antimicrobial compounds

Abstract

Provided herein are heterocyclic compounds and pharmaceutical compositions containing the compounds that are useful for inhibiting the growth of Gram-negative bacteria. The subject compounds and compositions are useful for treating bacterial infections, such as pneumonia.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 396,895, filed August 10, 2022, which is incorporated herein by reference in its entirety.

[0002] Statement Regarding Federally Sponsored Research This invention was made with government support under contract HHS0100201600038C awarded by HHS. The government has certain rights in this invention.

[0003] There is a need in the medical arts for effective treatments for diseases caused by bacterial infections. Summary of the Invention

[0004] Provided herein are heterocyclic compounds useful for inhibiting the growth of Gram-negative bacteria and pharmaceutical compositions comprising the compounds. The subject compounds and compositions are useful for treating bacterial infections, such as pneumonia. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulator compounds. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0005] In one aspect, the present disclosure provides a compound of formula (I):

[0006] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is C1-C4 alkyl, R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3 is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 4 is hydrogen or C1-C4 alkyl, Each R 5 and R 6 are independently halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-selected from R 9 is hydrogen or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 is substituted with a group, Each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; Each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; and At least one of the following: (i) s is 1 or 2, and at least one R 5 is a halogen, (ii) t is 1 or 2 and at least one R6 is halogen; and (iii)R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0007] In some embodiments, at least one R 5 , R 6 , or R 10 is -F. In some embodiments, at least one R 5 or R 6 is -F. In some embodiments, at least one R 10 is -F. In some embodiments, at least two R 5 , R 6 , or R 10 is -F. In some embodiments, at least two R 5 or R 6 is -F. In some embodiments, at least two R 10 is -F.

[0008] In some embodiments, R 1 is -CH3. In some embodiments, R 2a is hydrogen and R 2b is hydrogen. In some embodiments, R 4 is hydrogen. In some embodiments, each R 5 is independently -F, -Cl, or -CH. In some embodiments, each R 5 is -F. In some embodiments, each R 6 is -F.

[0009] In some embodiments, the compound is a compound of formula (IIa):

[0010] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Each R 5 is -F, and Each R 6 is -F.

[0011] In some embodiments, the compound is a compound of formula (IIIa):

[0012] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Each R 5 is -F, and Each R 6 is -F.

[0013] In some embodiments, R 3 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -(C1-C4 alkylene)-OH. In some embodiments, R 3 is —CHOH. In some embodiments, R 9 is hydrogen.

[0014] In some embodiments, L 1 is a bond, -(C1-C4 alkylene)-, -X 1 - or -X 2 -(C1-C4 alkylene)-, and X 1 and X 2 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)—, and —S(═O)(═NH)—. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)2—, and —S(═O)(═NH)—.

[0015] In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 Each is selected from -O-. In some embodiments, L 1 is -O-.

[0016] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C-C alkyl, —C(═O)—C-C alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from —F, —CN, —OH, —CHOH, —NH, —OMe, —N(CH), —COH, —CONH, —SOCH, —C(═NH)NH, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from —F, —CN, —OH, —NH, —OMe, —N(CH), —COH, —CONH, and —SOCH.

[0017] In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8)2, -NHSO2R 8 , —CHCN, C1-C4 alkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; each R 8 are independently hydrogen, C1-C4 alkyl, —C(═O)—C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted with 1, 2, or 3 groups selected from —F, —CN, —OH, —COH, —C(═NH)NH2, and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1-CONH2 group.

[0018] In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl.

[0019] In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently selected from —F, —OH, —OCH 3 , and —NH 2 .

[0020] In some embodiments, L 1 -R 7 teeth,

[0021] [ka] is.

[0022] In some embodiments, L 1 -R 7 teeth,

[0023] [ka] is.

[0024] In some embodiments, R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 4 is hydrogen, and each R 5 and R 6 is a halogen, and L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 are each selected from -O-, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C-C alkyl, —C(═O)—C-C alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups selected from —F, —CN, —OH, —CHOH, —NH, —OMe, —N(CH), —COH, —CONH, —SOCH, —C(═NH)NH, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from —F, —CN, —OH, —NH, —OMe, —N(CH), —COH, —CONH, and —SOCH.

[0025] In some embodiments, R 3 is hydrogen or -(C1-C4 alkylene)-OH, and L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 are each selected from -O-, and R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl.

[0026] In some embodiments, R 3 is CH2OH, L 1 is -O- and R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10groups, and each R 10 are independently selected from —F, —OH, —OCH 3 , and —NH 2 .

[0027] In some embodiments, the compound is a compound of formula (IV):

[0028] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 3 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 and R 6 are independently -F, -Cl, or C1-C4 alkyl; L 1 is -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen or C1-C4 alkyl; s is 0, 1, or 2; t is 0, 1, or 2; and u is 0, 1, or 2.

[0029] In some embodiments, the compound is a compound of formula (V):

[0030] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0031] In some embodiments, s is 1 or 2 and at least one R 5 In some embodiments, t is 1 or 2 and at least one R 6 In some embodiments, u is 1 or 2 and at least one R 10 is -F. In some embodiments, R 3 is -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -CHOH.

[0032] In another aspect, the present disclosure provides a compound of formula (VI):

[0033] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 11 is C1-C4 alkyl, R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 14is hydrogen or C1-C4 alkyl, Each R 15 and R 16 are independently halogen or C1-C4 alkyl; R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; Each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-selected from R 19 is hydrogen or C1-C6 alkyl, However, L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, then at least one of the following is true: (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; (ii)R 14 is C1-C4 alkyl; (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv)L 2 is -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0034] In some embodiments, R 11 is -CH3. In some embodiments, R 12a is hydrogen and R 12b is hydrogen. In some embodiments, R 14 is hydrogen. In some embodiments, each R 15 is independently -F, -Cl, or -CH. In some embodiments, each R 15 is independently -F. In some embodiments, each R 16 is independently -F, -Cl, or -CH. In some embodiments, each R 16 are independently -F.

[0035] In some embodiments, the compound is a compound of formula (VIIa):

[0036] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0037] In some embodiments, the compound is a compound of formula (VIIIa):

[0038] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0039] In some embodiments, v is 1 or 2. In some embodiments, v is 0. In some embodiments, w is 1 or 2. In some embodiments, w is 0. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, R 3 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -CHOH.

[0040] In some embodiments, R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 18 are independently hydrogen, C-C alkyl, —C(═O)—C-C alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups selected from —F, —CN, —OH, —CHOH, —NH, —OMe, —N(CH), —COH, —CONH, —SOCH, —C(═NH)NH, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from —F, —CN, —OH, —NH, —OMe, —N(CH), —COH, —CONH, and —SOCH.

[0041] In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or substituted with halogen, -OR 18 , -N(R 18 )2, -NHSO2R 18 , —CHCN, C1-C4 alkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; 18 are independently hydrogen, C1-C4 alkyl, —C(═O)—C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted with 1, 2, or 3 groups selected from —F, —CN, —OH, —COH, —C(═NH)NH2, and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1-CONH2 group.

[0042] In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with halogen, —OH, —OMe, —N(R 8 )2, -NHSO2R 18 and -CHCN, wherein each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl.

[0043] In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -OH, -OCH3, and -NH2.

[0044] In some embodiments, the compound is a compound of formula (IX):

[0045] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 13 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 are independently -F, -Cl, or C1-C4 alkyl; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 ) is selected from R 19 is hydrogen or C1-C6 alkyl, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen or C1-C4 alkyl; v is 0, 1, or 2; w is 0, 1, or 2; and y is 0, 1, or 2.

[0046] In some embodiments, the compound is a compound of formula (X):

[0047] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0048] In some embodiments, R 13 is -(C1-C4 alkylene)-OH. In some embodiments, R 13 In some embodiments, w and v are each 0.

[0049] In some embodiments, L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-; (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; (ii)R 14 is C1-C4 alkyl; (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv)L 2 is -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl.

[0050] In some embodiments, R 13 is -(C-C cycloalkylene)-OH or -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(cyclopropylene)-OH or -(cyclopropylene)-NH. In some embodiments, R 13 teeth,

[0051] [ka] In some embodiments, R 14 is C1-C4 alkyl. In some embodiments, R 14 is methyl.

[0052] In some embodiments, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0053] In some embodiments, R 17 is unsubstituted or substituted hexahydrofuro[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one —N(R 18 ) substituted oxetane.

[0054] In some embodiments, R 17 teeth

[0055] [ka] is.

[0056] In some embodiments, L 2 is a bond, —CH2—, —O—, or —O—CH2—.

[0057] In some embodiments, -L 2 -R 17 teeth,

[0058] [ka] is.

[0059] In some embodiments, L 2 is -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl. In some embodiments, R 17 is unsubstituted or substituted tetrahydrofuranyl.

[0060] In some embodiments, R 17 teeth,

[0061] [ka] In some embodiments, L 2 is —O—CH—. In some embodiments, —L 2 -R 17 teeth,

[0062] [ka] is.

[0063] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0064] In another aspect, the present disclosure provides a method of treating or preventing a Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0065] In some embodiments, the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the Gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia. In some embodiments, the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof.

[0066] In another aspect, the present disclosure provides a method of treating or preventing a P. aeruginosa infection in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0067] In some embodiments, the patient is identified as having a pulmonary disease. In some embodiments, the pulmonary disease is a structural pulmonary disease. In some embodiments, the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive pulmonary disease, or a combination thereof. In some embodiments, the administration is to treat an existing infection. In some embodiments, the administration is provided as prophylaxis.

[0068] In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

[0069] In some embodiments, the compound or salt is used as a therapeutically active substance. In some embodiments, the compound or salt is used to treat or prevent a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia. In some embodiments, the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. In some embodiments, the compound or salt is used to treat or prevent a P. aeruginosa infection. In some embodiments, the patient is identified as having a pulmonary disease. In some embodiments, the pulmonary disease is a structural pulmonary disease. In some embodiments, the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive pulmonary disease, or a combination thereof.

[0070] In another aspect, the disclosure provides use of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for treating or preventing a Gram-negative bacterial infection.

[0071] In another aspect, the disclosure provides use of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for treating or preventing a gram-negative bacterial infection.

[0072] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. Detailed Description of the Invention LpxC, lipid A and Gram-negative bacteria DETAILED DESCRIPTION OF THE INVENTION

[0073] LpxC, lipid A and Gram-negative bacteria Metalloproteins affect a wide variety of biological systems, biological processes, and diseases. For example, UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) is an essential enzyme involved in the first committed step in lipid A biosynthesis in Gram-negative bacteria. Lipid A is an essential component of the outer membrane of Gram-negative bacteria. LpxC is a zinc(II)-dependent metalloenzyme, with two histidine and aspartic acid residues bound to a zinc(II) ion. The structure of LpxC shows that the zinc(II) ion is bound to two water molecules, both of which are thought to be involved in the enzyme mechanism. LpxC is highly conserved among Gram-negative bacterial strains, making it an attractive target for treating Gram-negative infections. In contrast, LpxC is not a component of Gram-positive bacteria, such as Staphylococcus aureus.

[0074] In recent years, there has been an increase in resistant and multidrug-resistant bacteria. Therefore, there is a need for new antibiotics, especially those with novel mechanisms of action. There remains a need for metalloprotein modulators of LpxC that are useful in therapeutics, diagnostics, and research.

[0075] Some embodiments provide a method of inhibiting the UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase enzyme, comprising contacting the enzyme with a compound of formula (I).

[0076] In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0077] How to use Disclosed herein are methods for treating diseases for which inhibition of bacterial growth is indicated. Such diseases include gram-negative bacterial infections. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, a method for treating a gram-negative bacterial infection in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a method for treating a Pseudomonas aeruginosa infection in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0078] In some embodiments, the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the Gram-negative bacterial infection is a respiratory infection. In some embodiments, the Gram-negative bacterial infection is pneumonia. In some embodiments, the Gram-negative bacterial infection is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. In some embodiments, the Gram-negative bacterial infection is community-acquired pneumonia (CAP). In some embodiments, the Gram-negative bacterial infection is healthcare-associated pneumonia (HCAP). In some embodiments, the Gram-negative bacterial infection is hospital-acquired pneumonia (HAP). In some embodiments, the Gram-negative bacterial infection is ventilator-associated pneumonia (VAP).

[0079] In some embodiments, the patient is identified as having a pulmonary disease. In some embodiments, the pulmonary disease is a structural pulmonary disease. In some embodiments, the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive pulmonary disease, or a combination thereof. In some embodiments, the patient has cystic fibrosis. In some embodiments, the patient has bronchiectasis. In some embodiments, the patient has emphysema. In some embodiments, the patient has chronic obstructive pulmonary disease (COPD). In some embodiments, the patient has chronic destructive pulmonary disease.

[0080] In some embodiments, the administering is to treat an existing infection.

[0081] In some embodiments, administration is provided as a prophylaxis.

[0082] In some embodiments, the LpxC inhibitory compounds described herein are used to treat or prevent conditions caused by bacterial production of endotoxin, particularly by Gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin. In some embodiments, a method for treating or preventing an endotoxin- or LPS-induced condition in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another embodiment, the heterocyclic LpxC inhibitory compounds described herein are useful for treating conditions caused or exacerbated by bacterial production of lipid A and LPS or endotoxin, such as chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB). In some embodiments, a method for treating or preventing an endotoxin- or LPS-induced condition in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the endotoxin- or LPS-induced condition is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB).

[0083] In other embodiments, the compounds of the present disclosure are derived from Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Shigella sonnei, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, as well as Citrobacter freundi, Haemophilus influenzae, Kluyvera sp., Legionella sp., Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella species, Burkholderia species and They may be used to treat severe or chronic respiratory infections, including serious pulmonary and hospital-acquired infections, such as those caused by Proteus species, infections caused by other bacterial species, such as Neisseria species, Shigella species, Salmonella species, Helicobacillus pylori, Vibrionaceae, and Bordetella species, and infections caused by Brucella species, Francisella tularensis, and / or Yersinia pestis. In some embodiments, the infection is associated with Pseudomonas species. In some embodiments, the infection is associated with Pseudomonas aeruginosa. In some embodiments, the compounds of the present disclosure do not inhibit the growth of Gram-positive bacteria, such as Staphylococcus aureus.

[0084] In some embodiments, the LpxC inhibitory compounds described herein are used in methods to prevent the growth of Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa.

[0085] In some cases, antibiotics have suboptimal concentrations in the lungs, resulting in failure to treat pulmonary infections. In some embodiments, the heterocyclic LpxC inhibitor compound of formula (I) has optimal concentrations in the lungs for treating or preventing pulmonary Gram-negative bacterial infections. In some embodiments, the compound is present in the lungs in a therapeutically effective amount after administration.

[0086] In some embodiments, disclosed herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances.

[0087] In some embodiments, disclosed herein are compounds described herein or pharmaceutically acceptable salts thereof for use in treating or preventing a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia.

[0088] In some embodiments, the present disclosure provides a use of a compound described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia.

[0089] LpxC inhibitory compounds In some embodiments, provided herein are heterocyclic LpxC inhibitory compounds and pharmaceutical compositions comprising such compounds. The subject compounds and compositions are useful for inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and treating bacterial infections.

[0090] In some embodiments, compounds of Formula (I), including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulators. In some embodiments, compounds of Formula (I), including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, compounds of Formula (I), including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0091] One aspect of the present disclosure is a compound having the structure of formula (I):

[0092] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is C1-C4 alkyl, R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 4 is hydrogen or C1-C4 alkyl, Each R 5 and R 6 are independently halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-selected from R 9 is hydrogen or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 is substituted with a group, Each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; moreover, Each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; s is 0, 1, or 2; and t is 0, 1, or 2. In some embodiments, for compounds of formula (I): (i) s is 1 or 2, and at least one R 5 is a halogen, (ii) t is 1 or 2, and at least one R 6 is a halogen, and (iii)R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0093] In some embodiments, for compounds of Formula (I), s is 1 or 2 and at least one R 5 is a halogen.

[0094] In some embodiments, for compounds of Formula (I), t is 1 or 2 and at least one R 6 is a halogen.

[0095] In some embodiments, for compounds of formula (I), R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0096] In some embodiments, for compounds of formula (I), R 1 is C1-C4 alkyl, and R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 4 is hydrogen or C1-C4 alkyl, and each R 5 and R 6 are independently halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with one or two groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen atom are substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 8 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0097] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia) or Formula (Ib):

[0098] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0099] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, and is at least one of the following: (i) s is 1 or 2, (ii) t is 1 or 2, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is fluorine.

[0100] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9)-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, and is at least one of the following: (i) s is 1 or 2, (ii) t is 1 or 2, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10is fluorine.

[0101] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen or -(C1-C4 alkylene)-OH, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, and is at least one of the following: (i) s is 1 or 2, (ii) t is 1 or 2, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is fluorine.

[0102] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen or -(C1-C4 alkylene)-OH, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -NHSO2R 8 , —CHCN, C1-C4 alkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1-CONH2 groups, and at least one of the following: (i) s is 1 or 2, (ii) t is 1 or 2, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is fluorine.

[0103] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen or -CHOH, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9)-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 The groups are independently selected from halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with one or two groups independently selected from —CN, —OH, and oxadiazolyl, and is at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is fluorine.

[0104] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a and R 2b are each hydrogen, and R 3 is hydrogen or -CHOH, and R 4 is hydrogen, and each R 5 and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and S(=O)(=NR 9 )-, and R9 is hydrogen or C1-C6 alkyl, and R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently selected from -F, -OH, -OCH3, and -NH2, s is 0, 1, or 2, t is 0, 1, or 2, and is at least one of the following: (i) s is 1 or 2, (ii) t is 1 or 2, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is fluorine.

[0105] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0106] For any and all of the embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is unsubstituted C1-C4 alkyl. In some embodiments, R 1 is C1-C2 alkyl. In some embodiments, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 1 is -CH3 or -CH2CH3. In some embodiments, R 1 is -CH3.

[0107] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2a and R 2b are each independently R 2a and R 2b are each independently hydrogen, halogen, or unsubstituted C-C alkyl. In some embodiments, R 2a and R 2b are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 2a and R 2b are each independently hydrogen, —F, —Cl, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

[0108] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2a is hydrogen. In some embodiments, R 2b is hydrogen. In some embodiments, R 2a and R 2b are each hydrogen.

[0109] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3 and R 2a is hydrogen and R 2b is hydrogen.

[0110] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 4 is hydrogen or C-C alkyl. In some embodiments, R 4is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH). In some embodiments, R 4 is hydrogen, —CH, or —CHCH. In some embodiments, R 4 is hydrogen or —CH. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3.

[0111] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0112] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0113] In some embodiments of the compound of Formula (II), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 is halogen or C1-C4 alkyl, and each R 6 is halogen or C1-C4 alkyl, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R 8 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo, and s is 0, 1, or 2; t is 0, 1, or 2 and is at least one of the following: (i) s is 1 or 2 and at least one R 5is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0114] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is -F and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; s is 0, 1, or 2; t is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0115] In some embodiments of the compound of Formula (II), each R 5 is independently halogen or C1-C4 alkyl, and each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 5 are independently halogen, and each R 6 is independently halogen. In some embodiments, each R 5 is independently -F, and each R 6 is independently -F. In some embodiments, each R 5 is independently -Cl, and each R 6 are independently —Cl.

[0116] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IIa) or Formula (IIb):

[0117] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0118] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 is halogen or C1-C4 alkyl, and each R 6 is halogen or C1-C4 alkyl, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R 8 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo, and s is 0, 1, or 2; t is 0, 1, or 2 and is at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0119] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5is -F and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; s is 0, 1, or 2; t is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0120] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5 is independently halogen or C1-C4 alkyl, and each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 5 are independently halogen, and each R 6 is independently halogen. In some embodiments, each R 5 is independently -F, and each R 6 are independently -F.

[0121] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5is —F. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5 is -Cl.

[0122] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 6 is —F. In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 6 is -Cl.

[0123] In some embodiments of compounds of Formula (II), (IIa), or (IIb), s is 0 and each R 6 is -F. In some embodiments, each R 5 is -F and t is 0. In some embodiments, R 5 is -F and R 6 is -F.

[0124] In some embodiments of compounds of Formula (II), (IIa), or (IIb), s is 0 and each R 6 is -Cl. In some embodiments, each R 5 is -Cl and t is 0. In some embodiments, R 5 is -Cl, and R 6 is -Cl.

[0125] In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0126] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId),

[0127] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0128] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 is halogen or C1-C4 alkyl, and each R 6 is halogen or C1-C4 alkyl, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R 8 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo, and s is 0, 1, or 2; t is 0, 1, or 2 and is at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0129] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R5 is -F and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; s is 0, 1, or 2; t is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0130] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 is independently halogen or C1-C4 alkyl, and each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 5 are independently halogen, and each R 6 is independently halogen. In some embodiments, each R 5 is independently -F, and each R 6 is independently -F. In some embodiments, each R 5 is independently -Cl, and each R 6 are independently —Cl.

[0131] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 is —F. In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 is -Cl.

[0132] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 6 is —F. In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 6 is -Cl.

[0133] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), s is 0 and each R 6 is -F. In some embodiments, each R 5 is -F and t is 0. In some embodiments, R 5 is -F and R 6 is -F.

[0134] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), s is 0 and each R 6 is -Cl. In some embodiments, each R 5 is -Cl and t is 0. In some embodiments, R 5 is -Cl, and R 6 is -Cl.

[0135] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIId), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0136] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl. In some embodiments, L 1 is a bond, -(C1-C3 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, L 1 is a bond, -(C1-C2 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, L 1 is a bond, -CH2-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, each R 9 are independently hydrogen or methyl. In some embodiments, R 9 is hydrogen.

[0137] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, L 1 -CH2-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, L 1 is a bond, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, R 9 is hydrogen.

[0138] In some embodiments, L 1 -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 In some embodiments, L 1 -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 In some embodiments, L is selected from -S-, -S(=O)-, and -S(=O)-. 1 -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 In some embodiments, L 1 -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 In some embodiments, L 1 -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are each selected from -O- and -S-. In some embodiments, L 1 -X 1 - or -X2 -(C1-C6 alkylene)-, and X 1 and X 2 are respectively -N(R 9 In some embodiments, R 9 is hydrogen.

[0139] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)—, and —S(═O)(═NH)—. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, and X 1 and X 2 Each is selected from -O-. In some embodiments, L 1 is -O-.

[0140] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is —O— or —O—(C1-C6 alkylene)-. In some embodiments, L 1 is -N(R 9 )- or -N(R 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 is -S- or -S-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)- or -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 1is -S(=O)2- or -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)(=NR 9 )- or -S(=O)(=NR 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 is —O—. In some embodiments, L 1 is -N(R 9 In some embodiments, L 1 is -S-. In some embodiments, L 1 is -S(=O)-. In some embodiments, L 1 is -S(=O)2-. In some embodiments, L 1 is -S(=O)(=NR 9 In some embodiments, L 1 is —O—(C1-C6 alkylene)-. In some embodiments, L 1 is -N(R 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 is -S-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)(=NR 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 is —O— or —O—(CH)—. In some embodiments, L 1 is —N(H)— or —N(H)—(CH)—. In some embodiments, L 1 is -S- or -S-(CH)-. In some embodiments, L 1 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L 1 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L1 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH)-. In some embodiments, L 1 is —O—(CH)—. In some embodiments, L 1 is —N(H)—(CH)—. In some embodiments, L 1 is -S-(CH2)-. In some embodiments, L 1 is -S(=O)-(CH2)-. In some embodiments, L 1 is -S(=O)2-(CH2)-. In some embodiments, L 1 is -S(=O)(=NH)-(CH2)-.

[0141] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), in some embodiments, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C-C alkyl, —C(═O)—C-C alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from —F, —CN, —OH, —CHOH, —NH, —OMe, —N(CH), —COH, —CONH, —SOCH, —C(═NH)NH, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from —F, —CN, —OH, —NH, —OMe, —N(CH), —COH, —CONH, and —SOCH.

[0142] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -NHSO2R 8 , —CHCN, C1-C4 alkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; each R 8 are independently hydrogen, C1-C4 alkyl, —C(═O)—C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted with 1, 2, or 3 groups selected from —F, —CN, —OH, —COH, —C(═NH)NH2, and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1-CONH2 group.

[0143] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0144] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from —F and —OH.

[0145] In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0146] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10is independently selected from -F, -Cl, and -OH. In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from —F and —OH.

[0147] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R8 )2, and -CH2CN, and each R 8 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0148] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from —F and —OH.

[0149] In some embodiments, R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8, and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0150] In some embodiments, R 7 is a 6-membered heterocycloalkyl, and the 5-membered heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7is a 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0151] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R7 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from —F and —OH.

[0152] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a 6-membered heterocycloalkyl, and the 5-membered heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R 7 is a 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 10 groups, and each R 10 is independently selected from —F and —OH.

[0153] In some embodiments, R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or C1-C2 alkyl.

[0154] In some embodiments, R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 , and -CHCN, and each R 8 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 7is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 are independently halogen, -OH, -OR 8 , -N(R 8 )2, and -CH2CN, and each R 8 are independently hydrogen or C1-C2 alkyl.

[0155] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R 7is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from —F and —OH. In some embodiments, R 7 is three R 10 tetrahydrofuran substituted with a group, 10 is independently selected from —F and —OH.

[0156] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. In some embodiments, R 7 is a tetrahydropyran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from —F and —OH. In some embodiments, R 7 is three R 10 tetrahydrofuran substituted with a group, 10 is independently selected from —F and —OH.

[0157] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0158] [ka] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth,

[0159] [ka] is.

[0160] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0161] [ka] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth,

[0162] [ka] is.

[0163] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is -O- and R 7is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 1 is -O- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, L 1 is -O- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from -F, -Cl, and -OH. 1 is -O- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from —F and —OH. In some embodiments, L 1 is -O- and R 7 is three R 10 tetrahydrofuran substituted with a group, 10 is independently selected from —F and —OH.

[0164] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0165] [ka] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0166] [ka] is.

[0167] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0168] [ka] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth

[0169] [ka] is.

[0170] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0171] [ka] is.

[0172] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0173] [ka] is.

[0174] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0175] [ka] That is,

[0176] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is -NH- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 1 is -NH- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from halogen and —OH. In some embodiments, L 1 is -NH- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10groups, and each R 10 is independently selected from -F, -Cl, and -OH. 1 is -NH- and R 7 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 10 groups, and each R 10 is independently selected from —F and —OH. In some embodiments, L 1 is -O- and R 7 is three R 10 tetrahydrofuran substituted with a group, 10 is independently selected from —F and —OH.

[0177] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0178] [ka] is.

[0179] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 teeth,

[0180] [ka] is.

[0181] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a single diastereomer. In some embodiments, R 7is a single diastereomer, R 7 In some embodiments, R 7 is a single diastereomer, R 7 In some embodiments, R 7 is a single diastereomer, R 7 shows improved efficacy in vivo relative to a comparison compound of which the isomer is a different stereoisomer.

[0182] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is one or two R 10 groups, and each R 10 are independently halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 In some embodiments, R 7 is one or two R 10 groups, and each R 10 is independently selected from halogen, —OH, and —CHCN. In some embodiments, R 7 is one or two R 10 groups, and each R 10 is independently selected from -F, -Cl, -OH, and -CHCN. In some embodiments, R 7 is a 4-6 membered heterocycloalkyl substituted with -OH.

[0183] In some embodiments, R 7 is a 1,2-trans-disubstituted 4-6 membered heterocycloalkyl. In some embodiments, R 7 teeth,

[0184] [ka] In some embodiments, R 7 teeth,

[0185] [ka] In some embodiments, R 7 teeth,

[0186] [ka] In some embodiments, R 7 teeth,

[0187] [ka] is.

[0188] In some embodiments, R 7 is a 1,2-cis-disubstituted 4-6 membered heterocycloalkyl. In some embodiments, R 7 teeth,

[0189] [ka] In some embodiments, R 7 teeth,

[0190] [ka] In some embodiments, R 7 teeth,

[0191] [ka] In some embodiments, R 7 teeth,

[0192] [ka] is.

[0193] In some embodiments, the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIId), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0194] In some embodiments, the compound of formula (I) is a compound of formula (IV):

[0195] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0196] In some embodiments of the compound of Formula (IV), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 is halogen or C1-C4 alkyl, and each R 6 is halogen or C1-C4 alkyl, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and each R10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 8 and R are joined to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; and u is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is halogen; (iii) u is 0, 1, or 2 and at least one R 10 is a halogen.

[0197] In some embodiments of the compound of Formula (IV), R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is -F and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which are unsubstituted or selected from -F, - substituted with 1, 2, 3, or 4 groups independently selected from monocyclic heteroaryl substituted with 1 or 2 groups selected from CN, -OH, -NH, -OMe, -N(CH), -COH, -CONH, and -SOCH; s is 0, 1, or 2; t is 0, 1, or 2; and u is 0, 1, or 2, and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is halogen; (iii) u is 0, 1, or 2 and at least one R 10 is a halogen.

[0198] In some embodiments of the compound of Formula (IV), each R 5 is independently halogen or C1-C4 alkyl, and each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 5 are independently halogen, and each R 6 is independently halogen. In some embodiments, each R 5 is independently -F, and each R 6 is independently -F. In some embodiments, each R 5 is -F and t is 0. In some embodiments, R 5 is -F and R 6 is -F.

[0199] In some embodiments of the compound of Formula (IV), L 1 is a bond, -(C1-C2 alkylene)-, -X1 - or -X 2 -(C1-C2 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl. In some embodiments, L 1 is a bond, -(C1-C2 alkylene)-, -X 1 - or -X 2 -(C1-C2 alkylene)-, and X 1 and X 2 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)—, and —S(═O)(═NH)—. In some embodiments, L 1 is a bond, -(CH2)-, -X 1 - or -X 2 -(CH2)- and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl. In some embodiments, L 1 is a bond, -(CH2)-, -X 1 - or -X 2 -(CH2)- and X 1 and X 2 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)—, and —S(═O)(═NH)—. In some embodiments, L 1 is a bond, -(CH2)-, -X 1 - or -X 2 -(CH2)- and X 1 and X 2 are -O- and -N(R 9 In some embodiments, L 1 is a bond, -(CH2)-, -X1 - or -X 2 -(CH2)- and X 1 and X 2 Each is selected from -O-. In some embodiments, L 1 is -O-.

[0200] In some embodiments, the compound of formula (I) is a compound of formula (V):

[0201] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0202] In some embodiments of compounds of Formula (V), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 5 is halogen or C1-C4 alkyl, and each R 6 is halogen or C1-C4 alkyl, and L 1 is a bond, -(C1-C6 alkylene)-, -X 1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 8 and R are joined to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; and u is 0, 1, or 2; and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is halogen; (iii) u is 0, 1, or 2 and at least one R 10 is a halogen.

[0203] In some embodiments of compounds of Formula (V), R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is -F and R 6 is -F, and L 1 is a bond, -(C1-C6 alkylene)-, -X1 - or -X 2 -(C1-C6 alkylene)-, and X 1 and X 2 are -O- and -N(R 9 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 9 )-, and R 9 is hydrogen or C1-C6 alkyl, and each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which are unsubstituted or selected from -F, - substituted with 1, 2, 3, or 4 groups independently selected from monocyclic heteroaryl substituted with 1 or 2 groups selected from CN, -OH, -NH, -OMe, -N(CH), -COH, -CONH, and -SOCH; s is 0, 1, or 2; t is 0, 1, or 2; and u is 0, 1, or 2, and at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is halogen; (iii) u is 0, 1, or 2 and at least one R 10 is a halogen.

[0204] In some embodiments of the compound of Formula (V), each R 5 is independently halogen or C1-C4 alkyl, and each R 6 is independently halogen or C-C alkyl. In some embodiments, each R 5 are independently halogen, and each R 6 is independently halogen. In some embodiments, each R 5 is independently -F, and each R 6 is independently -F. In some embodiments, each R 5 is -F and t is 0. In some embodiments, R 5 is -F and R 6 is -F.

[0205] In some embodiments of a compound of Formula (IV) or (V), u is 0. In some embodiments, u is 1. In some embodiments, u is 2.

[0206] In some embodiments of a compound of Formula (IV) or (V), s is 0, 1, or 2 and u is 0. In some embodiments, s is 0, 1, or 2 and u is 1. In some embodiments, s is 0, 1, or 2 and u is 2. In some embodiments, s is 0 and u is 0. In some embodiments, s is 1 and u is 0. In some embodiments, s is 2 and u is 0. In some embodiments, s is 0 and u is 1. In some embodiments, s is 1 and u is 1. In some embodiments, s is 2 and t is 1. In some embodiments, s is 0 and u is 2. In some embodiments, s is 1 and u is 2. In some embodiments, s is 2 and u is 2.

[0207] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (V), t is 0, 1, or 2 and u is 0. In some embodiments, t is 0, 1, or 2 and u is 1. In some embodiments, t is 0, 1, or 2 and u is 2. In some embodiments, t is 0 and u is 0. In some embodiments, t is 1 and u is 0. In some embodiments, t is 2 and u is 0. In some embodiments, t is 0 and u is 1. In some embodiments, t is 1 and u is 1. In some embodiments, t is 2 and u is 1. In some embodiments, t is 0 and u is 2. In some embodiments, t is 1 and u is 2. In some embodiments, t is 2 and u is 2.

[0208] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (V), each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R 8 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo.

[0209] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (V), each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, and C-C alkyl; and further, each R 8 is independently hydrogen or C-C alkyl. In some embodiments, each R 10 are independently halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, —CH2CN, and C1-C4 alkyl; and further, each R 8 is independently hydrogen or C-C alkyl. In some embodiments, each R 10are independently halogen, -OR 8 , -N(R 8 )2, —CH2CN, and C1-C4 alkyl; and further, each R 8 is independently hydrogen or C-C alkyl. In some embodiments, each R 10 is independently selected from halogen, —OH, —NH, —COH, —CONH, —CHCN, and C-C alkyl. In some embodiments, each R 10 is independently selected from halogen, —OH, —NH, —CHCN, and C-C alkyl. In some embodiments, each R 10 is independently selected from halogen, —OH, —NH, and C-C alkyl. In some embodiments, each R 10 is independently selected from -F, -Cl, -OH, -NH, and C-C alkyl. In some embodiments, each R 10 is independently selected from -F, -Cl, -OH, -NH, and methyl. In some embodiments, each R 10 is independently selected from -F, -Cl, -OH, and -NH. In some embodiments, each R 10 is independently selected from -F, -OH, and -NH. In some embodiments, each R 10 is independently selected from —F and —OH.

[0210] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is hydrogen, —(C-C alkylene)-OH, —(C-C alkylene)-NH, —(C-C cycloalkylene)-OH, or —(C-C cycloalkylene)-NH. In some embodiments, R 3 is -(C-C alkylene)-OH, -(C-C alkylene)-NH, -(C-C cycloalkylene)-OH, or -(C-C cycloalkylene)-NH. In some embodiments, R3 is -(C1-C4 alkylene)-OH and -(C3-C6 cycloalkylene)-OH. In some embodiments, R 3 is -(C1-C4 alkylene)-NH2 or -(C3-C6 cycloalkylene)-OH.

[0211] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(cyclopropylene)-OH, or -(cyclopropylene)-NH2. In some embodiments, R 3 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(cyclopropylene)-OH, or -(cyclopropylene)-NH2. In some embodiments, R 3 is -(C1-C4 alkylene)-OH and -(cyclopropylene)-OH. In some embodiments, R 3 is -(C1-C4 alkylene)-NH2 or -(cyclopropylene)-OH.

[0212] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is hydrogen. In some embodiments, R 3 is -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -(C1-C2 alkylene)-OH.

[0213] In some embodiments, R 3is -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. In some embodiments, R 3 is —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 3 is —CHOH or —CHCHOH. In some embodiments, R 3 is —CHOH. In some embodiments, R 3 is -CH2CH2OH.

[0214] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is -(C1-C4 alkylene)-NH2. In some embodiments, R 3 is -(C1-C2 alkylene)-NH2. In some embodiments, R 3 is -CHNH, -CHCHNH, -CHCHCHNH, -CHCHCHCHNH, -CHCHCHCHNH, -CH(CH)NH, -CHCH(CH)NH, -CH(CH)CHNH, -CHCH(CHCH)NH, or -CH(CHCH)CHNH. In some embodiments, R 3 is —CHNH, —CHCHNH, or —CH(CH)NH. In some embodiments, R 3 is —CH 2 NH 2 or —CH 2 CH 2 NH 2 . In some embodiments, R 3 is -CH2NH2.

[0215] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 is hydrogen or -(C1-C2 alkylene)-OH. In some embodiments, R 3 is hydrogen, —CHOH, —CHCHOH, —CHCHCHOH, —CHCHCHOH, —CH(CH)OH, —CHCH(CH)OH, —CH(CH)CHOH, —CHCH(CHCH)OH, or —CH(CHCH)CHOH. In some embodiments, R 3 is hydrogen, —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 3 is hydrogen, —CHOH, or —CHCHOH. In some embodiments, R 3 is hydrogen or -CH2OH.

[0216] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is hydrogen, —(C-C alkylene)-OH, or —(C-C alkylene)-NH. In some embodiments, R 3 is hydrogen, —CHOH, —CHCHOH, or —CHNH. In some embodiments, R 3 is hydrogen, -CH2OH, or -CH2NH2.

[0217] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R is -(C-C cycloalkylene)-OH or -(C-C cycloalkylene)-NH. In some embodiments, R 3 is -(C-C cycloalkylene)-OH or -(C-C cycloalkylene)-NH. In some embodiments, R 3is -(C3-C4 cycloalkylene)-OH or -(C3-C4 cycloalkylene)-NH2. In some embodiments, R 3 is -(cyclopropylene)-OH or -(cyclopropylene)-NH. In some embodiments, R 3 teeth,

[0218] [ka] is.

[0219] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is —(C-C cycloalkylene)-OH. In some embodiments, it is —(C-C cycloalkylene)-OH. In some embodiments, R 3 is -(C3-C4 cycloalkylene)-OH. In some embodiments, R 3 is -(cyclopropylene)-OH. In some embodiments, R 3 teeth,

[0220] [ka] is.

[0221] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is -(C-C cycloalkylene)-NH. In some embodiments, R 3 is -(C-C cycloalkylene)-NH. In some embodiments, R 3 is -(C-C cycloalkylene)-NH. In some embodiments, R 3 is -(cyclopropylene)-NH. In some embodiments, R3 teeth,

[0222] [ka] is.

[0223] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 5 and R 6 is independently halogen, or unsubstituted C-C alkyl. In some embodiments, each R 5 and R 6 is independently -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 5 and R 6 is independently -F, -Cl, -CH, -CHCH, or -CH(CH). In some embodiments, each R 5 and R 6 are independently -F, -Cl, or -CH3.

[0224] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 5 is independently halogen, or unsubstituted C-C alkyl. In some embodiments, each R 5 is independently -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 5is independently -F, -Cl, -CH, -CHCH, or -CH(CH). In some embodiments, each R 5 are independently -F, -Cl, or -CH3.

[0225] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 6 is independently halogen, or unsubstituted C-C alkyl. In some embodiments, each R 6 is independently -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 6 is independently -F, -Cl, -CH, -CHCH, or -CH(CH). In some embodiments, each R 6 are independently -F, -Cl, or -CH3.

[0226] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 5 is independently -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH), and t is 0. In some embodiments, each R 5 is independently -F, -Cl, -CH, -CHCH, or -CH(CH), and t is 0. In some embodiments, each R 5 are independently -F, -Cl, or -CH3, and t is 0.

[0227] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), s is 0 and each R 6 is independently -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). In some embodiments, s is 0 and each R 6 is independently -F, -Cl, -CH, -CHCH, or -CH(CH). In some embodiments, s is 0 and each R 6 are independently -F, -Cl, or -CH3.

[0228] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0229] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0230] In some embodiments of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), s is 0, 1, or 2 and t is 0. In some embodiments, s is 0, 1, or 2 and t is 1. In some embodiments, s is 0, 1, or 2 and t is 2. In some embodiments, s is 0 and t is 0. In some embodiments, s is 1 and t is 0. In some embodiments, s is 2 and t is 0. In some embodiments, s is 0 and t is 1. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 1. In some embodiments, s is 0 and t is 2. In some embodiments, s is 1 and t is 2. In some embodiments, s is 2 and t is 2.

[0231] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), t is 0, 1, or 2 and s is 0. In some embodiments, t is 0, 1, or 2 and s is 1. In some embodiments, t is 0, 1, or 2 and s is 2. In some embodiments, t is 0 and s is 0. In some embodiments, t is 1 and s is 0. In some embodiments, t is 2 and s is 0. In some embodiments, t is 0 and s is 1. In some embodiments, t is 1 and s is 1. In some embodiments, t is 2 and s is 1. In some embodiments, t is 0 and s is 2. In some embodiments, t is 1 and s is 2. In some embodiments, t is 2 and s is 2.

[0232] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is halogen. In some embodiments, at least one of the following: (i) s is 1 or 2 and at least one R 5 is halogen; (ii) t is 1 or 2, and at least one R 6 is halogen. In some embodiments, at least one of the following: (i) s is 1 or 2 and at least one R 5 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is halogen. In some embodiments, at least one of the following: (ii) t is 1 or 2 and at least one R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is halogen. In some embodiments, s is 1 or 2 and at least one R 5 In some embodiments, t is 1 or 2 and at least one R 6 is halogen. In some embodiments, R 7The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is a halogen.

[0233] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one of the following: (i) s is 1 or 2 and R 5 is a halogen; (ii) t is 1 or 2; and R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is halogen. In some embodiments, at least one of the following: (i) s is 1 or 2 and R 5 is a halogen; (ii) t is 1 or 2; and R 6 is halogen. In some embodiments, at least one of the following: (i) s is 1 or 2 and R 5 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is halogen. In some embodiments, at least one of the following: (ii) t is 1 or 2 and R 6 is a halogen; (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is halogen. In some embodiments, s is 1 or 2 and R 5 is halogen. In some embodiments, t is 1 or 2 and R 6is halogen. In some embodiments, R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is a halogen.

[0234] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one of the following: (i) s is 1 or 2 and at least one R 5 is -F, (ii) t is 1 or 2, and at least one R 6 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is -F. In some embodiments, at least one of the following: (i) s is 1 or 2 and at least one R 5 is -F, (ii) t is 1 or 2, and at least one R 6 is -F. In some embodiments, at least one of the following: (i) s is 1 or 2 and at least one R 5 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is -F. In some embodiments, at least one of the following: (ii) t is 1 or 2 and at least one R 6 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10In some embodiments, s is 1 or 2 and at least one R 5 In some embodiments, t is 1 or 2 and at least one R 6 is -F. In some embodiments, R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 group and at least one R 10 is -F.

[0235] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one of the following: (i) s is 1 or 2 and R 5 is -F, (ii) t is 1 or 2, and R 6 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is -F. In some embodiments, at least one of the following: (i) s is 1 or 2 and R 5 is -F, (ii) t is 1 or 2, and R 6 is -F. In some embodiments, at least one of the following: (i) s is 1 or 2 and R 5 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is -F. In some embodiments, at least one of the following: (ii) t is 1 or 2 and R 6 is -F, (iii) R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of10 substituted with R 10 In some embodiments, s is 1 or 2 and R 5 In some embodiments, t is 1 or 2 and R 6 is -F. In some embodiments, R 7 The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of 10 substituted with R 10 is -F.

[0236] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one R 5 , R 6 , or R 10 is -F. In some embodiments, at least one R 5 or R 6 is -F. In some embodiments, at least one R 5 or R 10 is -F. In some embodiments, at least one R 10 or R 6 is -F. In some embodiments, at least one R 5 is -F. In some embodiments, at least one R 6 is -F. In some embodiments, at least one R 10 is -F. In some embodiments, at least two R 5 , R 6 , or R 10 is -F. In some embodiments, at least two R 5 or R 6 is -F. In some embodiments, at least two R 5 or R 10 is -F. In some embodiments, at least two R 10 or R 6is -F. In some embodiments, at least two R 5 is -F. In some embodiments, at least two R 6 is -F. In some embodiments, at least two R 10 is -F.

[0237] In some embodiments of a compound, salt, solvate, or stereoisomer of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one R 5 , R 6 , or R 10 is -Cl. In some embodiments, at least one R 5 or R 6 is -Cl. In some embodiments, at least one R 5 or R 10 is -Cl. In some embodiments, at least one R 10 or R 6 is -Cl. In some embodiments, at least one R 5 is -Cl. In some embodiments, at least one R 6 is -Cl. In some embodiments, at least one R 10 is -Cl. In some embodiments, at least two R 5 , R 6 , or R 10 is -Cl. In some embodiments, at least two R 5 or R 6 is -F. In some embodiments, at least two R 5 or R 10 is -Cl. In some embodiments, at least two R 10 or R 6 is -Cl. In some embodiments, at least two R 5 is -Cl. In some embodiments, at least two R 6is -Cl. In some embodiments, at least two R 10 is -Cl.

[0238] In some embodiments, the compound is

[0239] [ka] is selected from.

[0240] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a diastereomer of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0241] [Table 1-1]

[0242] [Table 1-2]

[0243] [Table 1-3]

[0244] [Table 1-4]

[0245] [Table 1-5]

[0246] [Table 1-6]

[0247] [Table 1-7]

[0248] [Table 1-8]

[0249] In another aspect, the present disclosure provides a compound having the structure of formula (VI):

[0250] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 11 is C1-C4 alkyl, R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 14 is hydrogen or C1-C4 alkyl, Each R 15 and R 16 are independently halogen or C1-C4 alkyl; R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; Each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-selected from R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2; and w is 0, 1, or 2.

[0251] In some embodiments, L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-, then at least one of the following: (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; (ii)R 14 is C1-C4 alkyl; (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv)L 2 is -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl.

[0252] In some embodiments, L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2.

[0253] In some embodiments, L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 14 is C1-C4 alkyl.

[0254] In some embodiments, L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0255] In some embodiments, L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, L 2 is -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl.

[0256] In some embodiments of the compound of Formula (VI), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 14 is hydrogen, and each R 15 and R 16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -O-(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-, then at least one of the following is true: (i) R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (ii) R 14 is C1-C4 alkyl, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv) L 2 is -O-(C1-C6 alkylene)-, and R 17is unsubstituted or substituted 5-membered heterocycloalkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0257] In some embodiments of the compound of Formula (VI), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0258] In some embodiments of the compound of Formula (VI), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH 2、 -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen, and each R 15 and R16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-, then at least one of the following is true: (i) R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (ii) R 14 is C1-C4 alkyl, (iii) R 17is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl, v is 0, 1, or 2, and w is 0, 1, or 2.

[0259] In another aspect, the present disclosure provides a compound having the structure of formula (VIa) or (VIb):

[0260] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0261] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-, then at least one of the following is true: (i) R 13is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (ii) R 14 is C1-C4 alkyl, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv) L 2 is -O-(C1-C6 alkylene)-, and R 17 is unsubstituted or substituted 5-membered heterocycloalkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0262] In some embodiments of compounds of Formula (VIa) or (VIb), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 14 is hydrogen, and each R 15 and R 16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -O-(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, —(C1-C6 alkylene)-, —O—, or —O—(C1-C6 alkylene)-, then at least one of the following is true: (i) R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (ii) R 14 is C1-C4 alkyl, (iii) R 17is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv) L 2 is -O-(C1-C6 alkylene)-, and R 17 is unsubstituted or substituted 5-membered heterocycloalkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0263] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo;18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0264] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0265] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 4-membered heterocycloalkyl substituted with 2, each of which is unsubstituted or a halogen, —OR 18 , -N(R18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the aryl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen are substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0266] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is a 5-membered heterocycloalkyl that is unsubstituted or is selected from the group consisting of halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the aryl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen are substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is —O—(C1-C6 alkylene)-, v is 0, 1, or 2, and w is 0, 1, or 2.

[0267] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is C1-C4 alkyl, and R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 14 is hydrogen or C1-C4 alkyl, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0268] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 14 is hydrogen, and each R 15 and R 16 is -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, (C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0269] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 14 is hydrogen, and each R 15 and R 16 is -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0270] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen or -CHOH, and R 14 is hydrogen, and each R 15 and R 16 is -F and R 17 is a 4- to 8-membered heterocycloalkyl that is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with one or two groups independently selected from —CN, —OH, and oxadiazolyl; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0271] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen or -CHOH, and R 14 is hydrogen, and each R 15 and R 16 is -F and R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with one or two groups selected from —CN, —OH, and oxadiazolyl; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2;

[0272] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen or -CHOH, and R 14 is hydrogen, and each R 15 and R 16 is -F and R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently selected from -F, -OH, -OCH3, and -NH; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted six-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0273] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 is -CH3 and R 12a and R 12b are each hydrogen, and R 13 is hydrogen or -CHOH, and R14 is hydrogen, and each R 15 and R 16 is -F and R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently -F, -OH, -OCH3, and -NH2, and L 2 But -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0274] In some embodiments, the compound is a compound of Formula (VIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0275] For any and all of the embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is unsubstituted C1-C4 alkyl. In some embodiments, R 11 is C1-C2 alkyl. In some embodiments, R 11 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 11 is -CH3 or -CH2CH3. In some embodiments, R 11is -CH3.

[0276] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (VI), (VIa), or (VIb), R 12a and R 12b are each independently R 12a and R 12b are each independently hydrogen, halogen, or unsubstituted C-C alkyl. In some embodiments, R 12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 12a and R 12b are each independently hydrogen, —F, —Cl, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

[0277] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (VI), (VIa), or (VIb), R 12a is hydrogen. In some embodiments, R 12b is hydrogen. In some embodiments, R 12a and R 12b are each hydrogen.

[0278] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (VI), (VIa), or (VIb), R 11 is -CH3 and R 12a is hydrogen and R 12b is hydrogen.

[0279] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (VI), (VIa), or (VIb), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14is hydrogen or C-C alkyl. In some embodiments, R 14 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH). In some embodiments, R 14 is hydrogen, —CH, or —CHCH. In some embodiments, R 14 is hydrogen or —CH. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is -CH3.

[0280] In some embodiments, the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0281] In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VII):

[0282] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0283] In some embodiments of the compound of Formula (VII), R 13 is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, then at least one of the following is true: (i) R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl; or (iv) L 2 is -O-(C1-C6 alkylene)-, and R 17 is unsubstituted or substituted 5-membered heterocycloalkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0284] In some embodiments of the compound of Formula (VII), R 13 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 14 is hydrogen, and each R 15 and R 16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl, where v is 0, 1, or 2, and w is 0, 1, or 2.

[0285] In some embodiments of the compound of Formula (VII), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0286] In some embodiments of the compound of Formula (VI), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH 2、 -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 8are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, —(C-C alkylene)-, —O—, or —O—(C-C alkylene)-, and then at least one of the following: (i) R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, (ii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl, v is 0, 1, or 2, and w is 0, 1, or 2.

[0287] In some embodiments, the compound of Formula (VI) or (VII) is a compound of Formula (VIIa) or Formula (VIIb):

[0288] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0289] In some embodiments of compounds of Formula (VIIa) or (VIIb), R 13is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and each R 15 and R 16 are independently -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and each R 8 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19)-, and R 19 is hydrogen or C1-C6 alkyl, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl, where v is 0, 1, or 2, and w is 0, 1, or 2.

[0290] In some embodiments of compounds of Formula (VII), (VIIa), or (VIIb), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is a 5-membered heterocycloalkyl that is unsubstituted or is selected from the group consisting of halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 is —O—(C1-C6 alkylene)-, v is 0, 1, or 2, and w is 0, 1, or 2.

[0291] In some embodiments of compounds of Formula (VII), (VIIa), or (VIIb), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 are independently halogen or C1-C4 alkyl, and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with a halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18)2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0292] In some embodiments, the compound is a compound of Formula (VIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0293] In some embodiments, the compound of Formula (VI) or (VII) is a compound of Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), or Formula (VIIId):

[0294] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0295] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen, —(C1-C4 alkylene)-OH, or —(C1-C4 alkylene)-NH2, and each R 15 and R 16 is -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0296] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13is hydrogen, —(C1-C4 alkylene)-OH, or —(C1-C4 alkylene)-NH2, and each R 15 and R 16 is -F and R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0297] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen or -CHOH, and each R 15 and R 16 is -F and R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently selected from -F, -OH, -OCH3, and -NH; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl, v is 0, 1, or 2, and w is 0, 1, or 2, provided that L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, R 17 is an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted six-membered oxygen-containing heterocycloalkyl, a di- or tri-substituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0298] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen or -CHOH, and each R 15 and R 16 is -F and R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently -F, -OH, -OCH3, and -NH2, and L 2 But -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; and w is 0, 1, or 2.

[0299] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIId), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0300] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -(C1-C6 alkylene)-, -X 3- or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl. In some embodiments, L 2 is a bond, -(C1-C3 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 is a bond, -(C1-C2 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 is a bond, -CH2-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, each R 19 are independently hydrogen or methyl. In some embodiments, R 19 is hydrogen.

[0301] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 -CH2-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 is a bond, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, R 19 is hydrogen.

[0302] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 In some embodiments, L is selected from -S-, -S(=O)-, and -S(=O)-. 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -O- and -N(R 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each selected from -O- and -S-. In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 In some embodiments, R 19 is hydrogen.

[0303] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from —O—, —N(H)—, —S—, —S(═O)—, —S(═O)—, and —S(═O)(═NH)—. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 Each is selected from -O-. In some embodiments, L 2 is -O-.

[0304] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is —O— or —O—(C1-C6 alkylene)-. In some embodiments, L 2 is -N(R 19 )- or -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -S- or -S-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)- or -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)2- or -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)(=NR 19 )- or -S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is —O—. In some embodiments, L 2 is -N(R 19 In some embodiments, R 19 is hydrogen. In some embodiments, L 2 is -S-. In some embodiments, L2 is -S(=O)-. In some embodiments, L 2 is -S(=O)2-. In some embodiments, L 2 is -S(=O)(=NR 19 In some embodiments, L 2 is —O—(C1-C6 alkylene)-. In some embodiments, L 2 is -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -S-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is —O— or —O—(CH)—. In some embodiments, L 2 is —N(H)— or —N(H)—(CH)—. In some embodiments, L 2 is -S- or -S-(CH)-. In some embodiments, L 2 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L 2 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L 2 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH)-. In some embodiments, L 2 is —O—(CH)—. In some embodiments, L 2 is —N(H)—(CH)—. In some embodiments, L 2 is -S-(CH)-. In some embodiments, L 2 is -S(=O)-(CH2)-. In some embodiments, L 2is -S(=O)2-(CH2)-. In some embodiments, L 2 is -S(=O)(=NH)-(CH2)-.

[0305] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), in some embodiments, R 17 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C-C alkyl, —C(═O)—C-C alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from —F, —CN, —OH, —CHOH, —NH, —OMe, —N(CH), —COH, —CONH, —SOCH, —C(═NH)NH, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from —F, —CN, —OH, —NH, —OMe, —N(CH), —COH, —CONH, and —SOCH.

[0306] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -NHSO2R 18 , —CHCN, C1-C4 alkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; each R 18 are independently hydrogen, C1-C4 alkyl, —C(═O)—C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted with 1, 2, or 3 groups selected from —F, —CN, —OH, —COH, —C(═NH)NH2, and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1-CONH2 group.

[0307] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 17is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0308] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20is independently selected from -F, -Cl, and -OH. In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from —F and —OH.

[0309] In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0310] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from —F and —OH.

[0311] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0312] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 17is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from —F and —OH.

[0313] In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 are independently hydrogen or —C(═O)—C1-C2 alkyl.

[0314] In some embodiments of compound (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 17 is a 5-membered heterocycloalkyl, which is unsubstituted or contains 1, 2, or 3 R 20 groups, and each R 20 is independently selected from —F and —OH.

[0315] In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 , and -CHCN, and each R 18 are independently hydrogen, C1-C2 alkyl, or —C(═O)—C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from —CN, —OH, and oxadiazolyl. In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 is independently hydrogen, C-C alkyl, or —C(═O)—C-C alkyl. In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 are independently halogen, -OH, -OR 18 , -N(R 18 )2, and -CH2CN, and each R 18 are independently hydrogen or C1-C2 alkyl.

[0316] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, R 17 is three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0317] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19In some embodiments, L is selected from -S-, -S(=O)-, and -S(=O)-. 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -S- and -N(R 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are -S(=O)2- and -N(R 19 In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -S(=O)(=NR 19 )- and -N(R 19 In some embodiments, R 19 is hydrogen.

[0318] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, L 2 -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are respectively -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0319] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, L 2is -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. 2 is -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, L 2 is -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0320] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -N(R 19 )- and -S-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is -N(R 19 )- and -S-, and R17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, L 2 is -N(R 19 )- and -S-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. 2 is -N(R 19 )- and -S-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, L 2 is -N(R 19 )- and -S-, and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0321] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene)-; R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L2 is -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene), and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, L 2 is -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene), and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. 2 is -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene), and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, L 2 is -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene), and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0322] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -N(R 19 )- and R 17is azetidine, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is -N(R 19 )- and R 17 is azetidine, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —CHCN. In some embodiments, L 2 is -N(R 19 )- and R 17 is azetidine, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -CHCN. In some embodiments, L 2 is -N(R 19 )- and R 17 is azetidine, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is -CHCN.

[0323] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -N(R 19 )- and R 17 is a cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is selected from the group consisting of halogen, -OR 18 , -N(R 18 In some embodiments, L 2 is -N(R 19 )- and R 17is a cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C1-C6 alkyl, and the C1-C6 alkyl is substituted with halogen or —N(R 18 In some embodiments, L 2 is -N(R 19 )- and R 17 is cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C-C alkyl, wherein the C-C alkyl is substituted with halogen or —N(H)(CHCN). In some embodiments, L 2 is -N(R 19 )- and R 17 is a cyclobutane, wherein the cyclobutane is substituted with a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a halogen or —N(H)(CH2CN).

[0324] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth

[0325] [ka] is.

[0326] In some embodiments of compound (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth

[0327] [ka] is.

[0328] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth

[0329] [ka] is. In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth

[0330] [ka] is.

[0331] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20is independently selected from halogen and —OH. In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2, and L 2 is -O- and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0332] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is -CH3, L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 13 teeth,

[0333] [ka] and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 13 teeth,

[0334] [ka] and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 13 teeth,

[0335] [ka] and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, R 13 teeth,

[0336] [ka] and L 2 is -O- and R 17 can contain one, two, or three R 20tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0337] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is C1-C4 alkyl, and L 2 -R 17 teeth,

[0338] [ka] In some embodiments, R 14 is C1-C4 alkyl, and L 2 -R 17 teeth,

[0339] [ka] In some embodiments, R 13 teeth,

[0340] [ka] and L 2 -R 17 teeth,

[0341] [ka] In some embodiments, R 13 teeth,

[0342] [ka] and L 2 -R 17 teeth,

[0343] [ka] is.

[0344] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is C1-C4 alkyl, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is R 14 is C1-C4 alkyl, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 14 is C1-C4 alkyl, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 14 is C1-C4 alkyl, and L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, R 14 is C1-C4 alkyl, and L 2 is -O- and R 17can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0345] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is -CH3, L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, R 14 is -CH3, L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, R 14 is -CH3, L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. In some embodiments, R 14 is -CH3, L 2 is -O- and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, R 14 is -CH3, L 2is -O- and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0346] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L is C-C alkyl; 2 -R 17 teeth,

[0347] [ka] In some embodiments, R 14 is C1-C4 alkyl, and L 2 -R 17 teeth,

[0348] [ka] In some embodiments, R 14 is -CH3, L 2 -R 17 teeth,

[0349] [ka] In some embodiments, R 14 is -CH3, L 2 -R 17 teeth,

[0350] [ka] is.

[0351] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 )2. In some embodiments, L 2 is -O- or -O-C1-C6 alkylene-, and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0352] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -CH2-, -O-, or -O-CH2-, and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 )2. In some embodiments, L 2 is -O- or -O-CH2-, and R 17is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 )2. In some embodiments, L 2 is -O- and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted sulfur-containing heterocycloalkyl, an unsubstituted or substituted bicyclic heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, a disubstituted or trisubstituted cycloalkyl, or at least one —N(R 18 ) 2-substituted 4-membered heterocycloalkyl.

[0353] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -(C1-C6 alkylene)-, -O-, or -O-(C1-C6 alkylene)-, and R 17 is unsubstituted or substituted hexahydrofuro[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one —N(R 18 In some embodiments, L is an oxetane substituted with 2 is -O- or -O-C1-C6 alkylene-, and R 17 is unsubstituted or substituted hexahydrofuran[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one -N(R 18 ) substituted oxetane.

[0354] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -CH2-, -O-, or -O-CH2-, and R 17 is unsubstituted or substituted hexahydrofuro[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one -N(R 18 In some embodiments, L is an oxetane substituted with 2 is -O- or -O-CH2-, and R 17 is unsubstituted or substituted hexahydrofuro[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one —N(R 18 In some embodiments, L is an oxetane substituted with 2 is -O- and R 17 is unsubstituted or substituted hexahydrofuro[3,2-b]furan, unsubstituted or substituted tetrahydrothiophene-1-oxide, unsubstituted or substituted 3-oxabicyclo[3.1.0]hexane, unsubstituted or substituted tetrahydropyran, disubstituted or trisubstituted cyclopropyl, or at least one —N(R 18 ) substituted oxetane.

[0355] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is a bond, -CH2-, -O-, or -O-CH2-, and R 17is an unsubstituted or substituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O- or -O-CH2-, and R 17 is an unsubstituted or substituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O- and R 17 is an unsubstituted or substituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O- and R 17 is an unsubstituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O- and R 17 is a substituted azaspiro[3.3]heptane, wherein the azaspiro[3.3]heptane is substituted with —CH CN.

[0356] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth,

[0357] [ka] is.

[0358] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -O-(C1-C6 alkylene)-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is -O-(C1-C6 alkylene)-, and R 17is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from halogen and —OH. In some embodiments, L 2 is -O-(C1-C6 alkylene)-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from -F, -Cl, and -OH. 2 is -O-(C1-C6 alkylene)-, and R 17 is tetrahydrofuran, which is unsubstituted or contains one, two, or three R 20 groups, and each R 20 is independently selected from —F and —OH. In some embodiments, L 2 is -O-(C1-C6 alkylene)-, and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0359] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -OCH2- and R 17 is tetrahydrofuran, unsubstituted or containing one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from halogen, —OH, —NH, and —CHCN. In some embodiments, L 2 is -OCH2- and R 17 is tetrahydrofuran, unsubstituted or containing one, two, or three R 20tetrahydrofuran substituted with a group, 20 is independently selected from halogen and —OH. In some embodiments, L 2 is -OCH2- and R 17 is tetrahydrofuran, unsubstituted or containing one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from -F, -Cl, and -OH. 2 is -OCH2- and R 17 is tetrahydrofuran, unsubstituted or containing one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH. In some embodiments, L 2 is -OCH2- and R 17 can contain one, two, or three R 20 tetrahydrofuran substituted with a group, 20 is independently selected from —F and —OH.

[0360] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth,

[0361] [ka] is.

[0362] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 teeth,

[0363] [ka] is.

[0364] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a single diastereomer. In some embodiments, R 17 is a single diastereomer, R 17 In some embodiments, R 17 is a single diastereomer, R 17 In some embodiments, R 17 is a single diastereomer, R 17 shows improved efficacy in vivo relative to a comparison compound of which the isomer is a different stereoisomer.

[0365] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is one or two R 20 groups, and each R 20 are independently halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 In some embodiments, R 17 is one or two R 20 groups, and each R 20 is independently selected from halogen, —OH, and —CHCN. In some embodiments, R 17 is one or two R 20 groups, and each R 20is independently selected from -F, -Cl, -OH, and -CHCN. In some embodiments, R 17 is a 4-6 membered heterocycloalkyl substituted with -OH.

[0366] In some embodiments, R 17 is 1,2-trans-disubstituted 4-6 membered heterocycloalkyl. In some embodiments, L 2 -R 17 teeth,

[0367] [ka] In some embodiments, L 2 -R 17 teeth,

[0368] [ka] In some embodiments, L 2 -R 17 teeth,

[0369] [ka] In some embodiments, L 2 -R 17 teeth,

[0370] [ka] is.

[0371] In some embodiments, R 17 is 1,2-cis-disubstituted 4-6 membered heterocycloalkyl. In some embodiments, L 2 -R 17 teeth,

[0372] [ka] In some embodiments, L2 -R 17 teeth,

[0373] [ka] In some embodiments, L 2 -R 17 teeth,

[0374] [ka] In some embodiments, L 2 -R 17 teeth,

[0375] [ka] is.

[0376] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen, —(C-C alkylene)-OH, —(C-C alkylene)-NH, —(C-C cycloalkylene)-OH, or —(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(C-C alkylene)-OH, -(C-C alkylene)-NH, -(C-C cycloalkylene)-OH, or -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(C1-C4 alkylene)-OH and -(C3-C6 cycloalkylene)-OH. In some embodiments, R 13 is -(C1-C4 alkylene)-NH2 or -(C3-C6 cycloalkylene)-OH.

[0377] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(cyclopropylene)-OH, or -(cyclopropylene)-NH2. In some embodiments, R 13 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(cyclopropylene)-OH, or -(cyclopropylene)-NH2. In some embodiments, R 13 is -(C1-C4 alkylene)-OH and -(cyclopropylene)-OH. In some embodiments, R 13 is -(C1-C4 alkylene)-NH2 or -(cyclopropylene)-OH.

[0378] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen. In some embodiments, R 13 is -(C1-C4 alkylene)-OH. In some embodiments, R 13 is -(C1-C2 alkylene)-OH.

[0379] In some embodiments, R 13 is -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. In some embodiments, R 13 is —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 13 is —CHOH or —CHCHOH. In some embodiments, R 13is —CHOH. In some embodiments, R 13 is -CH2CH2OH.

[0380] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is -(C1-C4 alkylene)-NH2. In some embodiments, R 13 is -(C1-C2 alkylene)-NH2. In some embodiments, R 13 is -CHNH, -CHCHNH, -CHCHCHNH, -CHCHCHCHNH, -CHCHCHCHNH, -CH(CH)NH, -CHCH(CH)NH, -CH(CH)CHNH, -CHCH(CHCH)NH, or -CH(CHCH)CHNH. In some embodiments, R 13 is —CHNH, —CHCHNH, or —CH(CH)NH. In some embodiments, R 13 is —CH 2 NH 2 or —CH 2 CH 2 NH 2 . In some embodiments, R 13 is -CH2NH2.

[0381] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 13 is hydrogen or -(C1-C2 alkylene)-OH. In some embodiments, R 13 is hydrogen, —CHOH, —CHCHOH, —CHCHCHOH, —CHCHCHOH, —CH(CH)OH, —CHCH(CH)OH, —CH(CH)CHOH, —CHCH(CHCH)OH, or —CH(CHCH)CHOH. In some embodiments, R 13is hydrogen, —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 13 is hydrogen, —CHOH, or —CHCHOH. In some embodiments, R 13 is hydrogen or -CH2OH.

[0382] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen, —(C-C alkylene)-OH, or —(C-C alkylene)-NH. In some embodiments, R 13 is hydrogen, —CHOH, —CHCHOH, or —CHNH. In some embodiments, R 13 is hydrogen, -CH2OH, or -CH2NH2.

[0383] In some embodiments of compound (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from —N(H)—, —S—, —S(═O)—, —S(═O)2—, and —S(═O)(═NH)—.

[0384] In some embodiments, the compound is a compound of Formula (VIIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (VIIId), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0385] In some embodiments, the compound of formula (VI) is a compound of formula (IX):

[0386] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0387] In some embodiments of the compound of Formula (IX), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 is -F, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; w is 0, 1, or 2; and y is 0, 1, or 2.

[0388] In some embodiments of the compound of Formula (IX), R 13 is -CH2-OH, CH2-NH2, (cyclopropylene)-OH, or -(cyclopropylene)-NH2, and each R 15 and R 16 is -F, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; w is 0, 1, or 2; and y is 0, 1, or 2.

[0389] In some embodiments, the compound of formula (VI) is a compound of formula (X):

[0390] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0391] In some embodiments of the compound of Formula (IX), R 13is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-NH2, and each R 15 and R 16 is -F, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0, 1, or 2; w is 0, 1, or 2; and y is 0, 1, or 2.

[0392] In some embodiments of the compound of Formula (IX), R 13 is -CH2-OH, CH2-NH2, (cyclopropylene)-OH, or -(cyclopropylene)-NH2, and each R 15 and R 16 is -F, and each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 - or -X 4 -(C1-C6 alkylene)-, and X 3 and X 4 are each independently -N(R 19 )-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR 19 )-, and R 19 is hydrogen or C1-C6 alkyl; v is 0; w is 0; and y is 0, 1, or 2.

[0393] In some embodiments of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), is -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 is -(C-C cycloalkylene)-OH or -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(C3-C4 cycloalkylene)-OH or -(C3-C4 cycloalkylene)-NH2. In some embodiments, R 13 is -(cyclopropylene)-OH or -(cyclopropylene)-NH. In some embodiments, R 13 teeth,

[0394] [ka] is.

[0395] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R 13 is —(C-C cycloalkylene)-OH. In some embodiments, it is —(C-C cycloalkylene)-OH. In some embodiments, R 13 is -(C3-C4 cycloalkylene)-OH. In some embodiments, R 13 is -(cyclopropylene)-OH. In some embodiments, R 13 teeth,

[0396] [ka] is.

[0397] In some embodiments of the compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R 13 is -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(C-C cycloalkylene)-NH. In some embodiments, R 13 is -(cyclopropylene)-NH. In some embodiments, R 13 teeth,

[0398] [ka] is.

[0399] In some embodiments of a compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from -N(H)-, -S-, -S(=O)-, -S(=O)-, and -S(=O)(=NH)-. 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from -N(H)-, -S-, -S(=O)-, and -S(=O)-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4are each selected from -N(H)-, -S-, -S(=O)-, and -S(=O)(=NH)-. 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from -N(H)-, -S-, -S(=O)-, and -S(=O)(=NH)-. 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, and X 3 and X 4 are each selected from -N(H)- and -S-.

[0400] In some embodiments of a compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), L 2 is -N(R 19 )- or -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -S- or -S-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)- or -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)2- or -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)(=NR 19 )- or -S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -N(R 19 In some embodiments, R 19 is hydrogen. In some embodiments, L 2 is -S-. In some embodiments, L 2 is -S(=O)-. In some embodiments, L2 is -S(=O)2-. In some embodiments, L 2 is -S(=O)(=NR 19 In some embodiments, L 2 is -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -S-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 2 is -S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is —N(H)— or —N(H)—(CH)—. In some embodiments, L 2 is -S- or -S-(CH)-. In some embodiments, L 2 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L 2 is —S(═O)— or —S(═O)—(CH)—. In some embodiments, L 2 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH)-. In some embodiments, L 2 is —N(H)—(CH)—. In some embodiments, L 2 is -S-(CH2)-. In some embodiments, L 2 is -S(=O)-(CH2)-. In some embodiments, L 2 is -S(=O)2-(CH2)-. In some embodiments, L 2 is -S(=O)(=NH)-(CH2)-.

[0401] In some embodiments of a compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 1 or 2.

[0402] In some embodiments of a compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 1 or 2.

[0403] In some embodiments of a compound of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), w is 0 and v is 0.

[0404] In some embodiments of a compound of Formula (IX) or (X), y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 1 or 2.

[0405] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (IX) or (X), each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18, —CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, —C(═O)—C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo; and further, each R 18 are independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R 18 are taken together to form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo.

[0406] In some embodiments of the compound, salt, solvate, or stereoisomer of Formula (IX) or (X), each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18 , -CON(R 18 )2, -CH2N(R 18 )2, -NHCOR 18 , -NHSO2R 18 , —CHCN, and C-C alkyl; and further, each R 18 is independently hydrogen or C-C alkyl. In some embodiments, each R 20 are independently halogen, -OR 18 , -N(R 18 )2, -CO2R 18, -CON(R 18 )2, —CH2CN, and C1-C4 alkyl; and further, each R 18 is independently hydrogen or C-C alkyl. In some embodiments, each R 20 are independently halogen, -OR 18 , -N(R 18 )2, —CH2CN, and C1-C4 alkyl; and further, each R 18 is independently hydrogen or C-C alkyl. In some embodiments, each R 20 is independently selected from halogen, —OH, —NH, —COH, —CONH, —CHCN, and C-C alkyl. In some embodiments, each R 20 is independently selected from halogen, —OH, —NH, —CHCN, and C-C alkyl. In some embodiments, each R 20 is independently selected from halogen, —OH, —NH, and C-C alkyl. In some embodiments, each R 20 is independently selected from -F, -Cl, -OH, -NH, and C-C alkyl. In some embodiments, each R 20 is independently selected from -F, -Cl, -OH, -NH, and methyl. In some embodiments, each R 20 is independently selected from -F, -Cl, -OH, and -NH. In some embodiments, each R 20 is independently selected from -F, -OH, and -NH. In some embodiments, each R 20 is independently selected from -F and -OH. In some embodiments, each R 20 is -OH.

[0407] In some embodiments, the compound is

[0408] [ka] Selected from JPEG2025526728000098.jpg178160.

[0409] In some embodiments, the compound is a compound of Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a diastereomer of a compound of Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0410] [Table 2-1]

[0411] [Table 2-2]

[0412] [Table 2-3]

[0413] [Table 2-4]

[0414] [Table 2-5]

[0415] In some embodiments, the compound is a compound of formula (XI):

[0416] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 11 is C1-C4 alkyl, R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 14 is hydrogen or C1-C4 alkyl, Each R 15 and R 16 are independently halogen or C1-C4 alkyl; R 23 and R 24 is R 23 R 24 and the intervening carbon atom to which they are attached form ring A which is C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl, and the C3-C6 cycloalkyl or 4-8 membered heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, -OR 25 , -N(R 25 )2, -CO2R 25 , -COR 25 , -CON(R 25 )2, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, and oxo; Each R 25 are independently hydrogen or C1-C4 alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, and oxo; or two R attached to the same nitrogen 25 taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; v is 0, 1, or 2; and

[0417] w is 0, 1, or 2. In some embodiments of the compound of Formula (XI), R 11 is unsubstituted C1-C4 alkyl. In some embodiments, R 11 is C1-C2 alkyl. In some embodiments, R 11 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 11 is -CH3 or -CH2CH3. In some embodiments, R 11 is -CH3.

[0418] In some embodiments of the compound of Formula (XI), R 12a and R 12b are each independently R 12a and R 12b are each independently hydrogen, halogen, or unsubstituted C-C alkyl. In some embodiments, R 12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 12a and R 12b are each independently hydrogen, —F, —Cl, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

[0419] In some embodiments of the compound of Formula (XI), R 12a is hydrogen. In some embodiments, R 12b is hydrogen. In some embodiments, R 12a and R 12b are each hydrogen.

[0420] In some embodiments of the compound of Formula (XI), R 13is hydrogen, —(C-C alkylene)-OH, —(C-C alkylene)-NH, —(C-C cycloalkylene)-OH, or —(C-C cycloalkylene)-NH. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is -(C1-C4 alkylene)-OH. In some embodiments, R 13 is -(C1-C2 alkylene)-OH.

[0421] In some embodiments of the compound of Formula (XI), R 13 is -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. In some embodiments, R 13 is —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 13 is —CHOH or —CHCHOH. In some embodiments, R 13 is -CHOH.

[0422] In some embodiments of the compound of Formula (XI), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14 is hydrogen or C-C alkyl. In some embodiments, R 14 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH). In some embodiments, R 14 is hydrogen, —CH, or —CHCH. In some embodiments of the compound of Formula (XI), R 14 is hydrogen or —CH. In some embodiments, R 14 is hydrogen. In some embodiments, R 14is -CH3.

[0423] In some embodiments of compounds of Formula (XI), w is 0 and v is 0. In some embodiments, w is 0. In some embodiments, v is 0.

[0424] In some embodiments of the compound of Formula (XI), R 23 and R 24 is R 23 R 24 and the intervening carbon atoms to which it is attached form ring A which is a C3-C6 cycloalkyl or a 4- to 8-membered heterocycloalkyl, where the C3-C6 cycloalkyl or the 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, and oxo.

[0425] In some embodiments of the compound of Formula (XI), R 23 and R 24 is R 23 R 24 and the intervening carbon atoms to which R is attached form ring A, which is a 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, C-C alkyl, and oxo. 23 and R 24 is R 23 R 24 and the intervening carbon atoms to which it is attached form ring A which is a 4-6 membered heterocycloalkyl containing 1-2 O atoms or 1-2 N atoms, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, C-C alkyl, and oxo.

[0426] In some embodiments of the compound of Formula (XI), R 23 and R 24 is R23 R 24 and the intervening carbon atom to which they are attached form ring A which is a 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, -OR 25 , -N(R 25 )2, -CO2R 25 , -COR 25 , -CON(R 25 )2, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, and oxo.

[0427] In some embodiments of the compound of Formula (XI), R 23 and R 24 is R 23 R 24 and the intervening carbon atoms to which it is attached form ring A, which is a 5- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and oxo.

[0428] In some embodiments of the compound of Formula (XI), R 23 and R 24 is R 23 R 24 together with the intervening carbon atom that bonds to

[0429] [ka] This forms ring A,

[0430] In some embodiments of the compound of formula (XI),

[0431] [ka] is.

[0432] In some embodiments, the compound is a compound of Table 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a diastereomer of a compound of Table 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0433] [Table 3]

[0434] In some embodiments, the compound is a compound of formula (XII):

[0435] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 11 is C1-C4 alkyl, R 12a and R 12b are each independently hydrogen, halogen, or C1-C4 alkyl; R 13 is hydrogen, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-NH2, —(C3-C6 cycloalkylene)-OH, or —(C3-C6 cycloalkylene)-NH2, R 14 is hydrogen or C1-C4 alkyl, Each R 15 and R 16 are independently halogen or C1-C4 alkyl; R 26 is C1-C6 alkyl, C1-C6 fluoroalkyl, 4- to 6-membered heterocycloalkyl, heteroaryl, -C(=O)-C1-C6 alkyl, -C(=O)-N(R 28 )2, -CH2-C(=O)-N(R 28)2, or —S(O)2—C1-C6 alkyl, wherein C1-C6 fluoroalkyl, C1-C6 alkyl, 4- to 6-membered heterocycloalkyl, and heteroaryl are unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, —OH, —NH2, and —CN; Each R 27 are independently hydrogen or C1-C6 alkyl; Each R 28 are independently hydrogen or C1-C6 alkyl; or two R attached to the same nitrogen 28 taken together form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH, -OMe, -COH, -CONH, -SOCH, and oxo; y is 0, 1, or 2; v is 0, 1, or 2; and w is 0, 1, or 2.

[0436] In some embodiments of the compound of Formula (XII), R 11 is unsubstituted C1-C4 alkyl. In some embodiments, R 11 is C1-C2 alkyl. In some embodiments, R 11 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 11 is -CH3 or -CH2CH3. In some embodiments, R 11 is -CH3.

[0437] In some embodiments of the compound of Formula (XII), R 12a and R 12b are each independently R 12a and R 12bare each independently hydrogen, halogen, or unsubstituted C-C alkyl. In some embodiments, R 12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). In some embodiments of the compound of Formula (XII), R 12a and R 12b are each independently hydrogen, —F, —Cl, —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

[0438] In some embodiments of the compound of Formula (XII), R 12a is hydrogen. In some embodiments, R 12b is hydrogen. In some embodiments, R 12a and R 12b are each hydrogen.

[0439] In some embodiments of the compound of Formula (XII), R 13 is hydrogen, —(C-C alkylene)-OH, —(C-C alkylene)-NH, —(C-C cycloalkylene)-OH, or —(C-C cycloalkylene)-NH. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is -(C1-C4 alkylene)-OH. In some embodiments, R 13 is -(C1-C2 alkylene)-OH.

[0440] In some embodiments of the compound of Formula (XII), R 13 is -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. In some embodiments, R 13is —CHOH, —CHCHOH, or —CH(CH)OH. In some embodiments, R 13 is —CHOH or —CHCHOH. In some embodiments, R 13 is -CHOH.

[0441] In some embodiments of the compound of Formula (XII), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14 is hydrogen or C-C alkyl. In some embodiments, R 14 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH). In some embodiments, R 14 is hydrogen, —CH, or —CHCH. In some embodiments, R 14 is hydrogen or —CH. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is -CH3.

[0442] In some embodiments of a compound of Formula (XII), w is 0 and v is 0. In some embodiments, w is 0. In some embodiments, v is 0.

[0443] In some embodiments of compounds of Formula (XI), y is 0. In some embodiments, y is 1. In some embodiments, y is 1 and R 28 is C1-C3 alkyl. In some embodiments, y is 1 and R 28 is CH3.

[0444] In some embodiments of the compound of Formula (XII), R 26is C1-C6 alkyl, C1-C6 fluoroalkyl, oxetanyl, imidazolyl, -C(=O)-CH3, -S(O)2-CH3, -C(=O)-C1-C6 alkyl, -C(=O)-N(R 28 )2, -CH2-C(=O)-NH(CH3), wherein C1-C6 fluoroalkyl, C1-C6 alkyl, oxetanyl, and imidazolyl are unsubstituted or substituted with 1, 2, or 3 groups independently selected from halogen, -CH3, -OH, -NH2, and -CN; and each R 28 are independently hydrogen or -CH3, and two R 28 together to form morpholinyl.

[0445] In some embodiments of the compound of Formula (XII), R 26 teeth

[0446] [ka] In some embodiments of the compound of Formula (XII), R 26 teeth,

[0447] [ka] is.

[0448] In some embodiments, the compound is a compound of Table 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a diastereomer of a compound of Table 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0449] [Table 4-1]

[0450] [Table 4-2]

[0451] [Table 4-3]

[0452] In some embodiments, the compound is a compound of Table 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound is a diastereomer of a compound of Table 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0453] [Table 5-1]

[0454] [Table 5-2]

[0455] [Table 5-3]

[0456] [Table 5-4]

[0457] [Table 5-5]

[0458] [Table 5-6]

[0459] [Table 5-7]

[0460] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0461] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included in the scope of the present disclosure.In addition, the compounds described herein can exist in unsolvated form and solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0462] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and that is relatively non-toxic at the concentrations or amounts used; i.e., the material may be administered to an individual without producing undesired biological effects or interacting in a deleterious way with any of the components of the composition in which it is contained.

[0463] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M.Berge, L.D.Bighley, D.C. Monkhouse, J.Pharm.Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and dissolve more rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one or other part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, thereby regulating passage through biological membranes.

[0464] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) with an acid. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, Glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid; tartaric acid (+L); thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0465] In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0466] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) with a base. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is acidic and reacts with a base. In such a situation, the acidic proton of the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein are coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0467] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0468] The methods and formulations described herein include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as well as active metabolites of these compounds that have the same type of activity.

[0469] In some embodiments, sites on the organic radical (e.g., alkyl group, aromatic ring) of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) are susceptible to various metabolic reactions. Incorporating appropriate substituents into the organic radical reduces, minimizes, or eliminates this metabolic pathway. In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuteroalkyl group.

[0470] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0471] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds include, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P and 33 and isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, such as P. In one aspect, isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0472] In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) contains one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) exists in the R configuration. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, enthegene (E), and zusanmene (Z) isomers, as well as the appropriate mixtures thereof.

[0473] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on either non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form diastereomeric compound / salt pairs, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, separation of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by forming diastereomeric salts and separating 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. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0474] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Additionally, or alternatively, the prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design increases effective water solubility. An example of a prodrug is, but is not limited to, a compound described herein that is administered as an ester ("prodrug") and then metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0475] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985, and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, pp. 1-38, which are incorporated herein by reference. In some embodiments, hydroxyl groups in the compounds disclosed herein are used to form prodrugs, wherein the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0476] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to produce a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) described herein, are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0477] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety, which in some embodiments is as described above.

[0478] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce a metabolite, which is used to produce a desired effect, including a desired therapeutic effect.

[0479] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of the processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis and reactions catalyzed by enzymes. Thus, enzymes can produce specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0480] In some cases, heterocycles may exist in tautomeric forms. In such situations, the structure of the compound is illustrated or named in one tautomeric form, but it is understood that it may be illustrated or named in an alternative tautomeric form. Alternative tautomeric forms are expressly included in the present disclosure, such as the structures exemplified below. For example, benzimidazole or imidazole may exist in the following tautomeric forms:

[0481] [ka]

[0482] Preparation of compounds The compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) disclosed herein are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0483] Unless otherwise indicated, conventional mass spectrometry methods, NMR, HPLC are used.

[0484] The compounds are described, for example, in March's Advanced Organic Chemistry, 6 th They are prepared using standard organic chemistry techniques, such as those described in The American Chemical Society, Vol. 1, No. 1, pp. 111-115, 1997. Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0485] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0486] [ka]

[0487] Organometallic coupling reactions, such as the Suzuki-Miyaura reaction, between intermediate A and an appropriate arylboronic acid or its ester or organotrifluoroborate (BF3K) B provided intermediate C. Removal of the protecting groups using an appropriate deprotection method afforded the final compound D.

[0488] In some other embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0489] [ka]

[0490] Reaction of the ketone containing intermediate E with an appropriate amine (R'''-NH2) under suitable reductive amination conditions (such as treatment with a borohydride reagent, e.g., NaBH4, NaCNBH3, or NaB(OAc)3H) affords intermediate F. Removal of the protecting group using a suitable deprotection method affords the final compound G.

[0491] In some embodiments, the compounds are prepared as described in the Examples.

[0492] Specific Terms As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents; a reference to a "cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art; and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a numerical value or numerical range, the term "about" means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the number or numerical range may, in some instances, vary by between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprises" or "including," or "having" or "including") is not intended to exclude that in other particular embodiments, such as compositions, compositions, methods, or processes of any of the things described herein, "consist" or "consist essentially of" the described features.

[0493] Unless otherwise stated, the following terms used in this application have the definitions set forth below. The use of the term "comprising" and other forms such as "includes," "including," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0494] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C6" indicates that there are from 1 to 6 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0495] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight-chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C6. 10 It is alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. In some embodiments, alkyl is methyl.

[0496] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above may be alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, alkylene is a C1-C6 alkylene. In other embodiments, alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, alkylene is -CH2-.

[0497] An "alkoxy" group refers to an --O(alkyl) group, where alkyl is as defined herein.

[0498] The term "alkylamine" refers to -N(alkyl) x H y It refers to a group wherein x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0499] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with a hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like. In some embodiments, the hydroxyalkyl is -CH2OH or -CH2CH2OH. In some embodiments, the hydroxyalkyl is -CH2OH. In some embodiments, the hydroxyalkyl is -CH2CH2OH.

[0500] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like. In some embodiments, the aminoalkyl is -CH2NH2 or -CH2CH2NH2. In some embodiments, the hydroxyalkyl is -CH2NH2. In some embodiments, the hydroxyalkyl is -CH2CH2NH2.

[0501] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0502] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, and -CH2C≡CH.

[0503] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6 heteroalkyl in which one or two atoms are independently selected from O, NH, and S.

[0504] The term "aromatic" refers to a planar ring having a delocalized electron system containing 4n+2 π electrons, where π and n are integers. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl", or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0505] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0506] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C6-C 10Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0507] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl.

[0508] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0509] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is -CF3.

[0510] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-bonded (or C-bonded) or N-bonded where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0511] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0512] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C 10 In another aspect, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. The heterocycloalkyl group is optionally substituted with one or two oxo (=O) moieties.

[0513] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining identified groups.

[0514] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0515] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituents are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0516] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is selected from the group consisting of halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR 21 , -CO2R 21 , -C(=O)N(R 21 )2, -N(R 21 )2, -NR 21 C(=O)R 22 , -SR 21 , -S(=O)R 22 , -SO2R 22 , and -SO2N(R 21 ) one or more R independently selected from the group consisting of s groups, and each R 21 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl, or two R 21 The groups, together with the N atom to which they are attached, form an N-containing heterocycle, and each R 22 is independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0517] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the general health of the subject being treated.

[0518] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0519] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions with an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inhibitor.

[0520] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be employed for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0521] As used herein, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0522] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein necessary to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0523] As used herein, the terms "enhance" or "enhancing" mean to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, in either potency or duration, the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0524] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities, either simultaneously, simultaneously, or sequentially, without any specific intervening time limit, and such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0525] The terms "article of manufacture" and "kit" are used synonymously.

[0526] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, humans, non-human primates such as chimpanzees, and other ape and monkey species, domestic animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0527] The terms "treat," "treating," or "treatment," as used herein, include alleviating, alleviating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., halting the onset or progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating secondary conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0528] Pharmaceutical Composition In certain embodiments, the heterocyclic LpxC inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the heterocyclic LpxC inhibitory compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st The compositions are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0529] Provided herein are pharmaceutical compositions comprising at least one heterocyclic LpxC inhibitory compound described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0530] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0531] In certain embodiments, the heterocyclic LpxC inhibitory compounds described by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0532] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that is easily dissolved in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 2012) st (See Ed. Mack Pub. Co., Easton, PA (2005)).

[0533] The dosage of the compositions comprising at least one heterocyclic LpxC inhibitory compound described herein will vary depending on the patient's condition, ie, stage of disease, general health, age, and other factors.

[0534] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented).The appropriate dosage and the appropriate administration period and administration frequency are determined by 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 administration method.In general, the appropriate dosage and treatment regimen provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (for example, improved clinical outcome) or reduce the severity of symptoms.The optimal dosage is generally determined using experimental models and / or clinical trials.The optimal dosage depends on the patient's body weight, body weight, or blood volume.

[0535] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0536] Combination treatment In certain instances, it may be appropriate to administer at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0537] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant by itself has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced), or in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (including a treatment regimen) that also has therapeutic benefit.

[0538] In one particular embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0539] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is merely additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0540] For the combination therapies described herein, the dose of the co-administered compound will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0541] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0542] The compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or pharmaceutically acceptable salts thereof, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administering the compositions containing the compounds can vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, and for as long as necessary to treat the disease. In some embodiments, the required length of treatment varies, and the length of treatment is adjusted to suit the specific needs of each subject.

[0543] Other embodiments and uses will be apparent to those skilled in the art in view of the present disclosure. The following examples are provided merely as illustrations of various embodiments and are not to be construed as limiting the invention in any way. [Example]

[0544] As used above, and throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings: Abbreviation: ACN or MeCN: acetonitrile, aq: aqueous solution, Boc or BOC: tert-butoxycarbonyl, DCM: dichloromethane, DIAD: diisopropyl azodicarboxylate; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide, DMP: Dess-Martin periodinane DPPA: diphenylphosphoryl azide; dr: diastereomeric ratio Eq. or equiv: equivalent, EtOAc: ethyl acetate, g: grams h or hr: hours, HPLC: high performance liquid chromatography; LC-MS, LC MS, or LCMS: liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; M: mole, MeOH: methanol, mg: milligram, min:minutes, mL: milliliter, mmol: millimolar, MsCl: methanesulfonyl (mesyl) chloride; MTBE: methyl tert-butyl ether; N: Normal, NBS: N-bromosuccinimide, NMR: nuclear magnetic resonance; Pet ether: petroleum ether, PPTS: pyridinium p-toluenesulfonate; p-TSA: para-toluenesulfonic acid rt: room temperature, SFC: supercritical fluid chromatography; TEA: Triethylamine (or Et3N), TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran; TLC: thin layer chromatography; TsCl: para-toluenesulfonyl (tosyl) chloride

[0545] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0546] I. Chemical synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ), and coupling constants, J, are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0547] Example A1: Synthesis of Compound 1, Compound 2, and Compound 3 Experimental procedure for compound 1

[0548] [ka] Step-1: To a stirred solution of 4-bromo-3-fluorophenol (A-1, 2.5 g, 13.09 mmol) in 1,4-dioxane (30 mL), 3,4-epoxytetrahydrofuran (A-2, 1.12 g, 13.09 mmol), cesium carbonate (6.38 g, 19.63 mmol), and benzyltriethylammonium chloride (0.594 g, 2.62 mmol) were added at room temperature. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad, and the bed was further washed with EtOAc (3 × 50 mL). The filtrate was concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography (SiO2, 100–200 mesh size, 26% EtOAc in n-hexane) to give A-3 (1.8 g, 50%) as an off-white solid.

[0549] Step-2: To a stirred solution of A-3 (1.8 g, 6.50 mmol) in 1,4-dioxane (20 mL) was added potassium acetate (1.91 g, 19.49 mmol) and bis(pinacolato)diboron (2.47 g, 9.74 mmol) at room temperature. The reaction mixture was degassed using nitrogen for 10 minutes. To this reaction mixture was added Pd(dppf)Cl (0.47 g, 0.65 mmol), and degassing was continued for 2 minutes. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and filtered through a Celite pad, washing the bed with additional EtOAc (80 mL). The filtrate was washed with water (80 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography (SiO, 100-200 mesh size, 26% EtOAc in pet ether) to give A-4 (1.8 g, 85%) as a pale yellow gum.

[0550] Step-3: To a stirred solution of A-4 (603 mg, 1.86 mmol) and A-5 (600 mg, 1.43 mmol) in acetonitrile (10 mL) and water (10 mL) was added potassium carbonate (593 mg, 4.29 mmol). The reaction mixture was degassed using nitrogen gas for 15 minutes. To this reaction mixture, Pd(dtbpf)Cl2 (93 mg, 0.14 mmol) was added and heated at 80 °C for 16 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography (SiO2, 100-200 mesh size, 80% EtOAc in pet ether) to give A-6 (0.2 g, 25%) as a brown gum. LCMS: C 30 H 33 Calculated value of FN2O6: 536.60, Measured value: 537.3 [M+1] + .

[0551] Step-4: To a stirred solution of A-6 (200 mg, 0.37 mmol) in MeOH (5 mL) was added p-toluenesulfonic acid monohydrate (142 mg, 0.74 mmol) in several portions at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure to give the crude compound (380 mg) as a brown gum. The reaction mixture was diluted with water and extracted with 10% methanol in dichloromethane (2 × 25 mL). The combined organic layers were washed with sodium bicarbonate solution (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound as a brown gum, which was purified by reverse-phase preparative HPLC (10 mM NH4HCO3 in water and acetonitrile) to give compound 1 as a white solid. Yield: 0.01 g (6%). LCMS: C 25 H 25 Calculated value of FN2O5: 452.482, Measured value: 453.2 [M+1] + .

[0552] Experimental procedures for compound 2 and compound 3

[0553] [ka]

[0554] Step-1: To a stirred solution of A-6 (1.8 g, 3.35 mmol) in MeOH (18 mL) was added p-toluenesulfonic acid monohydrate (1.276 g, 6.71 mmol) in several portions at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure to give a crude residue, which was basified with sodium bicarbonate solution. This was extracted with 10% MeOH in DCM (2 × 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by MPLC (manually packed cartridge, SiO2 100-200 mesh, 12% MeOH in DCM) to give 600 mg of compound 1 (mixture of diastereomers) as a brown solid. The isomers were separated by SFC (column: LUX A1-(250*4.6) mm, 5 μm; mobile phase: CO2:MeOH [70:30]). The collected fractions were evaporated under reduced pressure to give compound 2 (Peak-1 (first elution), 100% (%ee=100), 114 mg, 7%) as a white solid and compound 3 (Peak-2 (second elution), 100% (%ee=100), 140 mg, 9%) as an off-white solid. LCMS: calculated for C25H25FN2O5: 452.48, found: 453.2 [M+1] + .

[0555] Example A2: Synthesis of Compound 4

[0556] [ka] Step 1: To a stirred solution of methyl (tert-butoxycarbonyl)-D-serinate (B-1, 110 g, 502 mmol) in acetone (1500 mL), 2,2-dimethoxypropane (313 g, 3010 mmol) and p-toluenesulfonic acid monohydrate (9.54 g, 50.2 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure. Water (500 mL) was added to the resulting residue, which was then extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was purified by MPLC (manually packed cartridge SiO2, 100-200 mesh size; 5-10% EtOAc in hexane) to give B-2 (71 g, 55%) as a colorless liquid.

[0557] Step-2: To a stirred solution of B-2 (71 g, 274 mmol) in toluene (700 mL) was added DIBAL-H (1.2 M in toluene, 342 mL, 411 mmol) at −78° C. After stirring at −78° C. for 3 h, the reaction was quenched with MeOH (500 mL) at −78° C., and the resulting emulsion was slowly poured into ice-cold aqueous HCl (1.5 N, 500 mL) and extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give B-3 (62 g, 99%, crude product weight) as a colorless liquid.

[0558] Step 3: To a stirred solution of carbon tetrabromide (179 g, 541 mmol) in DCM (250 mL) was added a solution of triphenylphosphine (284 g, 1082 mmol) in DCM (250 mL) at -30 ℃The mixture was added at room temperature over 20 minutes and stirred at the same temperature for 20 minutes. After 20 minutes, the resulting orange-red solution was cooled to -60°C, and a solution of B-3 (62 g, 270 mmol) and trimethylamine (38.0 mL, 270 mmol) in DCM (250 mL) was added dropwise over 30 minutes. The reaction mixture was gradually warmed to 0°C and stirred for 4 hours. The reaction, monitored by TLC, showed complete consumption of the starting material. The reaction was quenched by adding saturated sodium bicarbonate solution (300 mL) and extracted with DCM (500 mL x 3). The combined organic extracts were washed with water (300 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was triturated with 20% EtOAc in hexane (1000 mL x 4), and the solid was filtered. The filtrate was concentrated under reduced pressure to give material which was purified by MPLC (manually packed cartridge, SiO2 100-200 mesh, 5-7% EtOAc in pet ether) to give dibromoalkene B-4 (50 g, 48%) as an off-white solid.

[0559] Step 4: To a stirred solution of dibromoalkene B-4 (50 g, 130 mmol) in dry THF (400 mL) was added EtMgBr (2.0 M in THF, 130 mL, 260 mmol) over 60 min at 0 °C and stirred at the same temperature for 3 h. After completion, the reaction was quenched by the addition of saturated NH4Cl solution (400 mL) and extracted with EtOAc (500 mL × 2). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by MPLC (manually loaded cartridge, SiO2 230-400 mesh, 2% EtOAc in pet ether) to give B-5 (21 g, 72%) as a colorless liquid.

[0560] Step 5: T...

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the formula, R １ C １ -C ４ It is alkyl, R ２ａ and R ２ｂ Each of these is independently hydrogen, halogen, or C １ -C ４ It is alkyl, R ３ is hydrogen, -(C １ -C ４ alkylene)-OH, -(C １ -C ４ alkylene)-NH ２ , -(C ３ -C ６ cycloalkylene)-OH, or -(C ３ -C ６ cycloalkylene)-NH ２ and R ４ is hydrogen or C １ -C ４ It is alkyl, Each R ５ and R ６ These are independently halogen or C １ -C ４ It is alkyl, L １ is a bond, -(C １ -C ６ Alkylene) -, -X １ - or -X ２ - (C １ -C ６ Alkylene) - and X １ and X ２ These are -O- and -N(R) respectively. ９ )-, -S-, -S(=O)-, -S(=O) ２ -, and -S (=O) (=NR ９ ) - Selected from, R ９ is hydrogen or C １ -C ６ It is alkyl, R ７ C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ６ The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is either unsubstituted or has 1, 2, or 3 R members. １０ It is substituted with the base, Each R １０ These are independently halogen, -OR ８ , -N(R ８ ) ２ , -CO ２ R ８ , -CON(R ８ ) ２ ien-CH ２ N(R) ８ ) ２ ,-NHCOR ８ , - NHSO ２ R ８ ien-CH ２ CN, C １ -C ４ Alkyl, C １ -C ４ Hydroxyalkyl, -C(=O)-C １ -C ４ Hydroxyalkyl, C １ -C ４ Methoxyalkyl, C １ -C ４ Selected from aminoalkyl and oxo, and further, Each R ８ is independently hydrogen, C １ -C ４ -alkyl, -C(=O)-C １ -C ４ -alkyl, or 4- to 6-membered heterocycloalkyl, wherein said alkyl or heterocycloalkyl is unsubstituted or is substituted with one or two groups selected from -F, -CN, -OH, -CH ２ OH, -NH ２ , -OMe, -N(CH ３ ) ２ , -CO ２ H, -CONH ２ , -SO ２ CH ３ , -C(=NH)NH ２ , oxo, phenyl, and monocyclic heteroaryl, wherein said monocyclic heteroaryl is unsubstituted or is substituted with one or two groups selected from -F, -CN, -OH, -NH ２ , -OMe, -N(CH ３ ) ２ , -CO ２ H, -CONH ２ , and -SO ２ CH ３ and is substituted with 1, 2, 3, or 4 groups independently selected from monocyclic heteroaryl substituted with one or two groups selected from or two Rs attached to the same nitrogen ８ together form a 4- to 6-membered heterocycloalkyl which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH ２ , -OMe, -CO ２ H, -CONH ２ , -SO ２ CH ３ and form a 4- to 6-membered heterocycloalkyl substituted with 1, 2, or 3 groups independently selected from oxo s is 0, 1, or 2. t is 0, 1, or 2, and It must be at least one of the following: (i) s is 1 or 2, and at least one R ５ It is a halogen. (ii) t is 1 or 2, and at least one R ６ It is a halogen, and (iii) R ７ The alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl group has 1, 2, or 3 R １０ Substituted with at least one R １０ is a halogen, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. At least one R ５ , R ６ , or R １０ The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -F.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is -CH3.

4. R 2a is hydrogen, and The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 2b is hydrogen.

5. R ３ is, -(C １ -C ４ A compound according to any one of claims 1 to 4, which is alkylene-OH, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. L1 is a bond, -(C1-C4 alkylene)-, -X1-, or -X2-(C1-C4 alkylene)-, The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X1 and X2 are each selected from -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-.

7. R7 is a C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-8 membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 R10 groups. Each R 10 is independently selected from halogen, -OR 8, -N(R 8) 2, -CO 2 R 8, -CON(R 8) 2, -CH 2 N(R 8) 2, -NHCOR 8, -NHSO 2 R 8, -CH 2 CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo, and further, Each R8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or a 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which are unsubstituted or -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is substituted with one, two, three, or four groups independently selected from a monocyclic heteroaryl which is substituted with one or two groups selected from the above.

8. R7 is a 4- to 8-membered heterocycloalkyl group, and the 4- to 8-membered heterocycloalkyl group is either unsubstituted or substituted with 1, 2, or 3 R10 groups. Each R 10 is independently selected from halogen, -OR 8, -N(R 8) 2, -NHSO 2 R 8, -CH 2 CN, C 1-C 4 alkyl, -C(=O)-C 1-C 4 hydroxyalkyl, C 1-C 4 hydroxyalkyl, and C 1-C 4 methoxyalkyl, and Each R8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or a 4- to 6-membered heterocycloalkyl, wherein the alkyl is unsubstituted or is substituted with -F, -CN, -OH, -CO2H, -C(=NH)NH2, and a 5-membered monocyclic heteroaryl, which is either unsubstituted or substituted with 1, 2, or 3 groups independently selected from a 5-membered monocyclic heteroaryl substituted with a 1-CONH2 group, as described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. L1-R7 is, 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. R1 is -CH3, R2a and R2b are hydrogen atoms, R3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, R4 is hydrogen, Each of R5 and R6 is a halogen, L1 is -X1- or -X2- (C1-C4 alkylene)-, X1 and X2 are each selected from -O-, and R7 is a C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 R10 groups. Each R 10 is independently selected from halogen, -OR 8, -N(R 8) 2, -CO 2 R 8, -CON(R 8) 2, -CH 2 N(R 8) 2, -NHCOR 8, -NHSO 2 R 8, -CH 2 CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo, and further, Each R8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or a 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, which are unsubstituted or -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is substituted with one, two, three, or four groups independently selected from a monocyclic heteroaryl which is substituted with one or two groups selected from the above.

11. Structure of formula (IV), 【Transformation 3】 or having a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the formula, R3 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH, or -(C3-C6 cycloalkylene)-NH2, Each R5 and R6 is independently -F, -Cl, or C1-C4 alkyl, L1 is -(C1-C6 alkylene)-, -X1-, or -X2-(C1-C6 alkylene)-, X1 and X2 are selected from -O-, -N(R9)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NR9)- respectively. R9 is hydrogen or C1-C6 alkyl, Each R 10 is independently selected from halogen, -OR 8, -N(R 8) 2, -CO 2 R 8, -CON(R 8) 2, -CH 2 N(R 8) 2, -NHCOR 8, -NHSO 2 R 8, -CH 2 CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl, and oxo, and further, Each R8 is independently hydrogen or a C1-C4 alkyl group. s is 0, 1, or 2. t is 0, 1, or 2, and The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein u is 0, 1, or 2. 【Request Item 12】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] A compound according to claim 1, selected from the above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request Item 13】 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the above. 【Request Item 14】 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 A compound selected from, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request Item 15】 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 【Transformation 7-5】 【Transformation 7-6】 A compound selected from, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. A pharmaceutical composition comprising the compound described in Claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

17. Use of the compound according to claim 1 in the manufacture of a drug for the treatment or prevention of Gram-negative bacterial infections in patients.

18. The use according to claim 17, wherein the Gram-negative bacterial infection is related to Pseudomonas aeruginosa.

19. The use according to claim 17, wherein the Gram-negative bacterial infection is a respiratory infection.

20. The use according to claim 17, wherein the patient is identified as having a lung disease.

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