] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may also refer to partially saturated monocyclic or polycyclic carbocyclic rings, such as cycloalkenyl. Cycloalkyl includes fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4). 15 C3-C including cycloalkenyl 15 Cycloalkyl), 3 to 10 carbon atoms (C3 to C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl), 3 to 6 carbon atoms (C-C cycloalkyl), 3 to 5 carbon atoms (C-C cycloalkyl), or 3 to 4 carbon atoms (C-C cycloalkyl). In some embodiments, cycloalkyls are 3 to 10-membered cycloalkyls, such as 3 to 10-membered cycloalkenyls. In some embodiments, cycloalkyls are 3 to 6-membered cycloalkyls, such as 3 to 6-membered cycloalkenyls. In some embodiments, cycloalkyls are 5 to 6-membered cycloalkyls, such as 5 to 6-membered cycloalkenyls. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified specifically in the specification, cycloalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0071] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having from 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, a cycloalkenyl contains from 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains from 5 to 7 carbon atoms. A cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0072] "Cycloalkylalkyl" refers to a group of the formula -R c -refers to a cycloalkyl radical, where R c is the alkylene chain as defined above. "Cycloalkylalkoxy" refers to a group of the formula -OR c -refers to a radical attached through an oxygen atom of a cycloalkyl, where R c is the alkylene chain as defined above.

[0073]

[0055] "Halo" or "halogen" refers to a halogen substituent such as bromo, chloro, fluoro, and iodo substituents. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0074] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radical, each halogen may be independently selected, such as 1-chloro, 2-fluoroethane.

[0075] "Fluoroalkyl" refers to an alkyl radical as defined above that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0076]

[0058] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0077]

[0059] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0078]

[0060] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0079] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2 to C6). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and the like. Examples of heterocycloalkyl include, but are not limited to, cyclohexane, cyclohexane-1,3-dihydroisobenzofuran-1-yl ... In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl.In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0080] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. "Heterocyclene" refers to a divalent heterocycle that links the remainder of the molecule to a radical group.

[0081]

[0063] "Heteroaryl" or "heteroaromatic ring" refers to a radical derived from a heteroaromatic ring radical containing 1 to 11 carbon atoms and at least one heteroatom, each heteroatom optionally selected from N, O, and S. As used herein, heteroaryl rings can be selected from monocyclic or bicyclic rings and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n + 2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl radical may be optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, if valence allows. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine. An "X-membered heteroaryl" refers to the number of ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, such as triazole, oxazole, thiophene, etc. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached via an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl.In some embodiments, heteroaryl is a 5-6 membered heteroaryl. In some embodiments, heteroaryl is a 6 membered heteroaryl. In some embodiments, heteroaryl is a 5 membered heteroaryl. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0082] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which said event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., CH2CH2F), or substituted at any level intermediate between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0083] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbon or substitutable heteroatoms, e.g., NH, of the structure. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the replacing atoms and substituents, as well as the implicit proviso that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on one carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0084] In some embodiments, substituents can include any substituent described herein, such as halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a, -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (wherein t is 1 or 2), and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b-OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2), and each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle; and each R a is, when valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2), and each R b are independently selected from a direct bond, or a straight or branched alkylene, alkenylene, or alkynylene chain; and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0085]

[0067] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0086] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0087]

[0070] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0088]

[0071] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cocoa butter, and suppository wax; and (10) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cocoa butter, and corn starch. (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0089]

[0072] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0090]

[0073] As used herein, the terms "treat," "treating," or "treatment" can include alleviating, reducing, or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating or preventing the underlying cause of the symptoms, inhibiting the disease or condition, for example, preventing the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving the conditions caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of the disease or condition.

[0091] B. Compounds of the Present Disclosure In one aspect, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0092] [ka]

[0093] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each is independently selected from H and halogen; R 3 -OR 11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , N.R. 22C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0094] In another aspect, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0095] [ka]

[0096] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each is independently selected from H and halogen; R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-C6 alkynyl, a substituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0097] In another aspect, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0098] [ka]

[0099] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each is independently selected from H and halogen; R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , N.R. 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0100] In some embodiments of Formula (I), wherein: R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 3 -SR 11 , SF5,-S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR21 , -P(=O)R 22 R 23 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 11 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0101] In some embodiments of Formula (I), wherein: R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 3 -OR 11 , -SR11 , SF5,-S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 3 -OR 11 When R 11is a substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0102] In another aspect, the present disclosure provides a compound represented by formula (I), a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof:

[0103] [ka]

[0104] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, and substituted or unsubstituted C1-C6 alky; R 3 -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0105] In another aspect, the present disclosure provides a compound represented by formula (I), a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof:

[0106] [ka]

[0107] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each of which is independently H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl; R 3 -OR11 , -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted C1-C8 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10bare each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-C6 alkynyl, a substituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0108] In some embodiments, the compound of Formula (I) is represented by Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0109] [ka]

[0110] In some embodiments, the compound of Formula (I) is represented by Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0111] [ka]

[0112] In some embodiments, the compound of Formula (I) is represented by Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:

[0113] [ka]

[0114] In some embodiments, the compound of Formula (I) is represented by Formula (Iab), or a pharmaceutically acceptable salt or solvate thereof:

[0115] [ka]

[0116] In some embodiments, the compound of Formula (I) is represented by Formula (Iba), or a pharmaceutically acceptable salt or solvate thereof:

[0117] [ka]

[0118] In some embodiments, the compound of Formula (I) is represented by Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof:

[0119] [ka]

[0120] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0121] [ka]

[0122] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7are independently selected from H, halogen, and substituted or unsubstituted C1-C6 alkyl; R 3 -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10bare each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0123] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:

[0124] [ka]

[0125] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each of which is independently H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl; R 3 -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21, -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0126] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (Iab), or a pharmaceutically acceptable salt or solvate thereof:

[0127] [ka]

[0128] (In the formula, R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12bare each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 each of which is independently H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl; R 3 -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 11 is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0129] In some embodiments of formula (I), (Ia), (Ib), (Iaa) (Iab), (Iba), or (Ibb), wherein: R 1 is halogen, -OH, -OR 10a , -SH, -SR 10a , -CN, amino, -NR 22 R 23, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C3-C8 cycloalkyl; R 2 is H or a halogen, or R 1 and R 2 Let's get together and 12a R 12b forms a double bond to R 12a is hydrogen and R 12b is hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, and substituted or unsubstituted C1-C6 alkyl; R 3 -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R 23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 10a and R 10b are each independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, or a substituted or unsubstituted C2-C6 alkynyl, R 11 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0130] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), or (Ibb), R 4 , R 5 , R 6 and R 7Each of the groups independently represents H, halogen, -OH, oxo, -NO2, CN, SH, or -OR. 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 In some embodiments of Formula (I), (Ia), (Ib), (Iaa)(Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 , R 5 , R 6 and R 7 each of which is independently H, -OR 11 , -NR 22 R 23 , halogen and substituted or unsubstituted C1-C6 alkyl.

[0131] In another aspect, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0132] [ka]

[0133] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0134] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0135] [ka]

[0136] wherein ring Q is a substituted or unsubstituted aryl (such as phenyl); The remaining groups have the same definitions as above). In some embodiments, the compound of Formula (II) has the structure of Formula (IIa), a pharmaceutically acceptable salt or solvate thereof:

[0137] [ka]

[0138] In some embodiments, the compound of Formula (II) has the structure of Formula (IIb), a pharmaceutically acceptable salt or solvate thereof:

[0139] [ka]

[0140] In some embodiments, the compound of Formula (II) has the structure of Formula (IIaa), a pharmaceutically acceptable salt or solvate thereof:

[0141] [ka]

[0142] In some embodiments, the compound of Formula (II) has the structure of Formula (IIab), a pharmaceutically acceptable salt or solvate thereof:

[0143] [ka]

[0144] In some embodiments, the compound of Formula (II) has the structure of Formula (IIba), a pharmaceutically acceptable salt or solvate thereof:

[0145] [ka]

[0146] In some embodiments, the compound of Formula (II) has the structure of Formula (IIbb), a pharmaceutically acceptable salt or solvate thereof:

[0147] [ka]

[0148]

[0100] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:

[0149] [ka]

[0150] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 10a and R 10bare each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0151]

[0101] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof:

[0152] [ka]

[0153] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12bare each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0154]

[0102] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof:

[0155] [ka]

[0156] wherein ring Q is a substituted or unsubstituted aryl (such as phenyl); The remaining groups have the same definitions as above).

[0103] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (IIab), or a pharmaceutically acceptable salt or solvate thereof:

[0157] [ka]

[0158] (In the formula, R 1 is H, halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H, halogen, -OH, -OR 10b , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, or R 1 and R 2 together with oxo or CR 12a R 12b forms a double bond to R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl; R 10a and R 10b are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; R 22 and R 23are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0159]

[0104] In another aspect, the present disclosure provides stereoisomeric compounds represented by formula (IIab), or a pharmaceutically acceptable salt or solvate thereof:

[0160] [ka]

[0161] wherein ring Q is a substituted or unsubstituted aryl (such as phenyl); The remaining groups have the same definitions as above). In some embodiments of the compound of Formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), wherein: R 1 is H, halogen, -OH, -OR 10a , -SH, -SR 10a , -CN, amino, -NR 22 R 23 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R 2 is H or a halogen, or R 1 and R 2 Let's get together and 12a R 12b forms a double bond to R 12a is hydrogen and R 12bis hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ring Q is a substituted or unsubstituted 5- or 6-membered heteroaryl, or a substituted or unsubstituted phenyl; R 10a and R 10b are each independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6 alkenyl, or a substituted or unsubstituted C2-C6 alkynyl, R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0162] In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is a substituted or unsubstituted 5-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is pyrrolyl, furyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, or oxadiazolyl, each of which is optionally substituted. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted pyrrolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted furyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted thiophenyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted pyrazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted imidazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted thiazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted isothiazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted triazolyl.In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted tetrazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted thiadiazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted phenyl. In some embodiments of Formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), ring Q is substituted or unsubstituted aryl.

[0163] In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is a substituted or unsubstituted 6-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S. In some embodiments of Formula (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), ring Q is a substituted or unsubstituted 6-membered heteroaryl having 1 to 3 ring nitrogen atoms.

[0164] In some embodiments of Formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), ring Q contains 0 to 3 halogen groups and 0 to 4 R 3 substituted with R 3 are independently -OH, -SH, oxo, and -OR 11 , halogen, -SR 11 , SF5, -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -N=S(=O)R 22 R23 , -S(=O)2NR 22 R 23 , -S(=O)(NR 21 )R 21 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , -P(=O)R 22 R 23 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0165] In some embodiments of Formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), ring Q contains 0 to 3 halogen groups and 0 to 1 R 3 substituted with R 3 -OR 11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0166] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11is substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is an optionally substituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is a substituted or unsubstituted C3-C8 cycloalkyl.

[0167] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0168] In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), ring Q is

[0169] [ka]

[0170] (In the formula, A 5 is N or CR 5 and A 4 is N or CR 4 and A 6 is N or CR 6 and A 7 is N or CR 7 and R 4 , R 5 , R 6 and R 7 each is independently selected from H and halogen; R 3 -OR 11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 11 is a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-C6 alkynyl, a substituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. is.

[0171] In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), ring Q is

[0172] [ka]

[0173] (In the formula, A 5 is N or CR 5 and A 4 is N or CR 4 and A 6 is N or CR 6 and A 7 is N or CR 7 and R 4 , R 5 , R 6 and R 7 Each of the groups independently represents H, halogen, -OH, oxo, -NO2, CN, SH, or -OR. 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 3 -OR 11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 11is a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-C6 alkynyl, a substituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C2-C7 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bicyclic or polycyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is substituted with at least one substituent selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic or polycyclic heteroaryl; R 21 , R 22 and R 23 are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. is.

[0174] In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb),

[0175] [ka]

[0176] teeth,

[0177] [ka]

[0178] In some embodiments,

[0179] [ka]

[0180] teeth,

[0181] [ka]

[0182] In some embodiments,

[0183] [ka]

[0184] teeth,

[0185] [ka]

[0186] In some embodiments,

[0187] [ka]

[0188] teeth,

[0189] [ka]

[0190] In some embodiments,

[0191] [ka]

[0192] teeth,

[0193] [ka]

[0194] In some embodiments,

[0195] [ka]

[0196] teeth,

[0197] [ka]

[0198] In some embodiments,

[0199] [ka]

[0200] teeth,

[0201] [ka]

[0202] In some embodiments,

[0203] [ka]

[0204] teeth,

[0205] [ka]

[0206] In some embodiments,

[0207] [ka]

[0208] teeth,

[0209] [ka]

[0210] In some embodiments,

[0211] [ka]

[0212] teeth,

[0213] [ka]

[0214] In some embodiments,

[0215] [ka]

[0216] teeth,

[0217] [ka]

[0218] In some embodiments,

[0219] [ka]

[0220] teeth,

[0221] [ka]

[0222] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), or (Ibb),

[0223] [ka]

[0224] teeth,

[0225] [ka]

[0226] In some embodiments,

[0227] [ka]

[0228] teeth,

[0229] [ka]

[0230] In some embodiments,

[0231] [ka]

[0232] teeth,

[0233] [ka]

[0234] In some embodiments,

[0235] [ka]

[0236] teeth,

[0237] [ka]

[0238] In some embodiments,

[0239] [ka]

[0240] teeth,

[0241] [ka]

[0242] In some embodiments,

[0243] [ka]

[0244] teeth,

[0245] [ka]

[0246] In some embodiments,

[0247] [ka]

[0248] teeth,

[0249] [ka]

[0250] is. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 5 is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 5 is CR 5 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 4 is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 4 is CR 4 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 6 is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 6 is CR 6 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 7 is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 7 is CR 7 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 5 is CR 5 and A4 is N and A 6 is CR 6 and A 7 is CR 7 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 5 is CR 5 and A 4 is CR 4 and A 6 is N and A 7 is CR 7 In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 4 , A 5 , A 6 , A 7 At least one of A is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), 4 , A 5 , A 6 , A 7 is N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 4 , A 5 , A 6 , A 7 and two of are N. In some embodiments of formula (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), A 4 , A 5 , A 6 , A 7 Three of them are N.

[0251] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is halogen, -OH, -SR 10a, -CN, amino, -NR 22 R 23 , -OR 10a , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl. 1 is —OH. In some embodiments, R 1 is -SH. In some embodiments, R 1 Ha-SR 10a In some embodiments, R 1 is -CN. In some embodiments, R 1 is amino. In some embodiments, R 1 Ha-NR 22 R 23 In some embodiments, R 1 HA-OR 10a In some embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 is substituted or unsubstituted C2-C6 alkenyl. In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkynyl. In some embodiments, R 1 is substituted or unsubstituted C1-C6 heteroalkyl. In some embodiments, R 1 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R 1 is a substituted or unsubstituted C2-C7 heterocycloalkyl.

[0252] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, or substituted or unsubstituted C3-C8 cycloalkyl. 1 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl.

[0253] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 -OH, -OR 10a , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 HA-OR 10a and R 10a is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 HA-OR 10a and R 10ais a substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is -OCH3.

[0254] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is halogen, -OH, amino, cyano, oxime, oxo, mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 and C1-C6 alkyl optionally substituted with 1 to 5 substituents selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0255] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is halogen, -OH, -OR 10a , -SR 10a , -CN, amino, -NR 22 R 23, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heteroalkyl is optionally independently selected from halogen, —OH, oxo, —NO2, CN, SH, —OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C7 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0256] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 are optionally independently selected from halogen, -OH, oxo, -NO2, CN, SH, -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C7 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 are optionally independently selected from halogen, -OH, oxo, -NO2, CN, SH, -OR 11, -SR 11 , -C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C7 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is optionally substituted with 1 to 3 substituents independently selected from halogen, —OH, oxo, NH, —NO, CN, SH, —O(C-C alkyl), —S(C-C alkyl), —C-C alkyl, C-C aminoalkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is optionally substituted with 1 to 3 substituents independently selected from halogen, OH, oxo, -NO, CN, SH, NH, -O(C-C alkyl), -S(C-C alkyl), -C-C alkyl, C-C aminoalkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C cycloalkyl, C-C heterocycloalkyl, aryl, and heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1is optionally substituted with 1 to 3 substituents independently selected from halogen, —OH, oxo, —NO, CN, NH, —O(C1-C6 alkyl), and —S(C1-C6 alkyl). In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is optionally independently substituted with 1 to 3 substituents. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is optionally substituted independently with 1 or 2 substituents.

[0257] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is halo (such as F or Cl), -CH3, -CHF2, -CF3, -CH2OH,

[0258] [ka]

[0259] , -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, or benzyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 teeth,

[0260] [ka]

[0261] In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is -CH-phenyl. In some embodiments, R 1 is —CH 2 CF 3 . In some embodiments, R 1 is -CHF2. In some embodiments, R 1 is -CH2OH.

[0262] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 teeth,

[0263] [ka]

[0264] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is a substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 is a substituted or unsubstituted C3-C5 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 teeth,

[0265] [ka]

[0266] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 is H.

[0267] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 2 is H, halogen, -OH, -OR 10b, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is H, halogen, —OH, or substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is H or halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is H. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 2 is -CH3.

[0268] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 and R 2are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered cyclic or heterocyclic ring. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 1 and R 2 together with the carbon atom to which they are attached to form cyclobutyl.

[0269] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 and R 2 together to form oxo.

[0270] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 1 and R 2 Let's get together and 12a R 12b forms a double bond to R 12a and R 12bare each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0271] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 12a and R 12b are each independently hydrogen, halogen, —OH, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0272] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12b is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0273] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12bis hydrogen or phenyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 12a is hydrogen and R 12b is hydrogen. In some embodiments, R 1 and R 2 Let's get together

[0274] [ka]

[0275] In some embodiments, R 1 and R 2 Let's get together

[0276] [ka]

[0277] Form. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 4 , R 5 , R 6 and R 7 each of which is independently selected from H, -OR 11 , -NR 22 R 23 , halogen and substituted or unsubstituted C1-C6 alkyl.

[0278] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 4 , R 5 , R 6and R 7 is independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 , R 5 , R 6 and R 7 is independently selected from H and halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 , R 5 , R 6 and R 7 is independently selected from H, halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0279] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 4 H, -OR 11 , -NR 22 R 23, halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 -OR 11 (e.g., C1-C6 alkoxy). In some embodiments, R 4 is -NR 22 R 23 (such as amino, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2). In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 is H and halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 is H, F, Cl, or Br. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 4 is H. In some embodiments, R 4is H, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl. 4 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl. In some embodiments, R 4 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. 4 is CF. In some embodiments, R 4 is methyl.

[0280] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 5 H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 5 -OR 11 (e.g., C1-C6 alkoxy). In some embodiments, R 5 is -NR 22 R 23 (such as amino, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2). In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5 is H and halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5is H, F, Cl, or Br. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 5 is H. In some embodiments, R 5 is H, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl. 5 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl. In some embodiments, R 5 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. 5 is CF. In some embodiments, R 5 is methyl.

[0281] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R6 H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 -OR 11 (e.g., C1-C6 alkoxy). In some embodiments, R 6 is -NR 22 R 23 (such as amino, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2). In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 is H and halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 is H, F, Cl, or Br. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 6is H. In some embodiments, R 6 is H, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl. 6 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl. In some embodiments, R 6 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. 6 is CF. In some embodiments, R 6 is methyl.

[0282] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 7 H, -OR 11 , -NR 22 R 23 , halogen, and substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 7 -OR 11 (e.g., C1-C6 alkoxy). In some embodiments, R 7 is -NR 22 R 23 (such as amino, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2). In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 is H and halogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R7 is H, F, Cl, or Br. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 is F. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 7 is H. In some embodiments, R 7 is H, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl. 7 is H, halogen, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl. 7 is H, halogen, —C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. 7 is CF. In some embodiments, R 7 is methyl.

[0283] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 -OR 11 , halogen, -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl.

[0284] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3is a substituted or unsubstituted monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S. In some embodiments, R 3 is a substituted or unsubstituted 5-membered monocyclic heteroaryl. In some embodiments, R 3 is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted 5-membered monocyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted 6-membered monocyclic heteroaryl.

[0285] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 teeth,

[0286] [ka]

[0287] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3teeth,

[0288] [ka]

[0289] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0290] [ka]

[0291] In some embodiments, R 3 teeth,

[0292] [ka]

[0293] In some embodiments, each R 31 is hydrogen, cyano, halogen, hydroxy, substituted or unsubstituted C 1~6 Alkyl, -OCH3, -OCD3, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6Alkoxy-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkoxy-heteroaryl and hydroxy-substituted C 1~6 Alkoxy, C 1~6 Alkoxy, Amino, Mono-C 1~6 Alkylamino and Di-C 1~6 alkylamino, and m is 0, 1, 2, or 3. In some embodiments, each R 31 are independently hydrogen, cyano, halogen, hydroxy, substituted or unsubstituted C 1~6 Alkyl, -OCH3, -OCD3, CN, NO2, -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkoxy-heteroaryl and hydroxy-substituted C 1~6 Alkoxy, C 1~6 Alkoxy, Amino, Mono-C 1~6 Alkylamino and Di-C 1~6 alkylamino; and m is 0, 1, 2, or 3.

[0294] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 can have 1, 2, 3, or 4 R's 31 and each R is a 6-membered heteroaryl substituted with 31 are independently cyano, halogen, hydroxy, substituted or unsubstituted C 1~6 Alkyl, -OCH3, -OCD3, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl, substituted or unsubstituted C 1~6Alkoxy-heteroaryl and hydroxy-substituted C 1~6 Alkoxy, C 1~6 Alkoxy, Amino, Mono-C 1~6 Alkylamino and Di-C 1~6 alkylamino; and m is 0, 1, 2, or 3.

[0295] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 teeth,

[0296] [ka]

[0297] In some embodiments, R 3 teeth,

[0298] [ka]

[0299] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 teeth,

[0300] [ka]

[0301] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0302] [ka]

[0303] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0304] [ka]

[0305] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0306] [ka]

[0307] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0308] [ka]

[0309] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R3 teeth,

[0310] [ka]

[0311] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0312] [ka]

[0313] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted bicyclic heteroaryl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a fused bicyclic heteroaryl having 8 to 10 ring atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, and S.

[0314] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3is a substituted or unsubstituted C2-C7 heterocycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is a monocyclic 5- or 6-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S.

[0315] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 teeth,

[0316] [ka]

[0317] and each R 31 are independently cyano, halogen, hydroxy, substituted or unsubstituted C 1~6 Alkyl, -OCH3, -OCD3, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkoxy-heteroaryl and hydroxy-substituted C1~6 Alkoxy, C 1~6 Alkoxy, Amino, Mono-C 1~6 Alkylamino and Di-C 1~6 alkylamino; and m is 0, 1, 2, 3, 4, or 5.

[0318] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 teeth,

[0319] [ka]

[0320] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0321] [ka]

[0322] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0323] [ka]

[0324] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0325] [ka]

[0326] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0327] [ka]

[0328] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is phenyl or naphthyl, each of which is optionally substituted. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is naphthyl.

[0329] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 is one or more R 31 Each R is replaced by31 are independently cyano, oxime, oxo, halogen, hydroxy, NO2, amino, -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21 , Mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C 1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl, and substituted or unsubstituted C 1~6In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 is one or more R 31 Each R is replaced by 31 are independently cyano, oxo, halogen, hydroxy, -SH, NO2, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl and C 1~6 heteroalkyl.

[0330] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21, halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 -OR 11 , -SR 11 , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 -OR 11 , -SR 11 , -S(=O)R 21 , -S(=O)2R 21 , -NHS(=O)2R 21 , -S(=O)2NR 22 R 23 , -C(=O)R 21 , -OC(=O)R 21 , -C(=O)OR 22 , -OC(=O)OR 22 , -C(=O)NR 22 R 23 , -OC(=O)NR 22 R 23 , -NR 22 R 23 , -NO2, -NHS(=O)2R 21 , -NR 22 C(=O)NR 22 R 23 , -NR 22 C(=O)R 21 , -NR 22 C(=O)OR 21In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 HA-OR 11 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 Ha-SR 11 is.

[0331] In some embodiments, R 3 -OR 11 , -SR 11 , -NR 22 R 23 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0332] [ka]

[0333] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0334] [ka]

[0335] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0336] [ka]

[0337] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0338] [ka]

[0339] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0340] [ka]

[0341] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0342] [ka]

[0343] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 3 teeth,

[0344] [ka]

[0345] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl.

[0346] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11is a substituted or unsubstituted C1-C6 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is a substituted or unsubstituted C3-C6 cycloalkyl.

[0347] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is a substituted C1-C4 alkyl.

[0348] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is cyano, oxime, oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, -S(=O)2(C1-C4 alkyl), mono-C 1~6 Alkylamino, Di-C 1~6 Alkylamino, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted C 2~8 Heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1~6 Alkyl, substituted or unsubstituted C1~6 Alkyl-heterocycloalkyl, substituted or unsubstituted C 1~6 Alkyl-aryl, substituted or unsubstituted C 1~6 Alkyl-heteroaryl, substituted or unsubstituted C 1~6 Alkoxy-aryl, substituted or unsubstituted C 1~6 Alkoxy-heterocycloalkyl and substituted or unsubstituted C 1~6 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R is substituted with one or more substituents selected from alkoxy-heteroaryl. 11 is substituted with one or more substituents selected from halogen, —OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 is substituted with one or more substituents selected from halogen, —OH and C3-C6 cycloalkyl.

[0349] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 is substituted with one or more F's.

[0350] In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 11 teeth,

[0351] [ka]

[0352] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0353] [ka]

[0354] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0355] [ka]

[0356] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0357] [ka]

[0358] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0359] [ka]

[0360] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0361] [ka]

[0362] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 11 teeth,

[0363] [ka]

[0364] is. In some embodiments of formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), R 21 , R 22 and R 23 are each independently selected from hydrogen and C1-C4 alkyl. 21 , R 22 and R 23are each independently selected from C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 21 is selected from hydrogen and C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 21 In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 22 is selected from hydrogen and C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 22 is hydrogen. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 23 is selected from hydrogen and C1-C4 alkyl. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), R 23 is hydrogen.

[0365] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa) (IIab), (IIba), or (IIbb), the compounds prepared in the examples below are prepared from racemic starting materials (and / or intermediates) and, as final products or intermediates, separated into individual enantiomers by chiral chromatography. Unless otherwise noted, it is understood that the absolute configurations of the separated intermediates and final compounds depicted are arbitrarily assigned and not determined.

[0366] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0367] [ka]

[0368] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0369] [ka]

[0370] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0371] [ka]

[0372] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0373] [ka]

[0374] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0375] [ka]

[0376] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0377] [ka]

[0378] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0379] [ka]

[0380] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0381] [ka]

[0382] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0383] [ka]

[0384] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0385] [ka]

[0386] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0387] [ka]

[0388] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0389] [ka]

[0390] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0391] [ka]

[0392] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0393] [ka]

[0394] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0395] [ka]

[0396] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0397] [ka]

[0398] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0399] [ka]

[0400] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0401] [ka]

[0402] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0403] [ka]

[0404] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0405] [ka]

[0406] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0407] [ka]

[0408] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0409] [ka]

[0410] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0411] [ka]

[0412] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0413] [ka]

[0414] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0415] [ka]

[0416] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0417] [ka]

[0418] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0419] [ka]

[0420] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0421] [ka]

[0422] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0423] [ka]

[0424] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0425] [ka]

[0426] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0427] [ka]

[0428] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0429] [ka]

[0430] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0431] [ka]

[0432] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0433] [ka]

[0434] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0435] [ka]

[0436] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0437] [ka]

[0438] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0439] [ka]

[0440] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0441] [ka]

[0442] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0443] [ka]

[0444] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0445] [ka]

[0446] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0447] [ka]

[0448] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0449] [ka]

[0450] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0451] [ka]

[0452] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0453] [ka]

[0454] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0455] [ka]

[0456] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0457] [ka]

[0458] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0459] [ka]

[0460] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0461] [ka]

[0462] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0463] [ka]

[0464] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0465] [ka]

[0466] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0467] [ka]

[0468] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0469] [ka]

[0470] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0471] [ka]

[0472] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0473] [ka]

[0474] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0475] [ka]

[0476] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0477] [ka]

[0478] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0479] [ka]

[0480] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0481] [ka]

[0482] In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0483] [ka]

[0484] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0485] [ka]

[0486] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0487] [ka]

[0488] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0489] [ka]

[0490] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0491] [ka]

[0492] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0493] [ka]

[0494] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0495] [ka]

[0496] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0497] [ka]

[0498] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0499] [ka]

[0500] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0501] [ka]

[0502] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0503] [ka]

[0504] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0505] [ka]

[0506] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0507] [ka]

[0508] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0509] [ka]

[0510] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0511] [ka]

[0512] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0513] [ka]

[0514] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0515] [ka]

[0516] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0517] [ka]

[0518] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0519] [ka]

[0520] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0521] [ka]

[0522] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0523] [ka]

[0524] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0525] [ka]

[0526] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0527] [ka]

[0528] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0529] [ka]

[0530] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0531] [ka]

[0532] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0533] [ka]

[0534] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0535] [ka]

[0536] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0537] [ka]

[0538] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0539] [ka]

[0540] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0541] [ka]

[0542] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0543] [ka]

[0544] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0545] [ka]

[0546] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0547] [ka]

[0548] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0549] [ka]

[0550] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0551] [ka]

[0552] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0553] [ka]

[0554] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0555] [ka]

[0556] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0557] [ka]

[0558] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0559] [ka]

[0560] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0561] [ka]

[0562] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0563] [ka]

[0564] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0565] [ka]

[0566] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0567] [ka]

[0568] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0569] [ka]

[0570] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0571] [ka]

[0572] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0573] [ka]

[0574] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0575] [ka]

[0576] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0577] [ka]

[0578] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0579] [ka]

[0580] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0581] [ka]

[0582] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0583] [ka]

[0584] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0585] [ka]

[0586] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0587] [ka]

[0588] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0589] [ka]

[0590] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0591] [ka]

[0592] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), the compounds described herein are

[0593] [ka]

[0594] or a pharmaceutically acceptable salt or solvate thereof.

[0165] Non-limiting examples of compounds described herein are the compounds shown in Table 1 and pharmaceutically acceptable salts or solvates thereof.

[0595] [Table 1-1]

[0596]

Table 1-2

[0597]

Table 1-3

[0598]

Table 1-4

[0599]

Table 1-5

[0600]

Table 1-6

[0601]

Table 1-7

[0602]

Table 1-8

[0603]

Table 1-9

[0604]

Table 1-10

[0605]

Table 1-11

[0606] [Table 1-12]

[0607] [Table 1-13]

[0608] [Table 1-14]

[0609] [Table 1-15]

[0610] [Table 1-16]

[0611] [Table 1-17]

[0612] [Table 1-18]

[0613] [Table 1-19]

[0614] [Table 1-20]

[0615] In some embodiments, the compounds described herein are in racemic form. For example,

[0616] [ka]

[0617] Racemic forms of compounds such as

[0618] [ka]

[0619] In some embodiments, provided herein are compounds in cis and racemic form. For example, compound 7 in cis and racemic form can be

[0620] [ka]

[0621] In some embodiments, provided herein are compounds in trans and racemic form. For example, compound 7 in trans and racemic form is

[0622] [ka]

[0623] As another example,

[0624] [ka]

[0625] Racemic forms of compounds such as

[0626] [ka]

[0627] It may include two stereoisomers, including: In some embodiments, described herein are compounds having a structure selected from Table 1 and existing in their racemic form. In some embodiments, described herein are compounds having a structure selected from Table 1 and existing in their cis and racemic forms. In some embodiments, described herein are compounds having a structure selected from Table 1 and existing in their trans and racemic forms. In some embodiments, described herein are compounds having a structure selected from Table 1 and existing in their trans and racemic forms. One of ordinary skill in the art will appreciate that all stereoisomers and racemic forms of the compounds disclosed in Table 1 are encompassed by the present disclosure.

[0628] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) is not racemic. In some embodiments, a compound of the present disclosure is substantially free of other isomers. In some embodiments, a compound is a single isomer substantially free of other isomers. In some embodiments, a compound contains 25% or less of other isomers. In some embodiments, a compound contains 20% or less of other isomers. In some embodiments, a compound contains 15% or less of other isomers. In some embodiments, a compound contains 10% or less of other isomers. In some embodiments, a compound contains 5% or less of other isomers. In some embodiments, a compound contains 1% or less of other isomers. In some embodiments, a compound of the present disclosure has at least 75% stereochemical purity. In some embodiments, a compound has at least 80% stereochemical purity. In some embodiments, a compound has at least 85% stereochemical purity. In some embodiments, a compound has at least 90% stereochemical purity. In some embodiments, a compound has at least 95% stereochemical purity. In some embodiments, the compound has at least 96% stereochemical purity. In some embodiments, the compound has at least 97% stereochemical purity. In some embodiments, the compound has at least 98% stereochemical purity. In some embodiments, the compound has at least 99% stereochemical purity. In some embodiments, the compound is stereochemically pure.

[0629]

[0169] Included in this disclosure are salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present invention that have sufficiently acidic, sufficiently basic, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form salts with a suitable counterion, e.g., a halide such as bromide, chloride, or fluoride, especially bromide.

[0630] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E, and tautomeric forms.

[0631]

[0171] "Tautomer" refers to a molecule capable of a proton shift from one atom of the molecule to another atom of the same molecule. The compounds presented herein, in certain embodiments, exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of the tautomers exists. The exact ratio of the tautomers depends on several factors, including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0632] [ka]

[0633]

[0172] The compounds disclosed herein may, in some embodiments, be 2 H, 3 H, 11 C. 13 C and / or 14 The compound is used in different enriched isotopic forms, enriched in C content. In one specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus prolonging the duration of action of the drug.

[0634]

[0173] Unless otherwise stated, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0635] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br and 125 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0636] In some embodiments of the compounds disclosed herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , R 10a , R 10b , R 12a , R 12b , R 21 , R 22 , R 23 and R 31 One or more of the groups contains a percentage of deuterium that is higher than the natural abundance of deuterium.

[0637] In some embodiments of the compounds disclosed herein, the following group R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10a , R 10b , R 12a , R 12b , R 21 , R 22 , R 23 and R 31 In one or more of, one or more hydrogens are replaced with one or more deuteriums.

[0638] In some embodiments of the compounds disclosed herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10a , R 10b , R 12a , R 12b , R 21 , R 22 , R 23 and R 31 The abundance of deuterium in each of is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogens and deuteriums.

[0639]

[0178] In some embodiments of the compounds disclosed herein, one or more hydrogens of ring Q are replaced with one or more deuteriums. In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is replaced by an H atom. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0640] Deuterium-substituted compounds are synthesized using a variety of methods, as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0641] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to result in the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0642]

[0182] The compounds of the present invention also include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity.

[0643]

[0183] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. Unless absolute stereochemistry is specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, the disclosure of which is incorporated herein by reference.) Stereoisomers can also be obtained by stereoselective synthesis.

[0644] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may also be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. Furthermore, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0645] In certain embodiments, a compound or a salt of a compound may be a prodrug, for example, where a hydroxyl in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted into the pharmaceutical agents of the present disclosure under physiological conditions. One method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity of a host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present disclosure.

[0646]

[0186] Prodrug forms of the compounds described herein are included within the scope of the claims, where the prodrug is metabolized in vivo to produce a compound described herein. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0647]

[0187] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, a prodrug may be bioavailable by oral administration, whereas the parent drug is not. A prodrug may serve to enhance the cell permeability of a compound compared to the parent drug. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues or increase drug retention inside cells.

[0648] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Drug Design, American Pharmaceutical Association, the disclosures of which are incorporated herein in their entirety. (See Edward B. Roche, Bioreversible Carriers, in Bioreversible Carriers and Pergamon Press, 1987). According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0649]

[0189] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0650] C. Pharmaceutical Compositions In certain embodiments, provided herein are compositions comprising a therapeutically effective amount of any compound or salt (also referred to herein as a "pharmaceutical agent") of any one of Formulas (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa), (IIab), (IIba), and (IIbb).

[0651]

[0191] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of pharmaceutical agents into pharmaceutical preparations. Appropriate formulations depend on the selected route of administration. Overviews of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999).

[0652] The compositions and methods of the present disclosure can be utilized to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or pharmaceutical agent is preferably administered as a pharmaceutical composition, for example, comprising the pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive routes of administration, such as injection or implantation, which avoid transport or diffusion through epithelial barriers, the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of a unit dosage such as a tablet, capsule, granule, lyophilized product for reconstitution, powder, solution, syrup, suppository, injection, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0653] Pharmaceutically acceptable excipients can include, for example, physiologically acceptable agents that act to stabilize, increase solubility, or enhance absorption of compounds such as pharmaceutical agents. Examples of such physiologically acceptable agents include carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, into which, for example, a compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0654] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally, e.g., as drenches, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, or pastes for application to the tongue, such as in aqueous or non-aqueous solutions or suspensions; by absorption through the oral mucosa, e.g., sublingually; by anal, rectal, or vaginal route, e.g., as pessaries, creams, or foams; parenterally, e.g., intramuscular, intravenous, subcutaneous, or intrathecal route, e.g., as a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, e.g., as a patch applied to the skin; and topically, e.g., as a cream, ointment, or spray applied to the skin, or as eye drops. The compounds may also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water.

[0655]

[0195] Pharmaceutical compositions may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions, such as microemulsions. The excipients described herein are exemplary and in no way limiting. An effective amount or therapeutically effective amount refers to the amount of one or more pharmaceutical agents administered to a subject, either in a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0656]

[0196] Subjects may generally be monitored for therapeutic effectiveness using assays and methods appropriate for the condition being treated, which assays will be familiar to those of skill in the art and are described herein. The pharmacokinetics of a pharmaceutical agent or one or more metabolites thereof administered to a subject can be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, e.g., blood, blood fractions, e.g., serum and / or urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art for detecting pharmaceutical agents and described herein may be used to measure the level of the pharmaceutical agent or metabolite during the course of treatment.

[0657] The dosage of the pharmaceutical agents described herein for treating a disease or disorder may depend on the subject's condition, i.e., the stage of the disease, the severity of symptoms caused by the disease, general health, as well as age, sex, and weight, as well as other factors apparent to those skilled in the medical arts. Pharmaceutical compositions may be administered in a manner appropriate to the disease being treated, as determined by those skilled in the medical arts. In addition to the factors described herein and above related to the use of pharmaceutical agents for treating a disease or disorder, the appropriate duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted depending on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Optimal dosages of pharmaceutical agents may generally be determined using experimental models and / or clinical trials. Optimal dosages may depend on the subject's body mass, weight, or blood volume. It is usually preferable to use the minimum dosage sufficient to provide effective treatment. The design and implementation of preclinical and clinical trials of the pharmaceutical agents described herein, including those administered for prophylactic benefit, is well within the skill of those skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dosage of each pharmaceutical agent may be different, e.g., lower than when either agent is administered alone as monotherapy. In certain specific embodiments, the combination of two pharmaceutical agents may have a synergistic or additive effect, allowing for the use of lower dosages than when either agent is administered alone. The amount of pharmaceutical agent that can be administered daily may be, for example, about 0.01 mg / kg to 100 mg / kg, e.g., about 0.1 to 1 mg / kg, about 1 to 10 mg / kg, about 10 to 50 mg / kg, or about 50 to 100 mg / kg of body weight. In other embodiments, the amount of pharmaceutical agent that can be administered daily may be about 0.01 mg / kg to 1000 mg / kg, about 100 to 500 mg / kg, or about 500 to 1000 mg / kg of body weight. The optimal dosage per day or per treatment course may vary depending on the disease or disorder being treated, the route of administration, and the treatment regimen.

[0658] Pharmaceutical compositions containing pharmaceutical agents can be formulated in a manner suitable for the delivery method using techniques routinely practiced in the art. The composition can be in the form of a solid, e.g., a tablet, a capsule, a semisolid, e.g., a gel, a liquid, or a gas, e.g., an aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0659] Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient. Alternatively, the compositions described herein can be formulated as a lyophilizate. The compositions described herein can be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions to solubilize and / or dilute the pharmaceutical agent of the composition upon administration. In other embodiments, the pharmaceutical agent can be encapsulated in liposomes using techniques known and practiced in the art. In certain specific embodiments, the pharmaceutical agent is not formulated in liposomes for application to stents used to treat arteries that are severely, but not completely, blocked. The pharmaceutical composition can be formulated for any suitable administration method described herein and in the art.

[0660] For example, pharmaceutical compositions for oral administration, or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods may be in liquid form. Liquid pharmaceutical compositions may contain, for example, one or more of the following: a sterile diluent, such as water, saline, preferably normal saline, Ringer's solution, isotonic sodium chloride, fixed oils that can function as solvents or suspending media, polyethylene glycol, glycerin, propylene glycol, or other solvents; antibacterial agents; antioxidants; chelating agents; buffers, and tonicity adjusters such as sodium chloride or dextrose. Parenteral compositions can be packaged in glass or plastic ampoules, disposable syringes, or multi-dose vials. Normal saline is preferably used, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, liquid pharmaceutical compositions can be applied to the eye in the form of eye drops for the treatment of ophthalmic conditions or diseases. Liquid pharmaceutical compositions may be delivered orally.

[0661]

[0201] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with suitable additives for preparing tablets, powders, granules, or capsules, and, if desired, diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. The pharmaceutical agent can be formulated with a buffer and / or an enteric coating to protect the compound from the low pH of the gastric environment. The pharmaceutical agent included in the pharmaceutical composition can be formulated for oral delivery, for example, in a liquid, solid, or semisolid formulation and / or using an enteric coating, along with a flavoring agent.

[0662] Pharmaceutical compositions containing any one of the pharmaceutical agents described herein may be formulated for sustained or extended release, also known as timed or controlled release. Such compositions are generally prepared using well-known techniques and may be administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlling membrane. Excipients for use within such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. The amount of pharmaceutical agent contained within a sustained-release formulation depends on the site of implantation, the rate and expected duration of release, and the nature of the condition, disease, or disorder to be treated or prevented.

[0663] In certain embodiments, pharmaceutical compositions containing pharmaceutical agents are formulated for transdermal, intradermal, or topical administration. The compositions can be administered as powders / talc or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, pastes, using syringes, bandages, transdermal patches, inserts, or syringe-like applicators. They are preferably in the form of controlled-release or sustained-release formulations administered topically, or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active composition can also be delivered by iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0664] Pharmaceutical compositions containing pharmaceutical agents can be formulated as emulsions for topical application. Emulsions contain one liquid dispersed in a bulk of a second liquid. Emulsions can be oil-in-water or water-in-oil emulsions. Either or both of the oil and aqueous phases can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase can also contain other oily, pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application can also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or moisturizing agent.

[0665] Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Liquid sprays can be delivered from pressurized packs, for example, via specially shaped closures. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems can be semisolid emulsions, microemulsions, or foam emulsion systems.

[0666]

[0206] In some embodiments, the pharmaceutical agents described herein can be formulated as inhalants. Inhalation methods can deliver drugs directly to the respiratory tract. Pharmaceutical agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. Pharmaceutical agents can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are optionally nebulized to a particle size that is preferentially deliverable to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and ultimately to the parenchymal tissues.

[0667] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device such as a jet, vibrating porous plate, or ultrasonic nebulizer, and are preferably selected to enable the formation of aerosol particles having a mass median mean diameter of preferably 1-5 μm. Furthermore, the formulations preferably have a balanced osmotic ionic strength and chloride concentration, and a minimum aerosolizable volume capable of delivering an effective dose of the pharmaceutical agent. Furthermore, the aerosolized formulations preferably do not adversely affect airway function or cause undesirable side effects.

[0668] Aerosolization devices suitable for administering the aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers, and energized dry powder inhalers, which can nebulize the formulations preferentially into aerosol particle sizes in the 1-5 μm size range. Preferential, in this application, means that at least 70%, but preferably more than 90%, of the total aerosol particles generated are within the 1-5 μm range. Jet nebulizers function by breaking up a liquid solution into aerosol droplets using air pressure. Vibrating porous plate nebulizers function by forcing solvent droplets through a porous plate using an acoustic vacuum created by a rapidly vibrating porous plate. Ultrasonic nebulizers function by shearing a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating perforated plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, UK), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0669] In some embodiments, the pharmaceutical agent may be formulated with an oleaginous base or ointment to form a semisolid composition having a desired shape. In addition to the pharmaceutical agent, these semisolid compositions may contain a solubilizing and / or suspending bactericide, a preservative, and / or a buffer system. Petrolatum components that may be included may be any paraffin ranging in viscosity from mineral oil to paraffin wax incorporating isobutylene, colloidal silica, or stearates. Absorbent bases may be used with the oleaginous system. Additives may include, alone or in combination, cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophilic-lipophilic balance) emulsifiers, and various ionic and nonionic surfactants.

[0670] Controlled or sustained-release transdermal or topical formulations can be achieved by adding time-release additives, such as polymeric structures, matrices, and the like, available in the art. For example, the compositions may be administered using hot-melt extrusions, such as bioadhesive hot-melt extruded films. The formulations can include cross-linked polycarboxylic acid polymer formulations. The cross-linking agent can be present in an amount that provides sufficient adhesiveness to allow the system to remain attached to the target epithelial or endothelial cell surface for a sufficient time to allow the desired release of the compound.

[0671] The insert, transdermal patch, bandage, or article can include a polymer blend or coating that provides a constant rate of release of the pharmaceutical agent over an extended period of time. In some embodiments, the article, transdermal patch, or insert includes a water-soluble pore-forming agent, such as polyethylene glycol (PEG), that can be blended with a water-insoluble polymer to increase the durability of the insert and extend the release of the active ingredient.

[0672]

[0212] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers may be useful for administration to sites where release can be achieved using pH changes. These rate-controlling polymers can be applied using a continuous coating film during the spray and dry process with the active compound. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient that are compressed to form a solid biodegradable insert.

[0673] Polymer formulations can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained-release gels and compounds can be incorporated into polymer matrices, such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. Microparticles can be microspheres, with the core being of a different material than the polymer shell. Alternatively, the polymer can be cast as a thin slab or film, a powder produced by milling or other standard techniques, or a gel, such as a hydrogel. Polymers can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. Matrices can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0674]

[0214] Kits containing one or more unit doses of the agents described herein, usually oral or injectable doses, are provided. Such kits can include a container containing the unit dose, an informational package insert describing the use of the drug in treating disease and associated benefits, and optionally an apparatus or device for delivering the composition. D. Treatment Method

[0215] The compounds described herein can be used in the preparation of a medicament for the prevention or treatment of a disease or condition. Additionally, a method for treating any of the diseases or conditions described herein in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0675]

[0216] Compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0676] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amounts also depend on the patient's health, weight, and the like. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0677]

[0218] If the patient's condition does not improve, at the physician's discretion, the compound may be administered chronically, i.e., for an extended period of time, including throughout the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0678]

[0219] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, can be reduced symptomatically, to a level at which the improved disease, disorder, or condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0679] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the characteristics (e.g., body weight) of the subject or host requiring treatment, and the like, but can nevertheless be determined in an art-recognized manner depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses utilized in adult human treatment will typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dose may conveniently be presented as a single dose or as divided doses administered simultaneously (or closely), or at appropriate intervals, e.g., as two, three, four, or more sub-doses per day.

[0680]

[0221] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of a precise dosage amount. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-resealable containers. Alternatively, multi-dose resealable containers may be used, in which case it is common to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, including, but not limited to, ampoules, or multi-dose containers with an added preservative.

[0681] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including LD 50 (a dose lethal to 50% of the population) and ED 50 These include, but are not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably adjusted to achieve an ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form and route of administration utilized.

[0682] In one aspect, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a brain / blood AUC of at most about 0.0001, 0.001, 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 5, or 10. The brain permeability values ​​and characteristics of the compounds described herein can be determined by any suitable method known in the art, such as in vivo or in vitro assays, e.g., Caco-2 permeability assays and MDR1-MDCK assays.

[0683] Glutaminyl-peptide cyclotransferase-like proteins (QPCTLs), located in an organelle called the Golgi apparatus, have been identified as key regulators of the CD47 / SIRPα axis. CD47 expression is frequently observed on cancer cells in both hematological malignancies and solid tumors, including NHL, acute myeloid leukemia, myelodysplastic syndromes, and glioblastoma, gastric cancer, breast cancer, colon cancer, hepatocellular carcinoma, and prostate cancer. Cancer cells use CD47, mediated by SIRPα, to avoid detection by the immune system and subsequent destruction by macrophages. The N-terminus of the CD47 protein contains a pyroglutamic acid residue that is essential for creating a high-affinity SIRPα binding site, and this modification immediately following protein synthesis has been shown to depend on the QPCTL protein. Inhibition of QPCTLs by pharmacological tools or bioengineered knockout methods has been shown to result in reduced or lost binding between CD47 and SIRPα and increased antibody-dependent cellular phagocytosis and neutrophil-induced cytotoxicity.

[0684] In addition to the involvement of the CD47 / SIRPα axis, QPCTLs also pyroglutamate the CC motif chemokine ligand proteins CCL2, CCL7, CCL8, and CCL13, which are ligands for the chemokine receptor CCR2, which directs the migration of myeloid cell lineages, including monocytes / macrophages and dendritic cells. Modification of CCL chemokine family members by QPCTLs increases the stability of these chemokines against degradation and enhances CCR2 activation and signaling. The CCL2 / CCR2 axis is involved in cancer cell survival, migration, and metastasis through the recruitment of immune cells to the tumor microenvironment. Therefore, downregulation of CCL2 / CCR2 signaling by inhibition of QPCLTs can be used to attenuate the biological function of CCL2 / CCR2 signaling in cancer pathogenesis.

[0685]

[0226] In one aspect, the present disclosure provides a method for modulating glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0686]

[0227] In one aspect, the present disclosure provides a method for inhibiting glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0687]

[0228] In one aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0688]

[0229] In one aspect, the present disclosure provides a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or condition is associated with aberrant glutaminyl-peptide cyclotransferase-like protein (QPCTL) activity. In some embodiments, the disease or condition associated with aberrant QPCTL activity is cancer.

[0689]

[0230] In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), multiple myeloma (MM), or myelodysplastic syndrome (MDS).

[0690] In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is non-Hodgkin's lymphoma (NHL). In some embodiments, the cancer is Hodgkin's lymphoma (HL). In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is myelodysplastic syndrome (MDS).

[0691] In some embodiments, the cancer is a solid cancer or a metastatic cancer. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a metastatic cancer.

[0692]

[0233] In some embodiments, the cancer is skin cancer, eye cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.

[0693] In certain embodiments, the present invention provides a method of treating or preventing a disease, condition, or disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of the embodiments of the present invention, or a pharmaceutically acceptable salt thereof. The disease, condition, or disease may be selected from the group consisting of colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myelogenous leukemia, cancer metastasis, fibrosis, and psychiatric disorders.

[0694]

[0235] In one aspect, described herein are methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, wherein the disease or condition is a disease involving the innate immune system. In some embodiments, the disease is atherosclerosis, a fibrotic disease, ischemia-reperfusion injury, or an infection caused by a pathogen. In some embodiments, the disease is a fibrotic disease selected from liver fibrosis, pulmonary fibrosis, renal fibrosis, and scleroderma.

[0695] In one aspect, described herein are methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, wherein the disease or condition is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is diabetic nephropathy. Diabetic nephropathy, a complication of diabetes and a major cause of CKD, is typically characterized by damage to the capillaries supplying the kidney glomeruli, resulting in decreased kidney filtration efficiency and a progressive loss of kidney function that can lead to end-stage renal disease, in which the patient requires dialysis or a kidney transplant. In some embodiments, the diabetic nephropathy is caused by type 2 diabetes or type 2 diabetes. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS). FSGS is a chronic, progressive kidney disease characterized by scarring (sclerosis) of the glomeruli. Scarring can be caused by infection, drugs such as anabolic steroids, or systemic diseases such as diabetes, HIV infection, sickle cell disease or lupus.

[0696] In one aspect, described herein is a method of treating a disease or condition in a subject in need thereof, comprising administering a compound of Formula (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa)(IIab), (IIba), or (IIbb), a stereoisomer thereof, or a salt or solvate thereof. In one aspect, described herein is a method of treating a disease or condition in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, wherein the disease or condition is selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infection, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathogenic psychotic states, schizophrenia, infertility, and the like. , neoplasms, inflammatory host responses, cancer, malignant metastasis, melanoma, psoriasis, humoral and cell-mediated immune response disorders, endothelial leukocyte adhesion and migration processes, food intake disorders, sleep-wake disorders, homeostatic dysregulation of energy metabolism, autonomic dysfunction, hormone balance disorders or fluid regulation disorders, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, familial British dementia, familial Danish dementia, neurodegeneration in Down syndrome, Huntington's disease, rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis. In some embodiments, the disease or condition is chronic kidney disease (CKD). In some embodiments, the disease or condition is an immuno-oncology disease. In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is a kidney disease. In some embodiments, the disease or condition is FSGS. In some embodiments, the FSGS is primary FSGS. In some embodiments, the FSGS is secondary FSGS. In some embodiments, the FSGS is hereditary FSGS. In some embodiments, the underlying cause of the FSGS cannot be determined.In some embodiments, the disease or condition is diabetic nephropathy. In some embodiments, the disease or condition is stage 1 diabetic nephropathy. In some embodiments, the disease or condition is stage 2 diabetic nephropathy. In some embodiments, the disease or condition is stage 4 diabetic nephropathy. In some embodiments, the disease or condition is stage 4 diabetic nephropathy. In some embodiments, the subject has diabetes. In some embodiments, the subject has type I diabetes. In some embodiments, the subject has type II diabetes.

[0697] In some embodiments, the method includes administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a monoclonal antibody. In some embodiments, the monoclonal antibody is an anti-CD20 antibody. In some embodiments, the monoclonal antibody is selected from edrecolomab, rituximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab, cetuximab, bevacizumab, and trastuzumab. In some embodiments, the second therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the second therapeutic agent is edrecolomab. In some embodiments, the second therapeutic agent is rituximab. In some embodiments, the second therapeutic agent is gemtuzumab ozogamicin. In some embodiments, the second therapeutic agent is alemtuzumab. In some embodiments, the second therapeutic agent is ibritumomab tiuxetan. In some embodiments, the second therapeutic agent is tositumomab. In some embodiments, the second therapeutic agent is cetuximab. In some embodiments, the second therapeutic agent is bevacizumab. In some embodiments, the second therapeutic agent is trastuzumab.

[0698] In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or cemiplimab. [Example]

[0699] The following examples are offered to illustrate, but not to limit, the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0700]

[0241] The following synthetic schemes are provided for illustrative purposes and not for limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that those skilled in the art may be able to make these compounds by analogous methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can make compounds in a similar manner to those described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0701] Compounds and salts of Formulas (I), (Ia), (Ib), (Iaa), (Iab), (Iba), (Ibb), (II), (IIa), (IIb), (IIaa), (IIab), (IIba), and (IIbb) can be synthesized according to one or more exemplary schemes herein and / or techniques known in the art. Materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents utilized for illustrative purposes. Various steps are described and depicted in the synthetic schemes below, although in some cases, steps may occur in a different order than shown below. The numbering or R groups in each scheme do not necessarily match those in the claims or other schemes or tables herein.

[0702]

[0243] As used herein in the examples and specification, the same structure may be given different numbering in different examples and / or sections of the specification. Example 1 Synthesis of Compounds 7A and 7B

[0245]

[0703] [ka]

[0704] Step 1: General Procedure for the Preparation of 2,6-Difluoro-4-(3-hydroxypropoxy)benzonitrile To a solution of 2,6-difluoro-4-hydroxybenzonitrile (5.00 g, 32.2 mmol, 1 equiv.) and K2CO3 (6.68 g, 48.3 mmol, 1.5 equiv.) in DMF (10 mL) was added 3-bromopropan-1-ol (6.72 g, 48.4 mmol, 4.36 mL, 1.5 equiv.). The mixture was stirred at 35 °C for 12 h. The reaction mixture was filtered. The filtrate was diluted with EtOAc (200 mL), washed with saturated NaCl (50 mL x 4), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 120 g, eluting with a 0-37% ethyl acetate / petroleum ether gradient at 85 mL / min). The target compound (5.5 g, 23.20 mmol, 71.98% yield) was obtained as a colorless oil.

[0705]

[0248] LCMS: Retention time: 0.834 min, (M+H) + =214.1, 10~80AB_2min_Agilent.

[0249] 1 HNMR: (400 MHz, DMSO-d6) δ = 7.11 - 7.05 (m, 2H), 4.61 (t, J = 5.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.57 - 3.49 (m, 2H), 1.90 - 1.82 (m, 2H).

[0706] Step 2: General Procedure for the Preparation of 2,6-Difluoro-4-(3-oxopropoxy)benzonitrile To a solution of 2,6-difluoro-4-(3-hydroxypropoxy)benzonitrile (1.00 g, 4.69 mmol, 1 equiv) in DCM (30 mL) was added DMP (2.98 g, 7.04 mmol, 2.18 mL, 1.5 equiv). The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaSO (30 mL). The organic layer was washed with aqueous NaHCO (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 20 g, eluting with a 0-30% ethyl acetate / petroleum ether gradient at 20 mL / min). The target compound (500 mg, 2.11 mmol, 44.92% yield) was obtained as a yellow solid.

[0707]

[0252] LCMS: Retention time: 0.791 min, (M+H)=212.1, 10~80AB_2 min_Agilent. Step 3: General Procedure for the Preparation of 4-(3,3-Difluoropropoxy)-2,6-difluorobenzonitrile To a solution of 2,6-difluoro-4-(3-oxopropoxy)benzonitrile (310 mg, 1.47 mmol, 1 equiv) in DCM (10 mL) at 0° C. under N was added DAST (473 mg, 2.94 mmol, 388 μL, 2 equiv). The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched by the addition of water (10 mL), diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 4 g, eluting with a 0–20% ethyl acetate / petroleum ether gradient at 20 mL / min). The target compound (120 mg, 515 μmol, yield 35.06%) was obtained as a colorless oil.

[0708] LCMS: Retention time: 1.005 min, (M+H) = 234.1, 10-80AB_2 min_220 and 254.

[0256] 1 HNMR: (400 MHz, DMSO-d6) δ = 7.16 - 7.14 (m, 1H), 7.13 - 7.11 (m, 1H), 6.40 - 6.07 (m, 1H), 4.27 (t, J = 6.0 Hz, 2H), 2.43 - 2.28 (m, 2H).

[0709] Step 4: General Procedure for the Preparation of 4-(3,3-Difluoropropoxy)-2,6-difluorobenzaldehyde To a solution of 4-(3,3-difluoropropoxy)-2,6-difluorobenzonitrile (9.50 g, 40.7 mmol, 1 equiv) in DCM (100 mL) at −78° C. under N was added DIBAL-H (1 M, 57.0 mL, 1.4 equiv). The mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched by the addition of 200 mL of saturated aqueous potassium sodium 2,3-dihydroxysuccinate and extracted with DCM (150 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 110 g, eluting with a 0–15% ethyl acetate / petroleum ether gradient at 85 mL / min). The target compound (5.1 g, 20.82 mmol, 51.11% yield) was obtained as a white solid.

[0710] LCMS: Retention time: 1.080 min, (M+H) = 237.2, 10-80AB_2 min_220 and 254.

[0260] 1HNMR: (400 MHz, DMSO-d6) δ = 10.07 (s, 1H), 6.96 - 6.88 (m, 2H), 6.43 - 6.06 (m, 1H), 4.27 (t, J = 6.0 Hz, 2H), 2.41 - 2.29 (m, 2H).

[0711] Step 5: General procedure for the preparation of 1-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanimine To a solution of 4-(3,3-difluoropropoxy)-2,6-difluorobenzaldehyde (1.17 g, 4.94 mmol, 1 equiv.) in toluene (50 mL) was added 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-amine (1.30 g, 4.94 mmol, 1 equiv.). The mixture was stirred at 120 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 20 g, eluent: 0-100% ethyl acetate / petroleum ether gradient at 25 mL / min). The target compound (1.80 g, 3.74 mmol, 75.74% yield) was obtained as an orange oil.

[0712]

[0263] 1HNMR: (400 MHz, DMSO-d6) δ = 8.63 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 9.6 Hz, 1H), 7.67 (dd, J = 6.4, 8.4 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.24 - 7.18 (m, 1H), 6.97 - 6.89 (m, 2H), 6.46 - 6.05 (m, 1H), 5.65 (d, J = 7.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H), 3.57 - 3.46 (m, 2H), 2.43 - 2.31 (m, 2H), 0.84 (t, J = 8.0 Hz, 2H), -0.09 (d, J = 3.6 Hz, 9H).

[0713] Step 6: General procedure for the preparation of 4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one To a solution of Zn (54.3 mg, 831 μmol, 2 equiv) in toluene (20 mL) under Ar, TMS-Cl (31.6 mg, 291 μmol, 36.9 μL, 0.7 equiv) was added. The mixture was stirred under reflux (120° C.) for 0.25 h. After cooling to 25° C., compound 7.5 was then obtained. * Compound 7.6A (128 mg, 706 μmol, 92.0 μL, 1.7 equiv.) and Compound 7.5 (200 mg, 415 μmol, 1 equiv.) were added. The resulting mixture was refluxed (120 °C) for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 4 g, eluent: 0-75% ethyl acetate / petroleum ether gradient at 20 mL / min). A mixture of Compound 7.6 and Compound 7.6A (180 mg, 334.81 μmol, 80.61% yield) was obtained as a yellow solid.

[0714] LCMS: Retention time: 1.191 min, (M+H) = 538.3, 10-80AB_2 min_220 and 254. Step 7: General procedure for the preparation of 1-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-3-methylazetidin-2-one To a solution of compound 7.6 (180 mg, 335 μmol, 1 equiv) was added TBAF (1 M, 4.50 mL, 13.4 equiv). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. To the residue was added a solution of TFA (2.77 g, 24.3 mmol, 1.8 mL, 72.6 equiv) and DCM (0.2 mL). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40 mm×3 um; mobile phase: [water (0.05% NH3H2O)-ACN]; B%: 33%-63%, 8 min). Compound 7 (30.72 mg, 71.55 μmol, 21.37% yield) was obtained as a white solid.

[0715] LCMS: Retention time: 0.943 min, (M+H) = 408.2, 10-80AB_2 min_220 and 254.

[0270] 1 HNMR: (400 MHz, DMSO-d6) δ = 12.61 - 12.24 (m, 1H), 8.23 ​​- 8.06 (m, 1H), 7.62 - 7.01 (m, 3H), 6.92 - 6.70 (m, 2H), 6.37 - 6.02 (m, 1H), 5.64 - 5.01 (m, 1H), 4.24 - 4.05 (m, 2H), 3.92 - 3.46 (m, 1H), 2.35 - 2.19 (m, 2H), 1.43 - 0.96 (m, 3H).

[0716] Step 8: General procedure for the preparation of (3S,4R)-1-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-3-methylazetidin-2-one (Compound 7A) and (3R,4R)-1-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-3-methylazetidin-2-one (Compound 7B) Compound 7 was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 30% to 30%, min). Compound 7A (17.80 mg, 41.24 μmol, yield 7.00%) was obtained as a white solid, and compound 7B (10.63 mg, 24.15 μmol, yield 4.10%) was obtained as a white solid.

[0717]

[0273] Compound 7A: SFC: Retention time: 5.117 minutes. LCMS: Retention time: 0.805 min, (M+H)=408.1, 5~95AB_220 and 254_Agilent. 1 HNMR: (400 MHz, DMSO-d6) δ = 12.55 - 12.29 (m, 1H), 8.20 - 8.10 (m, 1H), 7.59 - 7.45 (m, 1H), 7.40 - 7.27 (m, 1H), 7.26 - 7.00 (m, 1H), 6.87 - 6.76 (m, 2H), 6.37 - 6.03 (m, 1H), 5.09 - 5.04 (m, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.57 - 3.44 (m, 1H), 2.33 - 2.20 (m, 2H), 1.40 (d, J = 7.2 Hz, 3H).

[0718]

[0274] Compound 7B: SFC: Retention time: 6.271 minutes. LCMS: Retention time: 0.802 min, (M+H)=408.1, 5~95AB_220 and 254_Agilent. 1HNMR: (400 MHz, DMSO-d6) δ = 12.54 - 12.15 (m, 1H), 8.18 - 8.11 (m, 1H), 7.61 - 7.43 (m, 1H), 7.42 - 7.31 (m, 1H), 7.30 - 7.03 (m, 1H), 6.96 - 6.59 (m, 2H), 6.39 - 6.03 (m, 1H), 5.59 (d, J = 6.0 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.92 - 3.83 (m, 1H), 2.35 - 2.24 (m, 2H), 1.00 (d, J = 7.2 Hz, 3H.

[0719] Example 2 Synthesis of Compound 9

[0276]

[0720] [ka]

[0721] Step 1: General procedure for the preparation of 1-(4-bromo-2,6-difluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanimine A mixture of 4-bromo-2,6-difluorobenzaldehyde (2.68 g, 12.15 mmol, 1 equiv.), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-amine (3.2 g, 12.15 mmol, 1 equiv.) in toluene (40 mL) was degassed and purged with N three times, then the mixture was stirred at 120 °C under N atmosphere for 12 h. The mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column 40 g, eluent: 0–60% ethyl acetate / petroleum ether gradient at 60 mL / min) to give the target compound (4.7 g, 10.08 mmol, 82.95% yield) as a brown oil.

[0722]

[0279] 1 HNMR: (400 MHz, DMSO-d6) 8.70 (s, 1H), 8.40 (d, J = 6.4 Hz, 1H), 7.79 - 7.53 (m, 4H), 7.39 - 7.19 (m, 1H), 5.66 (d, J = 7.2 Hz, 2H), 3.58 - 3.41 (m, 2H), 0.84 (t, J = 8.0 Hz, 2H), 0.11 - -0.30 (m, 9H).

[0723] Step 2: General procedure for the preparation of 4-(4-bromo-2,6-difluorophenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one To a mixture of Zn (28.04 mg, 428.82 μmol, 2 equiv) in toluene (5 mL) under Ar at 25° C., TMS-Cl (16.31 mg, 150.09 μmol, 19.05 μL, 0.7 equiv) was added in one portion. The mixture was stirred at 120° C. for 15 min and then cooled to 25° C. Ethyl 2-bromoacetate (60.87 mg, 364.50 μmol, 40.31 μL, 1.7 equiv) and 1-(4-bromo-2,6-difluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanimine (100 mg, 214.41 μmol, 1 equiv) were added. The mixture was stirred at 120° C. for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluting with a 0-60% ethyl acetate / petroleum ether gradient at 18 mL / min) to give the target compound (62 mg, 121.94 μmol, 56.87% yield) as a brown oil.

[0724] LCMS: Retention time: 0.940 min, (M+H) = 509.9, 5-95AB_1.5 min_220 and 254_Shimadzu. Step 3: General procedure for the preparation of 4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one 4-(4-Bromo-2,6-difluorophenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one (30 mg, 59.01 μmol, 1 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.73 mg, 70.81 μmol, 1.2 equiv.), KCO (24.47 mg, 177.02 μmol, 3 equiv.), Pd(dppf)Cl (4.32 mg, 5.90 μmol, 0.1 equiv.) were dissolved in dioxane (2 mL) and HO (0.4 mL) under N in a microwave tube. The sealed tube was heated in a microwave at 100° C. for 30 minutes. The mixture was filtered. The filtrate was concentrated under reduced pressure to give the target compound (40 mg, crude) as a brown solid, which was used in the next step without further purification.

[0725] LCMS: Retention time: 3.257 min, (M+H) = 510.3, 10-80AB_7 min_220 and 254. Step 4: General procedure for the preparation of 1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)azetidin-2-one To a solution of 4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one compound 9.4 (40.00 mg, 78.49 μmol, 1 equiv.) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 h. The mixture was filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-30%, 7 min) to give compound 9 (1 mg, 2.64 μmol, 3.36% yield) as a white solid.

[0726] LCMS: Retention time: 0.734 min, (M+H) = 380.0, 5-95AB_1.5 min_220 and 254_Shimadzu. Example 3 Synthesis of Compound 4

[0290]

[0727] [ka]

[0728] Step 1: General procedure for the preparation of 4-(2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one 4-(4-Bromo-2,6-difluorophenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one. Compound 9.2 (250 mg, 491.71 μmol, 1 equiv.), 1-methylpiperazine (59.10 mg, 590.05 μmol, 65.45 μL, 1.2 equiv.), CsCO (320.42 mg, 983.42 μmol, 2 equiv.), and 1,4-dioxane (2 mL) were added to a 10 mL round-bottom flask, sparged with N for 5 minutes, and then treated with Xphos-Pd-G (41.62 mg, 49.17 μmol, 0.1 equiv.). The mixture was sparged with N for an additional 5 min and then stirred at 100 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (SiO, THF:MeOH = 4:1, R f =0.3) to give the target compound (60 mg, crude) as a white solid.

[0729]

[0293] LCMS: Retention time: 2.083 minutes, (M+H) + =528.2, 10~80CD_3min_220 and 254. Step 2: General procedure for the preparation of 1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)azetidin-2-one To a solution of 4-(2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one compound 4.1 (40 mg, 75.80 μmol, 1 equiv) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 178.17 equiv). The mixture was stirred at 40° C. for 1.5 hours. The reaction mixture was combined with another batch of reaction mixture (0.5 equiv) and concentrated under reduced pressure to give the crude product. The crude product was basified with NH₃·H₂O to pH = 9–10 and purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH₃·H₂O)-ACN]; B%: 34%–64%, 8 min) to give compound 4 (1.07 mg, 2.06 μmol, 1.81% yield) as a white solid.

[0730]

[0296] LCMS: Retention time: 1.464 minutes, (M+H) + =398.1, 10~80CD_3min_220 and 254.

[0297] 1 H NMR: (400 MHz, DMSO-d6) δ = 12.48 - 12.31 (m, 1H), 8.18 - 8.12 (m, 1H), 7.59 - 7.42 (m, 1H), 7.39 - 7.26 (m, 1H), 7.25 - 7.03 (m, 1H), 6.65 (d, J = 12.8 Hz, 2H), 5.42 - 5.32 (m, 1H), 3.61 - 3.52 (m, 1H), 3.20 - 3.15 (m, 4H), 3.11 - 3.03 (m, 1H), 2.41 - 2.33 (m, 4H), 2.18 (s, 3H).

[0731] Example 4 Synthesis of Compound 2

[0299]

[0732] [ka]

[0733] General procedure for the preparation of 1-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-3,3-dimethylazetidin-2-one To a mixture of Zn (37.23 mg, 569.32 μmol, 2 equiv) in toluene (5 mL) under Ar at 25° C., TMS-Cl (21.65 mg, 199.26 μmol, 25.29 μL, 0.7 equiv) was added in one portion. The mixture was stirred at 120° C. for 15 min and then cooled to 25° C. (Z)—N-(1H-benzo[d]imidazol-5-yl)-1-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)methanimine (100 mg, 284.66 μmol, 1 equiv) and ethyl 2-bromo-2-methylpropanoate (94.39 mg, 483.92 μmol, 70.97 μL, 1.7 equiv) were added, and the mixture was stirred at 120° C. for 12 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23% to 43%, 7 min) to obtain compound 2 (25.26 mg, 59.94 μmol, 21.06% yield) as a white solid.

[0734]

[0302] LCMS: Retention time: 2.750 minutes, (M+H) + =422.2, 10~80AB_7min_220 and 254.

[0303] 1 H NMR: (400 MHz, DMSO-d6) δ = 12.81 - 11.97 (m, 1H), 8.34 - 8.12 (m, 1H), 7.52 (s, 1H), 7.45 - 7.05 (m, 2H), 7.00 - 6.57 (m, 2H), 6.39 - 6.02 (m, 1H), 5.23 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 2.37 - 2.21 (m, 2H), 1.46 (s, 3H), 0.99 (s, 3H).

[0735] Example 5 Synthesis of Compound 3

[0305]

[0736] [ka]

[0737] General procedure for the preparation of 2-(1H-benzo[d]imidazol-5-yl)-3-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-2-azaspiro[3.3]heptan-1-one To a mixture of Zn (37.23 mg, 569.32 μmol, 2 equiv.) in toluene (5 mL) under Ar at 25° C., TMS-Cl (21.65 mg, 199.26 μmol, 25.29 μL, 0.7 equiv.) was added in one portion. The mixture was stirred at 120° C. for 15 min and then cooled to 25° C. (Z)—N-(1H-benzo[d]imidazol-5-yl)-1-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)methanimine Compound 2.1 (100 mg, 284.66 μmol, 1 equiv.) and ethyl 1-bromocyclobutane-1-carboxylate (100.20 mg, 483.92 μmol, 78.28 μL, 1.7 equiv.) were added, and the mixture was stirred at 120° C. for 12 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% to 50%, 7 min) to obtain compound 3 (24.35 mg, 56.18 μmol, 19.74% yield) as a white solid.

[0738]

[0308] LCMS: Retention time: 2.886 minutes, (M+H) + =434.2, 10~80AB_7min_220 and 254.

[0309] 1H NMR: (400 MHz, DMSO-d6) δ = 12.62 - 12.14 (m, 1H), 8.15 (s, 1H), 7.63 - 7.43 (m, 1H), 7.41 - 7.03 (m, 2H), 7.02 - 6.57 (m, 2H), 6.40 - 6.02 (m, 1H), 5.36 (s, 1H), 4.24 - 4.05 (m, 2H), 2.49 - 2.44 (m, 2H), 2.37 - 2.20 (m, 3H), 2.02 - 1.70 (m, 3H).

[0739] Example 6 Synthesis of compound 11CR

[0311]

[0740] [ka]

[0741] Step 1: General procedure for the preparation of (cis and racemic)-4-(4-bromo-2,6-difluorophenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one To a solution of N-isopropylpropan-2-amine (282.05 mg, 2.79 mmol, 393.92 μL, 1.3 equiv) in THF (4 mL) was added n-BuLi (2.5 M, 1.03 mL, 1.2 equiv) at −70° C. under N. The mixture was stirred at −70° C. for 1 h. A mixture of (Z)-1-(4-bromo-2,6-difluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanimine (218.98 mg, 2.14 mmol, 246.05 μL, 1 equiv) in THF (1 mL) was added at −70° C. under N, and the mixture was stirred at −70° C. for 1 h. A mixture of ethyl propionate (1 g, 2.14 mmol, 1 equiv.) in THF (1 mL) was added at −70°C under N2, and the mixture was stirred at 20°C for 12 h. Aqueous HCl (10 mL, 1 M) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ISCO®; SepaFlash® silica flash column 20 g, eluting with a 0–100% ethyl acetate / petroleum ether gradient at 40 mL / min) to give the target compound (900 mg, crude) as a brown oil.

[0742] LCMS: Retention time: 0.952 min, (M+H) = 523.7, 5-95AB_1.5 min_220 and 254_Shimadzu. Step 2: General procedure for the preparation of (cis and racemic)-4-(2,6-difluoro-4-(2-methylthiazol-5-yl)phenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one (3R,4R)-4-(4-Bromo-2,6-difluorophenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one (100 mg, 191.40 μmol, 1 equiv), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (64.63 mg, 287.11 μmol, 1.5 equiv), NaCO (60.86 mg, 574.21 μmol, 3 equiv), and Pd(PPh) (22.12 mg, 19.14 μmol, 0.1 equiv) were dissolved in dioxane (3 mL) and HO (0.6 mL) under N in a microwave tube. The sealed tube was heated in a microwave at 80°C for 30 min. The mixture was filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluting with a 0-60% ethyl acetate / petroleum ether gradient at 18 mL / min) to give the target compound (90 mg, crude) as a yellow oil.

[0743] LCMS: Retention time: 1.119 min, (M+H) = 541.3, 10-80AB_2 min_220 and 254. Step 3: General procedure for the preparation of (cis and racemic)-1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(2-methylthiazol-5-yl)phenyl)-3-methylazetidin-2-one To a solution of (cis and racemic)-4-(2,6-difluoro-4-(2-methylthiazol-5-yl)phenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one (90 mg, 166.45 μmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure and adjusted to pH 7 with saturated NaHCO. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH3H2O)-ACN]; B%: 27%-57%, 8 min) to give compound 11CR (10 mg, 24.36 μmol, 14.64% yield) as a white solid (in cis and racemic forms).

[0744] LCMS: Retention time: 0.656 min, (M+H) = 411.2, 5-95AB_220 and 254_Agilent.

[0321] 1 H NMR: (400MHz, DMSO-d6) δ = 8.22 - 8.18 (m, 1H), 8.14 (s, 1H), 7.59 - 7.33 (m, 4H), 7.23 - 7.13 (m, 1H), 5.68 (d, J = 6.0 Hz, 1H), 4.02 - 3.88 (m, 1H), 2.67 (s, 3H), 1.03 (d, J = 7.6 Hz, 3H).

[0745] Example 7 Synthesis of compound 10CR

[0323]

[0746] [ka]

[0747] Step 1: General procedure for the preparation of 2-methyl-4-(tributylstannyl)thiazole To 4-bromo-2-methylthiazole (2.00 g, 11.2 mmol, 1 equiv) in THF (40 mL) was added n-BuLi (1 M, 13.5 mL, 1.2 equiv) at −78° C. under N. The mixture was stirred at −78° C. for 1 h. A mixture of tributylchlorostannane (6.25 g, 19.2 mmol, 5.17 mL, 1.71 equiv) in THF (20 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL), diluted with HO (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column, 20 g, eluting with a 0-10% ethyl acetate / petroleum ether gradient at 30 mL / min) to give the target compound (1.00 g, 2.29 mmol, 20.41% yield) as a yellow oil.

[0748] LCMS: Retention time: 1.140 min, (M+H) = 389.4, 5-95AB_1.5 min_220 and 254_Shimadzu.

[0327] 1 HNMR: (400 MHz, DMSO-d6) δ = 7.59 - 7.54 (m, 1H), 2.69 (s, 3H), 1.61 - 1.43 (m, 6H), 1.33 - 1.25 (m, 6H), 1.17 - 1.01 (m, 6H), 0.86 (t, J = 7.2 Hz, 9H).

[0749] Step 2: General procedure for the preparation of (cis and racemic)-4-(2,6-difluoro-4-(2-methylthiazol-4-yl)phenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one A mixture of 2-methyl-4-(tributylstannyl)thiazole (156 mg, 402 μmol, 1.5 equiv), (3R,4R)-4-(4-bromo-2,6-difluorophenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one Compound 11.1 (140 mg, 268 μmol, 1 equiv), Pd(PPh3)4 (31.0 mg, 26.8 μmol, 0.1 equiv), CuI (51.0 mg, 268 μmol, 1 equiv), and LiCl (17.0 mg, 402 μmol, 8.23 ​​μL, 1.5 equiv) in toluene (3 mL) was degassed and purged with N2 three times. The mixture was stirred at 120 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column, 4 g, eluting with a 0-70% ethyl acetate / petroleum ether gradient at 12 mL / min). The target compound (110 mg, 116.71 μmol, 43.55% yield) was obtained as a white solid.

[0750] LCMS: Retention time: 0.907 min, (M+H) = 541.2, 5-95AB_1.5 min_220 and 254_Shimadzu. Step 3: General procedure for the preparation of (cis and racemic)-1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(2-methylthiazol-4-yl)phenyl)-3-methylazetidin-2-one To a solution of compound 10.2 (110 mg, 203 μmol, 1 equiv.) in DCM (0.4 mL) was added TFA (3.08 g, 27.0 mmol, 2 mL, 133 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 7 min). Compound 10CR (15.97 mg, 37.50 μmol, 18.43% yield) was obtained as a white solid (in cis and racemic forms).

[0751] LCMS: Retention time: 0.774 min, (M+H) = 411.0, 5-95AB_1.5 min_220 and 254_Shimadzu.

[0334] 1 HNMR: (400 MHz, DMSO-d6) δ = 12.37 - 11.82 (m, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.54 - 7.49 (m, 1H), 7.46 - 7.36 (m, 3H), 7.27 - 7.16 (m, 1H), 5.67 (d, J = 6.0 Hz, 1H), 3.99 - 3.90 (m, 1H), 2.68 (s, 3H), 1.06 (d, J = 7.6 Hz, 3H).

[0752] Example 8 Synthesis of compound 12CR

[0336]

[0753] [ka]

[0754] Step 1: General procedure for the preparation of (cis and racemic)-4-(4-(3,3-difluoropyrrolidinp-1-yl)-2,6-difluorophenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one A mixture of compound 11.1 (130 mg, 248.82 μmol, 1 equiv.), compound 12.1 (71.44 mg, 497.65 μmol, 2 equiv., HCl), RuPhos Pd G3 (83.24 mg, 99.53 μmol, 0.4 equiv.), LiHMDS (1 M, 1.24 mL, 5 equiv.) in THF (8 mL) was degassed and purged with N three times, then the mixture was stirred at 50° C. for 5 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient at 30 mL / min) to give compound 12.2 (100 mg, 182.27 μmol, 73.25% yield) as a brown oil.

[0755]

[0339] LCMS: Retention time: 1.005 min, (M+H) + =549.0, 5~95AB_1.5min_220 and 254_Shimadzu. Step 2: General procedure for the preparation of (cis and racemic)-1-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2,6-difluorophenyl)-3-methylazetidin-2-one To a solution of compound 12.2 (100 mg, 182.27 μmol, 1 equiv.) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give a residue, and the pH was adjusted to 7 with saturated NaHCO. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NHH0)-ACN]; B%: 34%-64%, 8 min) to give compound 12CR (5 mg, 11.95 μmol, 6.56% yield) as a white solid (in cis and racemic forms).

[0756]

[0342] LCMS: Retention time: 0.952 min, (M+H) + =419.2, 10~80AB_2min_220 and 254.

[0343] 1 H NMR: (400 MHz, DMSO-d6) δ = 12.55 - 12.18 (m, 1H), 8.20 - 8.07 (m, 1H), 7.61 - 7.44 (m, 1H), 7.42 - 7.31 (m, 1H), 7.29 - 7.02 (m, 1H), 6.55 - 6.12 (m, 2H), 5.53 (d, J = 5.6 Hz, 1H), 3.90 - 3.78 (m, 1H), 3.77 - 3.64 (m, 2H), 3.51 - 3.40 (m, 2H), 2.60 - 2.53 (m, 2H), 1.01 (br d, J = 7.6 Hz, 3H).

[0757] Example 9 Synthesis of Compounds 13A and 13B

[0345]

[0758] [ka]

[0759] Step 1: General procedure for the preparation of (cis and racemic)-4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one Compound 9.3 (43.01 mg, 206.72 μmol, 1.2 equiv.), compound 11.1 (90 mg, 172.26 μmol, 1 equiv.), KCO (71.43 mg, 516.79 μmol, 3 equiv.), Pd(dppf)Cl (12.60 mg, 17.23 μmol, 0.1 equiv.) were dissolved in dioxane (2 mL) and HO (0.4 mL) under N in a microwave tube. The sealed tube was heated at 100° C. in a microwave for 30 min. The mixture was filtered. The filtrate was concentrated under reduced pressure. Compound 13.1 (90 mg, crude) was obtained as a brown oil and was used in the next step without further purification.

[0760] LCMS: Retention time: 3.358 min, (M+H) = 524.3, 10-80AB_7 min_220 and 254. Step 2: General procedure for the preparation of (cis and racemic)-1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylazetidin-2-one To a solution of compound 13.1 (90 mg, 171.87 μmol, 1 equiv.) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 h. The mixture was filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 5% to 35%, 7 min). Compound 13 (18 mg, 45.76 μmol, 26.62% yield) was obtained as a white solid (in cis and racemic forms).

[0761] LCMS: Retention time: 0.846 min, (M+H) = 394.2, 10-80AB_2 min_220 and 254.

[0352] 1H NMR: (400MHz, DMSO-d6) δ = 13.51 - 10.97 (m, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.84 - 7.02 (m, 5H), 5.64 (d, J = 5.8 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.84 (s, 3H), 1.03 (d, J = 7.5 Hz, 3H).

[0762] Step 3: General procedure for the preparation of (3S,4S)-1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylazetidin-2-one (Compound 13A) and (3R,4R)-1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylazetidin-2-one (Compound 13B) Compound 13 (15 mg, 38.13 μmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃·H₂O ETOH]; B%: 35%–35%, min) to give compound 13A (4.84 mg, 12.30 μmol, 32.27% yield) as a white solid and compound 13B (5.28 mg, 13.42 μmol, 35.20% yield) as a white solid.

[0763] Compound 13A: SFC: Retention time: 1.743 min. LCMS: Retention time: 0.745 min, (M+H) = 394.1, 5-95AB_1.5 min_220 and 254_Shimadzu. 1H NMR: (400MHz, DMSO-d6) δ = 12.60 - 12.10 (m, 1H), 8.25 (s, 1H), 8.19 - 8.09 (m, 1H), 7.97 (s, 1H), 7.61 - 7.00 (m, 5H), 5.64 (d, J = 6.0 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.84 (s, 3H), 1.03 (d, J = 7.6 Hz, 3H).

[0764]

[0356] Compound 13B: SFC: Retention time: 1.935 minutes. LCMS: Retention time: 0.752 min. 1 H NMR: (400MHz, DMSO-d6) δ = 12.43 - 11.65 (m, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.60 - 7.45 (m, 1H), 7.42 (s, 1H), 7.35 - 7.03 (m, 3H), 5.63 (d, J = 6.0 Hz, 1H), 4.01 - 3.87 (m, 1H), 3.85 (s, 3H), 1.06 (d, J = 7.2 Hz, 3H).

[0765] Example 10 Synthesis of Compounds 14A and 14B

[0358]

[0766] [ka]

[0767] Step 1: General procedure for the preparation of (cis and racemic)-4-(2,6-difluoro-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)azetidin-2-one Compound 11.1 (100 mg, 191.40 μmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (75.23 mg, 287.11 μmol, 1.5 equiv.), KCO (79.36 mg, 574.21 μmol, 3 equiv.), and Pd(dppf)Cl (14.01 mg, ...

Claims

1. A compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof 【Chemical 1】 (wherein, R １ is halogen, -OH, -OR １０ａ , -SR １０ａ , -CN, amino, -NR ２２ R ２３ , substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C ２ ~C ６ alkenyl, substituted or unsubstituted C ２ ~C ６ alkynyl, substituted or unsubstituted C １ ~C ６ heteroalkyl, substituted or unsubstituted C ３ ~C ８ cycloalkyl, or substituted or unsubstituted C ２ ~C ７ heterocycloalkyl, and R ２ is H, halogen, -OH, -OR １０ｂ , substituted or unsubstituted C １ ~C ６ alkyl, or substituted or unsubstituted C １ ~C ６ heteroalkyl, or R １ and R ２ together with the carbon atoms to which they are attached form a 3- to 7-membered cyclo or heterocyclic ring, or R １ and R ２ together form an oxo or a double bond to CR １２ａ R １２ｂ and R １２ａ and R １２ｂ are each independently hydrogen, halogen, -OH, amino, substituted or unsubstituted C １ to C ６ alkyl, substituted or unsubstituted C ２ to C ６ alkenyl, substituted or unsubstituted C ２ to C ６ alkynyl, substituted or unsubstituted C １ to C ６ heteroalkyl, substituted or unsubstituted C ３ to C ８ cycloalkyl, substituted or unsubstituted C ２ to C ７ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ４ 、 R ５ 、 R ６ and R ７ each of which is independently selected from H and halogen, R ３ is - OR １１ , halogen, - SR １１ , - S(=O)R ２１ , - S(=O) ２ R ２１ , - NHS(=O) ２ R ２１ , - S(=O) ２ NR ２２ R ２３ , - C(=O)R ２１ , - OC(=O)R ２１ , - C(=O)OR ２２ , - OC(=O)OR ２２ , - C(=O)NR ２２ R ２３ , - OC(=O)NR ２２ R ２３ , - NR ２２ R ２３ , - NO ２ , - NHS(=O) ２ R ２１ , - NR ２２ C(=O)NR ２２ R ２３ , - NR ２２ C(=O)R ２１ , - NR ２２ C(=O)OR ２１ , substituted or unsubstituted C １ ~C ８ alkyl, substituted or unsubstituted C ２ ~C ８ alkenyl, substituted or unsubstituted C ２ ~C ８ alkynyl, substituted or unsubstituted C １ ~C ８ heteroalkyl, substituted or unsubstituted C ３ ~C ８ cycloalkyl, substituted or unsubstituted C ２ ~C ７ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, and R １０ａ and R １０ｂ are each independently a substituted or unsubstituted C １ -C ６ alkyl, a substituted or unsubstituted C ２ -C ６ alkenyl, a substituted or unsubstituted C ２ -C ６ alkynyl, or a substituted or unsubstituted C １ -C ６ heteroalkyl, R １１ is a substituted or unsubstituted C １ -C ６ alkyl, substituted or unsubstituted C ２ -C ６ alkenyl, substituted or unsubstituted C ２ -C ６ alkynyl, substituted or unsubstituted C １ -C ６ heteroalkyl, substituted or unsubstituted C ３ -C ８ cycloalkyl, substituted or unsubstituted C ２ -C ７ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic or polycyclic heteroaryl, and R ２１ 、 R ２２ and R ２３ are each independently hydrogen, C １ -C ６ alkyl, C １ -C ６ heteroalkyl, C ３ -C ８ cycloalkyl, or C ２ -C ７ heterocycloalkyl, and each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be substituted).

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (Iaa) or (Ibb) 【Chemical 2】

3. R １ is -OH, -OR １０ａ , substituted or unsubstituted C １ ~C ６ alkyl, or substituted or unsubstituted C ３ ~C ６ cycloalkyl, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt or solvate.

4. R １ is C substituted with 1 to 5 substituents selected from halogen, -OH, amino, cyano, oxime, oxo, mono-C １～６ alkylamino, di-C １～６ alkylamino, substituted or unsubstituted C １～６ alkoxy, substituted or unsubstituted C ３～７ cycloalkyl, substituted or unsubstituted C ２～８ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or a pharmaceutically acceptable salt or solvate thereof, according to claim 3, which is C １ -C ６ alkyl.

5. R １ is -CH ３ The compound according to claim 3, its stereoisomer, or a pharmaceutically acceptable salt or solvate, wherein R is -CH or cyclopropyl.

6. R ２ The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein R is H.

7. R ５ is F, and R ７ is F, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt or solvate thereof.

8. R ４ is H and R ６ is H, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt or solvate thereof.

9. R ３ The compound, stereoisomer, or pharmaceutically acceptable salt or solvate according to claim 1, wherein R is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S.

10. R ３ is [Chemical Formula 3] and each R ３１ is independently selected from hydrogen, cyano, halogen, hydroxy, substituted or unsubstituted C １～６ alkyl, -OCH ３ ３ ３ ２～６ ２～６ ２～６ ２～６ １～６ １～６ ３～７ ３～７ ２～８ ２～８ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ １～６ alkylamino and di-C １～６ alkylamino, m is 0, 1, 2, or 3, the compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt or solvate.

11. R ３ is 【Chemical Formula 4】 and each R ３１ is independently cyano, halogen, hydroxy, substituted or unsubstituted C １～ ６ alkyl, -OCH ３ , -OCD ３ , substituted or unsubstituted C ２～６ alkenyl, substituted or unsubstituted C ２～６ alkynyl, substituted or unsubstituted C １～６ alkoxy, substituted or unsubstituted C ３～７ cycloalkyl, substituted or unsubstituted C ２～８ heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C １～６ alkyl, substituted or unsubstituted C １～６ alkyl-aryl, substituted or unsubstituted C １～６ alkyl-heterocycloalkyl, substituted or unsubstituted C １～６ alkyl-heteroaryl, substituted or unsubstituted C １～６ alkoxy-aryl, substituted or unsubstituted C １～６ alkoxy-heterocycloalkyl, substituted or unsubstituted C １～６ alkoxy-heteroaryl, C substituted with hydroxy １～６ alkoxy, C １～６ alkoxy, amino, mono-C １～６ alkylamino and di-C １～６ The compound according to claim 2, its stereoisomers, or a pharmaceutically acceptable salt or solvate, which is selected from alkylamino and is such that m is 0, 1, 2, 3, 4 or 5.

12. R ３ is -OR １１ -SR １１ substituted or unsubstituted C １ -C ８ alkyl, substituted or unsubstituted C ２ -C ８ alkenyl, substituted or unsubstituted C ２ -C ８ alkynyl, or substituted or unsubstituted C １ -C ８ heteroalkyl, and R １１ is a substituted or unsubstituted C １ -C ６ alkyl, or a substituted or unsubstituted C ３ -C ６ cycloalkyl, and R １１ is replaced, a halogen, -OH, C １ to C ４ alkyl, C ３ to C ６ cycloalkyl, C １ to C ４ fluoroalkyl, C １ to C ４ heteroalkyl, C １ to C ４ alkoxy, or C １ to C ４ substituted with one or more substituents selected from fluoroalkoxy, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt or solvate.

13. The compound is 【Chemical Formula 5-1】 【Chemical Formula 5-2】 [Chemical Formula 5-3] 【Chemical Formula 5-4】 【Chemical Formula 5-5】 【Chemical Formula 5-6】 ​ 【Chemical Formula 5-8】 【Chemical Formula 5-9】 【Chemical Formula 5-10】 【Chemical Formula 5-11】 【Chemical Formula 5-12】 [[Chemical Formula 5-13]] 【Chemical Formula 5-14】 [Chemical Formula 5-15] ​ 【Chemical Formula 5-17】 【Chemical Formula 5-18】 【Chemical Formula 5-19】 The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, which is selected from the group consisting of

14. The compound is 【Chemical Formula 6】 The compound according to claim 13, its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, which is

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient

16. Use of the compound according to any one of claims 1 to 14, its stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer in a subject in need of treatment for cancer

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