Antibacterial compounds

Abstract

Provided herein are heterocyclic compounds, and pharmaceutical compositions comprising the compounds, which can be used to inhibit the growth of gram negative bacteria (gram-negative bacteria). The compounds and compositions of the invention are useful for the treatment of bacterial infections, such as pneumonia.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 396,895, filed on August 10, 2022, the entirety of which is incorporated herein by reference.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with Government support under Agreement No. HHS0100201600038C awarded by HHS. The Government has certain rights in this invention. Background Art

[0005] There is a need in the medical field for effective treatments of diseases caused by bacterial infections. Summary of the Invention

[0006] Provided herein are heterocyclic compounds and pharmaceutical compositions comprising the compounds, which can be used to inhibit the growth of gram-negative bacteria. The compounds of the present invention and compositions can be used to treat bacterial infections, such as pneumonia, etc. In certain embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetyl glucosamine deacetylase (LpxC) regulator compounds. In certain embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetyl glucosamine deacetylase (LpxC) antagonists. In certain embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetyl glucosamine deacetylase (LpxC) inhibitors.

[0007] In one aspect, the present disclosure provides a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0010] R 1 is a C1-C4 alkyl group;

[0011] R 2a and R 2b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0012] R 3is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0013] R 4 is hydrogen or C1-C4 alkyl;

[0014] Each R 5 and R 6 are independently halogen or C1-C4 alkyl;

[0015] L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein:

[0016] X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-,in:

[0017] R 9 is hydrogen or C1-C6 alkyl;

[0018] 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein:

[0019] Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, wherein:

[0020] Each R 8is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3;

[0021] or two R's attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0022] s is 0, 1, or 2;

[0023] t is 0, 1, or 2; and

[0024] At least one of the following:

[0025] (i) s is 1 or 2, and at least one R 5 is a halogen;

[0026] (ii) t is 1 or 2, and at least one R6 is halogen; and

[0027] (iii)R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0028] In some embodiments, at least one R 5 、R 6 or R 10 In some embodiments, at least one R 5 or R 6 In some embodiments, at least one R 10 In some embodiments, at least two R 5 、R 6 or R 10 In some embodiments, at least two R 5 or R 6 In some embodiments, at least two R 10 is -F.

[0029] In some embodiments, R 1 In some embodiments, R 2a is hydrogen; and R 2b In some embodiments, R 4 In some embodiments, each R 5 is independently -F, -Cl or -CH3. In some embodiments, each R 5 In some embodiments, each R 6 is -F.

[0030] In some embodiments, the compound is of Formula (IIa):

[0031]

[0032] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0033] Each R 5 is -F; and

[0034] Each R 6 is -F.

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

[0036]

[0037] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0038] Each R 5 is -F; and

[0039] Each R 6 is -F.

[0040] In some embodiments, R 3 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 9 For hydrogen.

[0041] In some embodiments, L 1 is a bond, -(C1-C4 alkylene)-, -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2Each is selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from the group consisting of: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-.

[0042] In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from: -O-. In some embodiments, L 1 It is -O-.

[0043] 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

[0044] In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -NHSO2R 8 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

[0045] In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

[0046] In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F, -OH, -OCH3 and -NH2.

[0047] In some embodiments, L 1 -R 7 for

[0048] In some embodiments, L 1 -R 7 for

[0049] In some embodiments, R 1-CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 4 is hydrogen; each R 5 and R 6 is a halogen; L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

[0050] In some embodiments, R 3 is hydrogen or -(C1-C4 alkylene)-OH; L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2Each selected from: -O-; R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

[0051] In some embodiments, R 3 is CH2OH; L 1 -O-; R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F, -OH, -OCH3 and -NH2.

[0052] In some embodiments, the compound is of formula (IV):

[0053]

[0054] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0055] R 3 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; each R 5 and R 6 are independently -F, -Cl or C1-C4 alkyl; L 1 -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; each R 10 Independently selected from: halogen, -OR 8 、-N(R 8)2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 are 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.

[0056] In some embodiments, the compound is of Formula (V):

[0057]

[0058] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0059] 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 In some embodiments, R 3 In some embodiments, R 3 It is -CH2OH.

[0060] In another aspect, the present disclosure provides a compound of formula (VI):

[0061]

[0062] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0063] R 11 is a C1-C4 alkyl group;

[0064] R 12a and R 12b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0065] R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0066] R 14 is hydrogen or C1-C4 alkyl;

[0067] Each R 15 and R 16 are independently halogen or C1-C4 alkyl;

[0068] 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein:

[0069] Each R 18 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3;

[0070] or two R's attached to the same nitrogen 18 together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0071] L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein:

[0072] X 3 and X 4 Each independently selected from: -O-, -N(R19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-,in:

[0073] R 19 is hydrogen or C1-C6 alkyl;

[0074] The condition is that when L 2 is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then at least one of the following:

[0075] (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0076] (ii)R 14 is a C1-C4 alkyl group,

[0077] (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; or

[0078] (iv)L 2 is -O-(C1-C6 alkylene)- and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl group;

[0079] v is 0, 1, or 2; and

[0080] w is 0, 1, or 2.

[0081] In some embodiments, R 11 In some embodiments, R 12a is hydrogen; and R 12b In some embodiments, R 14 In some embodiments, each R 15 is independently -F, -Cl or -CH3. In some embodiments, each R 15 is independently -F. In some embodiments, each R 16 is independently -F, -Cl or -CH3. In some embodiments, each R 16 Independently -F.

[0082] In some embodiments, the compound is of Formula (VIIa):

[0083]

[0084] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0085] In some embodiments, the compound is of Formula (VIIIa):

[0086]

[0087] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0088] 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 Each independently selected from: -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 In some embodiments, R 3 It is -CH2OH.

[0089] 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

[0090] In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -OR 18 、-N(R 18 )2, -NHSO2R 18 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and each R 18 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

[0091] In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 18 and -CH2CN; and each R 18 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

[0092] In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of -F, -OH, -OCH3 and -NH2.

[0093] In some embodiments, the compound is of formula (IX):

[0094]

[0095] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0096] R 13 is -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; 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 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 );R 19 is hydrogen or C1-C6 alkyl; each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, 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.

[0097] In some embodiments, the compound is of formula (X):

[0098]

[0099] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0100] In some embodiments, R 13 In some embodiments, R 13 In some embodiments, w and v are each 0.

[0101] In some embodiments, L 2 is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-; and

[0102] (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0103] (ii)R 14 is a C1-C4 alkyl group,

[0104] (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; or

[0105] (iv)L 2 is -O-(C1-C6 alkylene)- and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl group.

[0106] In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 is -(cyclopropylene)-OH or -(cyclopropylene)-NH2. In some embodiments, R 13 for In some embodiments, R 14 In some embodiments, R 14 It is a methyl group.

[0107] In some embodiments, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0108] In some embodiments, R 17is 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 substituted with at least one -N(R 18 ) substituted oxetane.

[0109] In some embodiments, R 17 for

[0110] In some embodiments, L 2 It is a bond, -CH2-, -O- or -O-CH2-.

[0111] In some embodiments, -L 2 -R 17 for

[0112] In some embodiments, L 2 is -O-(C1-C6 alkylene)-; and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl. 17 is unsubstituted or substituted tetrahydrofuranyl.

[0113] In some embodiments, R 17 for In some embodiments, L 2 In some embodiments, -L 2 -R 17 for

[0114] In another aspect, the present 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.

[0115] In another aspect, the present disclosure provides a method of treating or preventing a Gram-negative bacterial infection in a patient in need thereof, the method 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.

[0116] In certain embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In certain embodiments, the gram-negative bacterial infection is a respiratory tract infection. In certain embodiments, the respiratory tract infection is pneumonia. In certain embodiments, the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof.

[0117] In another aspect, the present disclosure provides a method of treating or preventing a Pseudomonas aeruginosa infection in a patient in need thereof, the method 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.

[0118] In some embodiments, the patient has been identified as having a lung disease. In some embodiments, the lung disease is a structural lung disease. In some embodiments, the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease, or a combination thereof. In some embodiments, administration is for treating an existing infection. In some embodiments, administration is provided as a prophylactic.

[0119] In some embodiments, the 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.

[0120] 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 gram-negative bacterial infection. In some embodiments, gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, wherein the gram-negative bacterial infection is a respiratory tract infection. In some embodiments, the respiratory tract infection is pneumonia. In some embodiments, 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 Pseudomonas aeruginosa infection. In some embodiments, the patient has been identified as suffering from lung disease. In some embodiments, the lung disease is structural lung disease. In some embodiments, the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease or a combination thereof.

[0121] In another aspect, the present disclosure provides the 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 Gram-negative bacterial infection.

[0122] In another aspect, the present disclosure provides the 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 Gram-negative bacterial infection.

[0123] Incorporated by Reference

[0124] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purpose identified herein. DETAILED DESCRIPTION

[0125] LpxC, lipid A, and Gram-negative bacteria

[0126] 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 key step of 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 one aspartic acid residue that bind to the zinc (II) ion. The structure of LpxC shows that the zinc (II) ion is bound to two water molecules, both of which are involved in the mechanism of the enzyme. LpxC is highly conserved in strains of Gram-negative bacteria, 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.

[0127] In recent years, drug-resistant and multidrug-resistant strains of bacteria have increased. Therefore, new antibiotics, particularly those with novel mechanisms of action, are needed. There remains a need for metalloproteinase modulators of LpxC that could be used in therapeutics, diagnostics, and research.

[0128] Some embodiments provide a method of inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase comprising contacting the enzyme with a compound of formula (I).

[0129] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0130] How to use

[0131] Disclosed herein are methods for treating diseases in which bacterial growth is inhibited. Such diseases include gram-negative bacterial infections. In certain embodiments, gram-negative bacterial infections are associated with Pseudomonas aeruginosa. In certain embodiments, the method for treating gram-negative bacterial infections in patients in need comprises administering to the patient a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the method for treating Pseudomonas aeruginosa infections in patients in need comprises administering to the patient a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0132] In certain embodiments, gram-negative bacteria infect is relevant to Pseudomonas aeruginosa.In certain embodiments, gram-negative bacteria infect is respiratory tract infection.In certain embodiments, gram-negative bacteria infect is pneumonia.In certain embodiments, gram-negative bacteria infect is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP) or its combination.In certain embodiments, gram-negative bacteria infect is community-acquired pneumonia (CAP).In certain embodiments, gram-negative bacteria infect is healthcare-associated pneumonia (HCAP).In certain embodiments, gram-negative bacteria infect is hospital-acquired pneumonia (HAP).In certain embodiments, gram-negative bacteria infect is ventilator-associated pneumonia (VAP).

[0133] In some embodiments, the patient has been identified as having a lung disease. In some embodiments, the lung disease is a structural lung disease. In some embodiments, the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung 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 lung disease.

[0134] In some embodiments, administration is for the treatment of an existing infection.

[0135] In some embodiments, administration is provided as prophylaxis.

[0136] In some embodiments, the LpxC inhibitory compounds described herein are used to treat or prevent conditions caused by bacterial production of endotoxins, particularly conditions caused by Gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharides (LPS) or endotoxins. In some embodiments, a method of treating or preventing a condition caused by endotoxins or LPS 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 endotoxins, such as chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB). In some embodiments, the method of treating or preventing a condition caused by endotoxin or LPS 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 condition caused by endotoxin or LPS is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB).

[0137] In other embodiments, the compounds of the present disclosure can be used to treat severe or chronic respiratory tract infections, including severe pulmonary and nosocomial infections, such as those caused by 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, and Enterobacter spp. baumannii), Alcaligenes xylosoxidans, Flavobacterium meningosepticum, and Citrobacter freundi, Haemophilus influenzae, Kluyvera species, Legionella species, Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella species, Burkholderia species, and Proteus species, as well as infections caused by other bacteria, such as Neisseria species, Shigella species, Salmonella species, Helicobacter pylori 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. 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.

[0138] In some embodiments, an LpxC inhibitory compound as described herein is used in a method for preventing the growth of Pseudomonas. In some embodiments, the Pseudomonas is Pseudomonas aeruginosa.

[0139] In some cases, antibiotics have suboptimal concentrations in the lungs, leading to treatment failure of lung infections. In some embodiments, heterocyclic LpxC inhibitory compounds of Formula (I) have optimal concentrations in the lungs for treating or preventing Gram-negative bacterial infections in the lungs. In some embodiments, the compounds are present in the lungs in a therapeutically effective amount following administration.

[0140] Disclosed herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances.

[0141] In some embodiments, disclosed herein are compounds described herein or pharmaceutically acceptable salts thereof for use in treating or preventing Gram-negative bacterial infections. In some embodiments, the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the Gram-negative bacterial infection is a respiratory tract infection. In some embodiments, the respiratory tract infection is pneumonia.

[0142] In some embodiments, disclosed herein are uses of a compound as 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 tract infection. In some embodiments, the respiratory tract infection is pneumonia.

[0143] LpxC inhibitory compounds

[0144] In some embodiments, provided herein are heterocyclic LpxC inhibitory compounds and pharmaceutical compositions comprising the compounds. The compounds and compositions of the present invention can be used to inhibit UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and to treat bacterial infections.

[0145] In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulators. In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0146] One aspect of the present disclosure provides a compound having the structure of Formula (I):

[0147]

[0148] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0149] R 1 is a C1-C4 alkyl group;

[0150] R 2a and R 2b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0151] R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0152] R 4 is hydrogen or C1-C4 alkyl;

[0153] Each R 5 and R 6 are independently halogen or C1-C4 alkyl;

[0154] L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein:

[0155] X 1 and X 2 Each selected from: -O-, -N(R 9)-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-,in:

[0156] R 9 is hydrogen or C1-C6 alkyl;

[0157] 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein:

[0158] Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo;

[0159] In addition:

[0160] Each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3;

[0161] or two R's attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0162] s is 0, 1, or 2; and

[0163] t is 0, 1, or 2.

[0164] In some embodiments, for the compound of formula (I),

[0165] (i) s is 1 or 2, and at least one R 5 is a halogen;

[0166] (ii) t is 1 or 2, and at least one R 6 is a halogen; and

[0167] (iii)R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0168] In some embodiments, for compounds of Formula (I), s is 1 or 2, and at least one R 5 It is a halogen.

[0169] In some embodiments, for compounds of Formula (I), t is 1 or 2, and at least one R 6 It is a halogen.

[0170] In some embodiments, for compounds of formula (I), R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0171] In some embodiments, for compounds of formula (I), R 1 is a C1-C4 alkyl group; 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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl 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 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0172] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or formula (Ib):

[0173]

[0174] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0175] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0176] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 82. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0177] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen or -(C1-C4 alkylene)-OH; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0178] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen or -(C1-C4 alkylene)-OH; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: R 9is hydrogen or C1-C6 alkyl; R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -NHSO2R 8 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0179] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen or -CH2OH; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH, and oxadiazolyl; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0180] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen or -CH2OH; R 4 is hydrogen; each R 5 and R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 independently selected from: -F, -OH, -OCH3 and -NH2; s is 0, 1 or 2; t is 0, 1 or 2; wherein at least one of the following: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 For fluorine.

[0181] 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.

[0182] For any and all embodiments, the substituents are selected from a subset of the listed alternatives. For example, in some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is an unsubstituted C1-C4 alkyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -CH3.

[0183] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2a and R 2b Each independently is R 2a , and R 2b are each independently hydrogen, halogen or unsubstituted C1-C4 alkyl. In some embodiments, R 2a and R 2b are each independently hydrogen, -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, R 2a and R 2b Each is independently hydrogen, -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2.

[0184] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2a In some embodiments, R 2b In some embodiments, R 2a and R 2b Each is hydrogen.

[0185] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R1 -CH3; R 2a is hydrogen; and R 2b For hydrogen.

[0186] 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 C1-C2 alkyl. In some embodiments, R 4 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 4 is hydrogen, -CH3 or -CH2CH3. In some embodiments, R 4 is hydrogen or -CH3. In some embodiments, R 4 In some embodiments, R 4 is -CH3.

[0187] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0188]

[0189] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0190] 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; each R 5 is halogen or C1-C4 alkyl; each R 6 is halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0191] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 5 -F; R 6 -F;L1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -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 wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0192] In some embodiments of compounds of Formula (II), each R 5 are independently halogen or C1-C4 alkyl; and each R 6 is independently halogen or C1-C4 alkyl. In some embodiments, each R 5 are independently halogen; and each R 6 In some embodiments, each R 5 is independently -F; and each R 6 is independently -F. In some embodiments, each R 5 are independently -Cl; and each R 6 is independently -Cl.

[0193] In some embodiments, the compound of formula (I) or (II) is a compound of formula (IIa) or formula (IIb):

[0194]

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

[0196] 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; each R 5 is halogen or C1-C4 alkyl; each R 6 is halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0197] In some embodiments of compounds of Formula (II), (IIa), or (IIb), R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 5 -F; R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9)-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -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 wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0198] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5 are independently halogen or C1-C4 alkyl; and each R 6 is independently halogen or C1-C4 alkyl. In some embodiments, each R 5are independently halogen; and each R 6 In some embodiments, each R 5 is independently -F; and each R 6 Independently -F.

[0199] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5 In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 5 It is -Cl.

[0200] In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 6 In some embodiments of compounds of Formula (II), (IIa), or (IIb), each R 6 It is -Cl.

[0201] In some embodiments of compounds of Formula (II), (IIa), or (IIb), s is 0; and each R 6 In some embodiments, each R 5 is -F; and t is 0. In some embodiments, R 5 is -F; and R 6 is -F.

[0202] In some embodiments of compounds of Formula (II), (IIa), or (IIb), s is 0; and each R 6 In some embodiments, each R 5 is -Cl; and t is 0. In some embodiments, R 5 is -Cl; and R 6 It is -Cl.

[0203] 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.

[0204] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (Ilia), Formula (IIIb), Formula (IIIc), or Formula (IIId):

[0205]

[0206] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0207] 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; each R 5 is halogen or C1-C4 alkyl; each R 6 is halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0208] 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; R 5 -F; R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -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 wherein 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0209] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 are independently halogen or C1-C4 alkyl; and each R 6 is independently halogen or C1-C4 alkyl. In some embodiments, each R 5 are independently halogen; and each R 6 In some embodiments, each R 5 is independently -F; and each R 6 is independently -F. In some embodiments, each R 5 are independently -Cl; and each R 6 is independently -Cl.

[0210] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 5 It is -Cl.

[0211] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 6 In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), each R 6 It is -Cl.

[0212] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), s is 0; and each R 6 In some embodiments, each R 5 is -F; and t is 0. In some embodiments, R 5 is -F; and R 6 is -F.

[0213] In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc), or (IIId), s is 0; and each R 6 In some embodiments, each R 5 is -Cl; and t is 0. In some embodiments, R 5 is -Cl; and R 6 It is -Cl.

[0214] In certain embodiments, the compound is a compound of formula (IIIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIIb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIIc) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIId) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0215] In some embodiments of compounds 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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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)-, wherein: X 1 and X 2 Each selected from: -O-, -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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-. In some embodiments, L 1 For bonds, -CH2-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -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 For hydrogen.

[0216] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-. In some embodiments, L 1 For key, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-. In some embodiments, R 9 For hydrogen.

[0217] In some embodiments, L 1 -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)- and -S(=O)2-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )- and -S-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X1 and X 2 Each selected from: -O- and -N(R 9 )-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each is selected from: -O- and -S-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -N(R 9 )- and -S-. In some embodiments, R 9 For hydrogen.

[0218] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from: -O-. In some embodiments, L 1 It is -O-.

[0219] In some embodiments of compounds 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 -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 1is -S(=O)- or -S(=O)-(C1-C6 alkylene)-. In some embodiments, L 1 is -S(=O)2- or -S(=O)2-(C1-C6 alkylene)-. In some embodiments, L 1 -S(=O)(=NR 9 )-or-S(=O)(=NR 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 In some embodiments, L 1 -N(R 9 )-. In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 -S(=O)(=NR 9 )-. In some embodiments, L 1 In some embodiments, L 1 -N(R 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 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 -S(=O)(=NR 9 )-(C1-C6 alkylene)-. In some embodiments, L 1 In some embodiments, L 1 is -N(H)- or -N(H)-(CH2)-. In some embodiments, L 1 In some embodiments, L 1 is -S(=O)- or -S(=O)-(CH2)-. In some embodiments, L 1 is -S(=O)2- or -S(=O)2-(CH2)-. In some embodiments, L 1 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH2)-. In some embodiments, L 1 In some embodiments, L 1 is -N(H)-(CH2)-. In some embodiments, L1 In some embodiments, L 1 is -S(=O)-(CH2)-. In some embodiments, L 1 is -S(=O)2-(CH2)-. In some embodiments, L 1 It is -S(=O)(=NH)-(CH2)-.

[0220] 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 substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

[0221] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10Group substitution, wherein: each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -NHSO2R 8 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and each R 8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

[0222] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R8 are independently hydrogen or C1-C2 alkyl.

[0223] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F and -OH.

[0224] In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0225] 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 group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F and -OH.

[0226] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0227] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10Group substitution, wherein: each R 10 Independently selected from: -F and -OH.

[0228] In some embodiments, R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0229] In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0230] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F and -OH.

[0231] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10Group substitution, wherein: each R 10 In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: -F and -OH.

[0232] In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0233] In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 and -CH2CN; and each R 8 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 Independently selected from: halogen, -OH, -OR 8 、-N(R 8 )2 and -CH2CN; and each R 8 are independently hydrogen or C1-C2 alkyl.

[0234] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R10 In some embodiments, R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 For the 3 R 10 Tetrahydrofuran substituted with a group, wherein: each R 10 Independently selected from: -F and -OH.

[0235] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 is tetrahydropyran, wherein the tetrahydropyran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, R 7 For the 3 R 10 Tetrahydrofuran substituted with a group, wherein: each R 10 Independently selected from: -F and -OH.

[0236] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 for In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R7 for

[0237] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 for In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 for

[0238] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is -O-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 1 is -O-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -O-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -O-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -O-; and R 7 For the 3 R 10 Tetrahydrofuran substituted with a group, wherein: each R 10 Independently selected from: -F and -OH.

[0239] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0240] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0241] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0242] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0243] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0244] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 is -NH-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 The group is taken, where: each R 10 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 1 is -NH-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -NH-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -NH-; and R 7 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, wherein: each R 10 In some embodiments, L 1 is -O-; and R 7 For the 3 R 10 Tetrahydrofuran substituted with a group, wherein: each R 10 Independently selected from: -F and -OH.

[0245] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0246] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), L 1 -R 7 for

[0247] 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 7 As a single diastereomer, and with R 7 In some embodiments, R 7 As a single diastereomer, and with R 7 In some embodiments, R 7 As a single diastereomer, and with R 7 Compared to a comparator compound that is a different stereoisomer, it exhibits improved in vivo efficacy.

[0248] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 For 1 or 2 R 10 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 10 Independently selected from: halogen, -OH, -OMe, -N(R 8 )2, -NHSO2R 8 In some embodiments, R 7 For 1 or 2 R 10 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 10 In some embodiments, R 7 For 1 or 2 R 10 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 10 In some embodiments, R 7 It is a 4- to 6-membered heterocycloalkyl group substituted with -OH.

[0249] In some embodiments, R 7 is a 1,2-trans-disubstituted 4- to 6-membered heterocycloalkyl. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for

[0250] In some embodiments, R 7 is a 1,2-cis-disubstituted 4- to 6-membered heterocycloalkyl. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for

[0251] In certain embodiments, the compound is a compound of formula (IIIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIIb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIIc) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, the compound is a compound of formula (IIId) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0252] In some embodiments, the compound of formula (I) is a compound of formula (IV):

[0253]

[0254] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0255] In some embodiments of compounds of Formula (IV), R 3 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; each R 5 is halogen or C1-C4 alkyl; each R 6 is halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; each R 10 Independently selected from: halogen, -OR8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; u is 0, 1, or 2; and wherein 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; and (iii) u is 0, 1 or 2, and at least one R 10 It is a halogen.

[0256] In some embodiments of compounds of Formula (IV), R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 5 -F; R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9)-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; s is 0, 1, or 2; t is 0, 1, or 2; u is 0, 1, or 2; and wherein 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; and (iii) u is 0, 1 or 2, and at least one R 10 It is a halogen.

[0257] In some embodiments of compounds of Formula (IV), each R 5 are independently halogen or C1-C4 alkyl; and each R 6 is independently halogen or C1-C4 alkyl. In some embodiments, each R 5 are independently halogen; and each R 6 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 R6 is -F.

[0258] In some embodiments of the compound of formula (IV), L 1 is a bond, -(C1-C2 alkylene)-, -X 1 -or-X 2 -(C1-C2 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: 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)-, wherein: X 1 and X 2 Each is selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 1 For bonds, -(CH2)-, -X 1 -or-X 2 -(CH2)-, where: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 Is hydrogen or C1-C6 alkyl. In some embodiments, L 1 For bonds, -(CH2)-, -X 1 -or-X 2 -(CH2)-, where: X 1 and X 2 Each is selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 1 For bonds, -(CH2)-, -X 1 -or-X 2 -(CH2)-, where: X 1 and X 2 Each selected from: -O-, -N(R 9 )- and -S-. In some embodiments, L 1 For bonds, -(CH2)-, -X 1 -or-X 2-(CH2)-, where: X 1 and X 2 Each is selected from: -O-. In some embodiments, L 1 It is -O-.

[0259] In some embodiments, the compound of formula (I) is a compound of formula (V):

[0260]

[0261] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0262] 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; each R 5 is halogen or C1-C4 alkyl; each R 6 is halogen or C1-C4 alkyl; L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 together to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3, and oxo; s is 0, 1, or 2; t is 0, 1, or 2; u is 0, 1, or 2; and wherein 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; and (iii) u is 0, 1 or 2, and at least one R 10 It is a halogen.

[0263] In some embodiments of compounds of Formula (V), R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 5 -F; R 6 -F;L 1 is a bond, -(C1-C6 alkylene)-, -X 1 -or-X 2 -(C1-C6 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-, where: R 9 is hydrogen or C1-C6 alkyl; each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8, -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; s is 0, 1, or 2; t is 0, 1, or 2; u is 0, 1, or 2; and wherein 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; and (iii) u is 0, 1 or 2, and at least one R 10 It is a halogen.

[0264] In some embodiments of compounds of Formula (V), each R 5 are independently halogen or C1-C4 alkyl; and each R 6 is independently halogen or C1-C4 alkyl. In some embodiments, each R 5 are independently halogen; and each R 6 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.

[0265] In some embodiments of compounds of Formula (IV) or (V), u is 0. In some embodiments, u is 1. In some embodiments, u is 2.

[0266] In some embodiments of compounds 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.

[0267] In some embodiments of the compounds, salts, solvates, or stereoisomers 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.

[0268] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (V), each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 8 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo.

[0269] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (V), each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN and C1-C4 alkyl, wherein: each R 8 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2, -CH2CN and C1-C4 alkyl, wherein: each R 8 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2, -CH2CN and C1-C4 alkyl, wherein: each R 8 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 10 In some embodiments, each R 10In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 Independently selected from: -F and -OH.

[0270] 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, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is -(C1-C4 alkylene)-NH2 or -(C3-C6 cycloalkylene)-OH.

[0271] 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 In some embodiments, R 3In some embodiments, R 3 It is -(C1-C4 alkylene)-NH2 or -(cyclopropylene)-OH.

[0272] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 In some embodiments, R 3 In some embodiments, R 3 It is -(C1-C2 alkylene)-OH.

[0273] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is -CH2CH2OH.

[0274] 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 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3In some embodiments, R 3 It is -CH2NH2.

[0275] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 is hydrogen or -(C1-C2 alkylene)-OH. In some embodiments, R 3 In some embodiments, R 3 is hydrogen, -CH2OH, -CH2CH2OH or -CH(CH3)OH. In some embodiments, R 3 is hydrogen, -CH2OH or -CH2CH2OH. In some embodiments, R 3 It is hydrogen or -CH2OH.

[0276] 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-C2 alkylene)-OH or -(C1-C2 alkylene)-NH2. In some embodiments, R 3 is hydrogen, -CH2OH, -CH2CH2OH or -CH2NH2. In some embodiments, R 3 It is hydrogen, -CH2OH or -CH2NH2.

[0277] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 3 is -(C3-C5 cycloalkylene)-OH or -(C3-C5 cycloalkylene)-NH2. In some embodiments, R 3is -(C3-C4 cycloalkylene)-OH or -(C3-C4 cycloalkylene)-NH2. In some embodiments, R 3 is -(cyclopropylene)-OH or -(cyclopropylene)-NH2. In some embodiments, R 3 for

[0278] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 In some embodiments, -(C3-C5 cycloalkylene)-OH. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 for

[0279] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R 3 is -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 3 is -(C3-C5 cycloalkylene)-NH2. In some embodiments, R 3 is -(C3-C4 cycloalkylene)-NH2. In some embodiments, R 3 is -(cyclopropylene)-NH2. In some embodiments, R 3 for

[0280] In some embodiments of the compounds, salts, solvates, or stereoisomers 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 C1-C4 alkyl. In some embodiments, each R 5 and R 6 is independently -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, each R5 and R 6 is independently -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, each R 5 and R 6 is independently -F, -Cl or -CH3.

[0281] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 5 is independently halogen or unsubstituted C1-C4 alkyl. In some embodiments, each R 5 is independently -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, each R 5 is independently -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, each R 5 is independently -F, -Cl or -CH3.

[0282] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R 6 is independently halogen or unsubstituted C1-C4 alkyl. In some embodiments, each R 6 is independently -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, each R 6 is independently -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, each R 6 is independently -F, -Cl or -CH3.

[0283] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), each R5 is independently -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3; and t is 0. In some embodiments, each R 5 is independently -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2; and t is 0. In some embodiments, each R 5 are independently -F, -Cl or -CH3; and t is 0.

[0284] 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; and each R 6 is independently -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, s is 0; and each R 6 is independently -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, s is 0; and each R 6 is independently -F, -Cl or -CH3.

[0285] In some embodiments of the compounds, salts, solvates, or stereoisomers 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.

[0286] In some embodiments of the compounds, salts, solvates, or stereoisomers 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.

[0287] In some embodiments of compounds 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.

[0288] In some embodiments of the compounds, salts, solvates, or stereoisomers 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.

[0289] In some embodiments of the compounds, salts, solvates, or stereoisomers 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 halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 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 6In some embodiments, at least one of the following: (i) s is 1 or 2, and at least one R 5 is halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 In some embodiments, at least one of the following: (ii) t is 1 or 2, and at least one R 6 is halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 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, R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

[0290] In some embodiments of the compounds, salts, solvates, or stereoisomers 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 halogen; (ii) t is 1 or 2, and R 6 is halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, at least one of the following: (i) s is 1 or 2, and R 5 is halogen; and (ii) t is 1 or 2, and R 6 In some embodiments, at least one of the following: (i) s is 1 or 2, and R 5 is halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, at least one of the following: (ii) t is 1 or 2, and R 6 is halogen; and (iii) R7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, s is 1 or 2, and R 5 In some embodiments, t is 1 or 2, and R 6 In some embodiments, R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 It is a halogen.

[0291] In some embodiments of the compounds, salts, solvates, or stereoisomers 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 In some embodiments, at least one of the following: (i) s is 1 or 2, and at least one R 5 is -F; and (ii) t is 1 or 2, and at least one R 6 In some embodiments, at least one of the following: (i) s is 1 or 2, and at least one R 5 is -F; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 In some embodiments, at least one of the following: (ii) t is 1 or 2, and at least one R 6 is -F; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 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, R 7The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 is -F.

[0292] In some embodiments of the compounds, salts, solvates, or stereoisomers 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; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, at least one of the following: (i) s is 1 or 2, and R 5 is -F; and (ii) t is 1 or 2, and R 6 In some embodiments, at least one of the following: (i) s is 1 or 2, and R 5 is -F; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, at least one of the following: (ii) t is 1 or 2, and R 6 is -F; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 In some embodiments, s is 1 or 2, and R 5 In some embodiments, t is 1 or 2, and R 6 In some embodiments, R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and R 10 is -F.

[0293] In some embodiments of the compounds, salts, solvates, or stereoisomers of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), at least one R 5 、R 6 or R10 In some embodiments, at least one R 5 or R 6 In some embodiments, at least one R 5 or R 10 In some embodiments, at least one R 10 or R 6 In some embodiments, at least one R 5 In some embodiments, at least one R 6 In some embodiments, at least one R 10 In some embodiments, at least two R 5 、R 6 or R 10 In some embodiments, at least two R 5 or R 6 In some embodiments, at least two R 5 or R 10 In some embodiments, at least two R 10 or R 6 In some embodiments, at least two R 5 In some embodiments, at least two R 6 In some embodiments, at least two R 10 is -F.

[0294] In some embodiments of the compounds, salts, solvates, or stereoisomers 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 In some embodiments, at least one R 5 or R 6 In some embodiments, at least one R 5 or R 10 In some embodiments, at least one R 10 or R 6 In some embodiments, at least one R 5 In some embodiments, at least one R 6 In some embodiments, at least one R 10 In some embodiments, at least two R 5 、R 6 or R 10In some embodiments, at least two R 5 or R 6 In some embodiments, at least two R 5 or R 10 In some embodiments, at least two R 10 or R 6 In some embodiments, at least two R 5 In some embodiments, at least two R 6 In some embodiments, at least two R 10 It is -Cl.

[0295] In some embodiments, the compound is selected from:

[0296]

[0297]

[0298] 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.

[0299] Table 1:

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] **Arbitrary assignment of stereochemistry. Following chiral separation, a single stereoisomer is isolated, but the absolute configuration of the stereochemical center is unknown.

[0308] In another aspect, the present disclosure provides compounds having the structure of Formula (VI):

[0309]

[0310] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0311] R 11 is a C1-C4 alkyl group;

[0312] R 12a and R 12b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0313] R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0314] R 14 is hydrogen or C1-C4 alkyl;

[0315] Each R 15 and R 16 are independently halogen or C1-C4 alkyl;

[0316] 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein:

[0317] Each R 18 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3;

[0318] or two R's attached to the same nitrogen 18together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0319] L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein:

[0320] X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-,in:

[0321] R 19 is hydrogen or C1-C6 alkyl;

[0322] v is 0, 1, or 2; and

[0323] w is 0, 1, or 2.

[0324] In some embodiments, when L 2 is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then at least one of the following:

[0325] (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0326] (ii)R 14 is a C1-C4 alkyl group;

[0327] (iii)R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; or

[0328] (iv)L 2 is -O-(C1-C6 alkylene)- and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl group.

[0329] In some embodiments, when L 2When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 13 It is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2.

[0330] In some embodiments, when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 14 It is a C1-C4 alkyl group.

[0331] In some embodiments, when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0332] In some embodiments, when L 2 When L is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)- 2 is -O-(C1-C6 alkylene)- and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl group.

[0333] In some embodiments of compounds of Formula (VI), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8, -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; provided that when 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 a C1-C4 alkyl group, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with 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.

[0334] In some embodiments of compounds of Formula (VI), R 11 is a C1-C4 alkyl group; R 12a and R 12bare 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0335] In some embodiments of compounds of Formula (VI), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH 2、 -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 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 14is a C1-C4 alkyl group; (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0336] In another aspect, the present disclosure provides compounds having the structure of Formula (VIa) or (VIb):

[0337]

[0338] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0339] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; provided that when 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 a C1-C4 alkyl group, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with 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.

[0340] In some embodiments of compounds of Formula (VIa) or (VIb), R 11 -CH3; R12a and R 12b Each is hydrogen; R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; provided that when L 2 is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then at least one of the following: (i) R 13is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; (ii) R 14 is a C1-C4 alkyl group, (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with 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.

[0341] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0342] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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 a C1-C4 alkyl group; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0343] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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 R15 and R 16 are independently halogen or C1-C4 alkyl; R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; each of which is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0344] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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 a 5-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently 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 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is -O-(C1-C6 alkylene)-; v is 0, 1 or 2; and w is 0, 1 or 2.

[0345] In some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is a C1-C4 alkyl group; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0346] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 -F; 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 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0347] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 -F; 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 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0348] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen or -CH2OH; R 14 is hydrogen; each R 15 and R 16 -F; R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 L is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0349] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen or -CH2OH; R 14 is hydrogen; each R 15 and R 16 -F; R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 L is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl; 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2;

[0350] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11-CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen or -CH2OH; R 14 is hydrogen; each R 15 and R 16 -F; R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F, -OH, -OCH3 and -NH; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0351] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 11 -CH3; R 12a and R 12b Each is hydrogen; R 13 is hydrogen or -CH2OH; R 14 is hydrogen; each R 15 and R 16 -F; R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F, -OH, -OCH3 and -NH2; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0352] 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.

[0353] For any and all embodiments, the substituents are selected from a subset of the listed alternatives. For example, in some embodiments of compounds of Formula (VI), (VIa), or (VIb), R 11 is an unsubstituted C1-C4 alkyl. In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 is -CH3.

[0354] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (VI), (VIa) or (VIb), R 12a and R 12b Each independently is R 12a , and R 12b are each independently hydrogen, halogen or unsubstituted C1-C4 alkyl. In some embodiments, R 12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, R 12a and R 12b Each is independently hydrogen, -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2.

[0355] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (VI), (VIa) or (VIb), R 12a In some embodiments, R 12b In some embodiments, R 12a and R 12b Each is hydrogen.

[0356] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (VI), (VIa) or (VIb), R 11 -CH3; R 12a is hydrogen; and R 12b For hydrogen.

[0357] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (VI), (VIa) or (VIb), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14 is hydrogen or C1-C2 alkyl. In some embodiments, R 14 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 14 is hydrogen, -CH3 or -CH2CH3. In some embodiments, R 14 is hydrogen or -CH3. In some embodiments, R 14 In some embodiments, R 14 is -CH3.

[0358] In certain embodiments, compound is a compound of formula (VII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, compound is a compound of formula (VIIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In certain embodiments, compound is a compound of formula (VIIb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0359] In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VII):

[0360]

[0361] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0362] In some embodiments of compounds of Formula (VII), R 13is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19is hydrogen or C1-C6 alkyl; provided that when 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; (iii) R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with 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.

[0363] In some embodiments of compounds of Formula (VII), R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 14 is hydrogen; each R 15 and R 16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0364] In some embodiments of compounds of Formula (VII), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18)2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0365] In some embodiments of compounds 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; each R 15 and R 16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 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 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0366] In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VIIa) or formula (VIIb):

[0367]

[0368] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0369] In some embodiments of compounds of Formula (VIIa) or (VIIb), R 13 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; each R 15 and R16 independently -F; 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 8 、-N(R 8 )2, -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 8 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0370] 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; each R 15 and R 16 are independently halogen or C1-C4 alkyl; R 17 is a 5-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently 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 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is -O-(C1-C6 alkylene)-; v is 0, 1 or 2; and w is 0, 1 or 2.

[0371] 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; each R15 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0372] 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.

[0373] In some embodiments, the compound of Formula (VI) or (VII) is a compound of Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), or Formula (VIIId):

[0374]

[0375] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0376] 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; each R 15 and R 16 -F; 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 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0377] 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; each R 15 and R 16 -F; 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 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0378] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen or -CH2OH; each R 15 and R 16 -F; R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F, -OH, -OCH3 and -NH; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2; provided that when L 2 When it is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-, then R 17 is an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0379] In some embodiments of compounds of Formula (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen or -CH2OH; each R 15 and R 16 -F; R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F, -OH, -OCH3 and -NH2; L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

[0380] 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.

[0381] In some embodiments of compounds 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)-, wherein: X 3 and X 4 Each selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: 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)-, wherein: X 3 and X 4 Each selected from: -O-, -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)-, wherein: X 3 and X 4 Each selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-. In some embodiments, L 2 For bonds, -CH2-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O-, -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 For hydrogen.

[0382] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O-, -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)-, wherein: X 3 and X 4 Each selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-. In some embodiments, L 2 For key, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-. In some embodiments, R 19 For hydrogen.

[0383] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O-, -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)-, wherein: X3 and X 4 Each selected from: -O-, -N(R 19 )-, -S-, -S(=O)- and -S(=O)2-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O-, -N(R 19 )- and -S-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -O- and -N(R 19 )-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each is selected from: -O- and -S-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )- and -S-. In some embodiments, R 19 For hydrogen.

[0384] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X 4 Each is selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X 4 Each is selected from: -O-. In some embodiments, L 2 It is -O-.

[0385] In some embodiments of compounds 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 -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 -S(=O)(=NR 19 )-or-S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 In some embodiments, L 2 -N(R 19 )-. In some embodiments, R 19 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 -S(=O)(=NR 19 )-. In some embodiments, L 2 In some embodiments, L 2 -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 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 -S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 In some embodiments, L2 is -N(H)- or -N(H)-(CH2)-. In some embodiments, L 2 In some embodiments, L 2 is -S(=O)- or -S(=O)-(CH2)-. In some embodiments, L 2 is -S(=O)2- or -S(=O)2-(CH2)-. In some embodiments, L 2 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH2)-. In some embodiments, L 2 In some embodiments, L 2 is -N(H)-(CH2)-. In some embodiments, L 2 In some embodiments, L 2 is -S(=O)-(CH2)-. In some embodiments, L 2 is -S(=O)2-(CH2)-. In some embodiments, L 2 It is -S(=O)(=NH)-(CH2)-.

[0386] 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 substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

[0387] 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 group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -NHSO2R 18 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and each R 18 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

[0388] 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 group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen or C1-C2 alkyl.

[0389] 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 group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20Independently selected from: -F and -OH.

[0390] In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen or C1-C2 alkyl.

[0391] 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 group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F and -OH.

[0392] 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 group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen or C1-C2 alkyl.

[0393] 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 group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F and -OH.

[0394] In some embodiments, R 17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the 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 group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen or C1-C2 alkyl.

[0395] In some embodiments of compounds of (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: -F and -OH.

[0396] In some embodiments, R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 and -CH2CN; and each R 18 is independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R 17is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl. In some embodiments, R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 Independently selected from: halogen, -OH, -OR 18 、-N(R 18 )2 and -CH2CN; and each R 18 are independently hydrogen or C1-C2 alkyl.

[0397] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 17 For the 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0398] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -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)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )-, -S-, -S(=O)- and -S(=O)2-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )- and -S-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -S- and -N(R 19 )-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -S(=O)2- and -N(R 19 )-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -S(=O)(=NR 19 )- and -N(R 19 )-. In some embodiments, R 19 For hydrogen.

[0399] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0400] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 Selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 Selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0401] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 Selected from: -N(R 19 )- and -S-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 Selected from: -N(R 19 )- and -S-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )- and -S-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2Selected from: -N(R 19 )- and -S-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )- and -S-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0402] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 Selected from: -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 Selected from: -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene); and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20Group substitution, wherein: each R 20 In some embodiments, L 2 Selected from: -N(R 19 )- and -N(R 19 )-(C1-C6 alkylene)-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0403] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -N(R 19 )-and R 17 is azetidine, wherein the azetidine is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 -N(R 19 )-and R 17 is azetidine, wherein the azetidine is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 -N(R 19 )-and R 17 is azetidine, wherein the azetidine is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 -N(R 19 )-and R 17 is azetidine, wherein the azetidine is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is -CH2CN.

[0404] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -N(R 19)-and R 17 is cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with halogen, -OR 18 、-N(R 18 ) 2 is substituted. In some embodiments, L 2 -N(R 19 )-and R 17 is cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with halogen or -N(R 18 ) 2 is substituted. In some embodiments, L 2 -N(R 19 )-and R 17 is cyclobutane, wherein the cyclobutane is unsubstituted or substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with halogen or -N(H)(CH2CN). In some embodiments, L 2 -N(R 19 )-and R 17 is cyclobutane, wherein the cyclobutane is substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with halogen or -N(H)(CH2CN).

[0405] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0406] In some embodiments of compounds of (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0407] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0408] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0409] 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; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; L 2is -O-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0410] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 -CH3; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 for L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 for L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 for L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 13 for L 2 is -O-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0411] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is a C1-C4 alkyl group; and L 2 -R 17 for In some embodiments, R 14 is a C1-C4 alkyl group; and L 2 -R 17 for In some embodiments, R 13 for And L 2 -R 17 for In some embodiments, R 13 for And L 2 -R 17 for

[0412] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 is a C1-C4 alkyl group; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 R 14 is a C1-C4 alkyl group; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 is a C1-C4 alkyl group; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 is a C1-C4 alkyl group; L 2 is -O-; and R17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 is a C1-C4 alkyl group; L 2 is -O-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0413] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 14 -CH3; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 -CH3; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 -CH3; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 -CH3; L 2 is -O-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, R 14 -CH3; L 2 is -O-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R20 Independently selected from: -F and -OH.

[0414] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), is C1-C4 alkyl; and L 2 -R 17 for In some embodiments, R 14 is a C1-C4 alkyl group; and L 2 -R 17 for In some embodiments, R 14 is -CH3; and L 2 -R 17 for In some embodiments, R 14 is -CH3; and L 2 -R 17 for

[0415] In some embodiments of compounds 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 group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 ) 2 substituted 4-membered heterocycloalkyl. In some embodiments, L 2 is -O- or -O-C1-C6 alkylene-, R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0416] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2is a bond, -CH2-, -O- or -O-CH2-; and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 ) 2 substituted 4-membered heterocycloalkyl. In some embodiments, L 2 is -O- or -O-CH2-; R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 ) 2 substituted 4-membered heterocycloalkyl. In some embodiments, L 2 is -O-; and R 17 is an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted sulfur-containing heterocycloalkyl group, an unsubstituted or substituted bicyclic heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, a disubstituted or trisubstituted cycloalkyl group, or a cycloalkyl group substituted with at least one -N(R 18 )2-substituted 4-membered heterocycloalkyl.

[0417] In some embodiments of compounds 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 substituted with at least one -N(R 18 ) substituted oxetane. In some embodiments, L 2 is -O- or -O-C1-C6 alkylene-, 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 substituted with at least one -N(R 18 ) substituted oxetane.

[0418] In some embodiments of compounds 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 substituted with at least one -N(R 18 ) substituted oxetane. In some embodiments, L 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 substituted with at least one -N(R 18 ) substituted oxetane. In some embodiments, L 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 substituted with at least one -N(R 18 ) substituted oxetane.

[0419] In some embodiments of compounds 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 azaspiro[3.3]heptane. In some embodiments, L 2 is -O- or -O-CH2-; and R 17 is unsubstituted or substituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O-; and R 17 is unsubstituted or substituted azaspiro[3.3]heptane. In some embodiments, L 2 is -O-; and R 17is 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 -CH2CN.

[0420] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0421] In some embodiments of compounds 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, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 is -O-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -O-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -O-(C1-C6 alkylene)-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -O-(C1-C6 alkylene)-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R20 Independently selected from: -F and -OH.

[0422] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 is -OCH2-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 is independently selected from: halogen, -OH, -NH2 and -CH2CN. In some embodiments, L 2 is -OCH2-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -OCH2-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -OCH2-; and R 17 is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R 20 Group substitution, wherein: each R 20 In some embodiments, L 2 is -OCH2-; and R 17 For 1, 2 or 3 R 20 Tetrahydrofuran substituted with a group, wherein: each R 20 Independently selected from: -F and -OH.

[0423] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0424] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L 2 -R 17 for

[0425] 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 As a single diastereomer, and with R 17 In some embodiments, R 17 As a single diastereomer, and with R 17 In some embodiments, R 17 As a single diastereomer, and with R 17 Compared to a comparator compound that is a different stereoisomer, it exhibits improved in vivo efficacy.

[0426] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 17 For 1 or 2 R 20 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 20 Independently selected from: halogen, -OH, -OMe, -N(R 18 )2, -NHSO2R 18 In some embodiments, R 17 For 1 or 2 R 20 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 20 In some embodiments, R 17 For 1 or 2 R 20 A 4- to 6-membered heterocycloalkyl group substituted by a group, wherein each R 20 In some embodiments, R 17 It is a 4- to 6-membered heterocycloalkyl group substituted with -OH.

[0427] In some embodiments, R17 is a 1,2-trans-disubstituted 4- to 6-membered heterocycloalkyl. 2 -R 17 for In some embodiments, L 2 -R 17 for In some embodiments, L 2 -R 17 for In some embodiments, L 2 -R 17 for

[0428] In some embodiments, R 17 is a 1,2-cis-disubstituted 4- to 6-membered heterocycloalkyl. 2 -R 17 for In some embodiments, L 2 -R 17 for In some embodiments, L 2 -R 17 for In some embodiments, L 2 -R 17 for

[0429] 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, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -(C1-C4 alkylene)-NH2 or -(C3-C6 cycloalkylene)-OH.

[0430] 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 In some embodiments, R 13 In some embodiments, R 13 It is -(C1-C4 alkylene)-NH2 or -(cyclopropylene)-OH.

[0431] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 In some embodiments, R 13 In some embodiments, R 13 It is -(C1-C2 alkylene)-OH.

[0432] In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -CH2CH2OH.

[0433] 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, R13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -CH2NH2.

[0434] 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 In some embodiments, R 13 is hydrogen, -CH2OH, -CH2CH2OH or -CH(CH3)OH. In some embodiments, R 13 is hydrogen, -CH2OH or -CH2CH2OH. In some embodiments, R 13 It is hydrogen or -CH2OH.

[0435] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R 13 is hydrogen, -(C1-C2 alkylene)-OH or -(C1-C2 alkylene)-NH2. In some embodiments, R 13 is hydrogen, -CH2OH, -CH2CH2OH or -CH2NH2. In some embodiments, R 13It is hydrogen, -CH2OH or -CH2NH2.

[0436] 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)-, wherein: X 3 and X 4 Each is selected from the group consisting of: -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-.

[0437] 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.

[0438] In some embodiments, the compound of formula (VI) is a compound of formula (IX):

[0439]

[0440] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0441] In some embodiments of compounds of Formula (IX), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-NH2; each R 15 and R 16 For -F; each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R18 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

[0442] In some embodiments of compounds of Formula (IX), R 13 is -CH2-OH, CH2-NH2, (cyclopropylene)-OH or -(cyclopropylene)-NH2; each R 15 and R 16 For -F; each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

[0443] In some embodiments, the compound of formula (VI) is a compound of formula (X):

[0444]

[0445] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0446] In some embodiments of compounds of Formula (IX), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-NH2; each R 15 and R 16 For -F; each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R18 L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

[0447] In some embodiments of compounds of Formula (IX), R 13 is -CH2-OH, CH2-NH2, (cyclopropylene)-OH or -(cyclopropylene)-NH2; each R 15 and R 16 For -F; each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18L is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-, where: R 19 is hydrogen or C1-C6 alkyl; v is 0; w is 0; y is 0, 1 or 2.

[0448] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 is -(C3-C5 cycloalkylene)-OH or -(C3-C5 cycloalkylene)-NH2. 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)-NH2. In some embodiments, R 13 for

[0449] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R 13 In some embodiments, -(C3-C5 cycloalkylene)-OH. In some embodiments, R 13In some embodiments, R 13 In some embodiments, R 13 for

[0450] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R 13 is -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 is -(C3-C5 cycloalkylene)-NH2. In some embodiments, R 13 is -(C3-C4 cycloalkylene)-NH2. In some embodiments, R 13 is -(cyclopropylene)-NH2. In some embodiments, R 13 for

[0451] In some embodiments of compounds 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)-, wherein: X 3 and X 4 Each is selected from: -N(H)-, -S-, -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X 4 Each is selected from: -N(H)-, -S-, -S(=O)-, and -S(=O)2-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X 4 Each is selected from: -N(H)-, -S-, -S(=O)-, and -S(=O)(=NH)-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X4 Each is selected from: -N(H)-, -S-, -S(=O)2-, and -S(=O)(=NH)-. In some embodiments, L 2 -X 3 -or-X 4 -(C1-C4 alkylene)-, wherein: X 3 and X 4 Each is selected from: -N(H)- and -S-.

[0452] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), L 2 -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 -S(=O)(=NR 19 )-or-S(=O)(=NR 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 -N(R 19 )-. In some embodiments, R 19 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 -S(=O)(=NR 19 ). In some embodiments, L 2 -N(R 19 )-(C1-C6 alkylene)-. In some embodiments, L 2 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 -S(=O)(=NR19 )-(C1-C6 alkylene)-. In some embodiments, L 2 is -N(H)- or -N(H)-(CH2)-. In some embodiments, L 2 In some embodiments, L 2 is -S(=O)- or -S(=O)-(CH2)-. In some embodiments, L 2 is -S(=O)2- or -S(=O)2-(CH2)-. In some embodiments, L 2 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH2)-. In some embodiments, L 2 is -N(H)-(CH2)-. In some embodiments, L 2 In some embodiments, L 2 is -S(=O)-(CH2)-. In some embodiments, L 2 is -S(=O)2-(CH2)-. In some embodiments, L 2 It is -S(=O)(=NH)-(CH2)-.

[0453] In some embodiments of compounds 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.

[0454] In some embodiments of compounds 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.

[0455] In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), w is 0; and v is 0.

[0456] In some embodiments of compounds 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.

[0457] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (IX) or (X), each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition, each R 18 R is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the 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, -C02H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from: -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -C02H, -CONH2, and -SO2CH3; or two R attached to the same nitrogen 18 Together they form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo.

[0458] In some embodiments of the compound, salt, solvate or stereoisomer of Formula (IX) or (X), each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. NHCOR 18 、-NHSO2R 18 , -CH2CN and C1-C4 alkyl, wherein: each R 18 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CO2R 18、-CON(R 18 )2, -CH2CN and C1-C4 alkyl, wherein: each R 18 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 )2, -CH2CN and C1-C4 alkyl, wherein: each R 18 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 In some embodiments, each R 20 It is -OH.

[0459] In some embodiments, the compound is selected from:

[0460]

[0461]

[0462] 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.

[0463] Table 2:

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] **Arbitrary assignment of stereochemistry. Following chiral separation, a single stereoisomer is isolated, but the absolute configuration of the stereochemical center is unknown.

[0470] In some embodiments, the compound is of formula (XI):

[0471]

[0472] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0473] R 11 is a C1-C4 alkyl group;

[0474] R 12a and R 12b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0475] R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0476] R 14 is hydrogen or C1-C4 alkyl;

[0477] Each R 15 and R 16 are independently halogen or C1-C4 alkyl;

[0478] R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms of the rings together form ring A, which is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: 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; wherein:

[0479] Each R 25independently hydrogen or C1-C4 alkyl, wherein the 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;

[0480] or two R's attached to the same nitrogen 25 together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0481] v is 0, 1, or 2; and

[0482] w is 0, 1 or 2. In some embodiments of the compound of formula (XI), R 11 is an unsubstituted C1-C4 alkyl. In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 is -CH3.

[0483] In some embodiments of compounds of Formula (XI), R 12a and R 12b Each independently is R 12a , and R 12b are each independently hydrogen, halogen or unsubstituted C1-C4 alkyl. In some embodiments, R 12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments, R 12a and R 12b Each is independently hydrogen, -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2.

[0484] In some embodiments of compounds of Formula (XI), R 12a In some embodiments, R 12bIn some embodiments, R 12a and R 12b Each is hydrogen.

[0485] In some embodiments of compounds of Formula (XI), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -(C1-C2 alkylene)-OH.

[0486] In some embodiments of compounds of Formula (XI), R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -CH2OH.

[0487] In some embodiments of compounds of Formula (XI), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14 is hydrogen or C1-C2 alkyl. In some embodiments, R 14 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 14 is hydrogen, -CH3 or -CH2CH3. In some embodiments of the compound of formula (XI), R 14 is hydrogen or -CH3. In some embodiments, R 14 In some embodiments, R 14 is -CH3.

[0488] 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.

[0489] In some embodiments of compounds of Formula (XI), R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms of the rings together form ring A, which is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl and oxo.

[0490] In some embodiments of compounds of Formula (XI), R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms of the rings together form ring A, which is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2, or 3 groups independently selected from the following: halogen, C1-C4 alkyl, and oxo. In some embodiments, R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms of the rings together form ring A, which is a 4-membered to 6-membered heterocycloalkyl containing 1-2 O atoms or 1-2 N atoms, wherein the 4-membered to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: halogen, C1-C4 alkyl and oxo.

[0491] In some embodiments of compounds of Formula (XI), R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms of the rings together form ring A, said ring A being a 4- to 8-membered heterocycloalkyl, wherein said 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: 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.

[0492] In some embodiments of compounds of Formula (XI), R 23 and R 24 Connect with R 23 to R 24The middle carbon atoms of the alkyl radicals together form ring A, which is a 5- to 6-membered heterocycloalkyl radical, wherein the 5- to 6-membered heterocycloalkyl radical is unsubstituted or substituted with 1, 2 or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl and oxo.

[0493] In some embodiments of compounds of Formula (XI), R 23 and R 24 Connect with R 23 to R 24 The middle carbon atoms together form ring A, and the ring A is

[0494] In some embodiments of compounds of Formula (XI), for

[0495] 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.

[0496] Table 3:

[0497]

[0498] In some embodiments, the compound is of formula (XII):

[0499]

[0500] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0501] R 11 is a C1-C4 alkyl group;

[0502] R 12a and R 12b Each is independently hydrogen, halogen or C1-C4 alkyl;

[0503] R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2;

[0504] R 14 is hydrogen or C1-C4 alkyl;

[0505] Each R 15 and R 16 are independently halogen or C1-C4 alkyl;

[0506] R 26 is C1-C6 alkyl, C1-C6 fluoroalkyl, 4-membered 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-membered to 6-membered heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, C1-C6 alkyl, -OH, -NH2 and -CN;

[0507] Each R 27 are independently hydrogen or C1-C6 alkyl;

[0508] Each R 28 are independently hydrogen or C1-C6 alkyl;

[0509] or two R's attached to the same nitrogen 28 together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo;

[0510] y is 0, 1, or 2;

[0511] v is 0, 1, or 2; and

[0512] w is 0, 1, or 2.

[0513] In some embodiments of compounds of Formula (XII), R 11 is an unsubstituted C1-C4 alkyl. In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 is -CH3.

[0514] In some embodiments of compounds of Formula (XII), R 12a and R 12b Each independently is R 12a , and R 12b are each independently hydrogen, halogen or unsubstituted C1-C4 alkyl. In some embodiments, R12a and R 12b are each independently hydrogen, -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. In some embodiments of compounds of formula (XII), R 12a and R 12b Each is independently hydrogen, -F, -Cl, -CH3, -CH2CH3 or -CH(CH3)2.

[0515] In some embodiments of compounds of Formula (XII), R 12a In some embodiments, R 12b In some embodiments, R 12a and R 12b Each is hydrogen.

[0516] In some embodiments of compounds of Formula (XII), R 13 is hydrogen, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-NH2, -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2. In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -(C1-C2 alkylene)-OH.

[0517] In some embodiments of compounds of Formula (XII), R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is -CH2OH.

[0518] In some embodiments of compounds of Formula (XII), R 14 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 14 is hydrogen or C1-C2 alkyl. In some embodiments, R14 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. In some embodiments, R 14 is hydrogen, -CH3 or -CH2CH3. In some embodiments, R 14 is hydrogen or -CH3. In some embodiments, R 14 In some embodiments, R 14 is -CH3.

[0519] In some embodiments of compounds of Formula (XII), w is 0 and v is 0. In some embodiments, w is 0. In some embodiments, v is 0.

[0520] In some embodiments of compounds of Formula (XII), y is 0. In some embodiments, y is 1. In some embodiments, y is 1 and R 28 is a C1-C3 alkyl group. In some embodiments, y is 1 and R 28 For CH3.

[0521] In some embodiments of compounds of Formula (XII), R 26 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; each R 28 are independently hydrogen or -CH3; or two R attached to the same nitrogen 28 Together they form a morpholinyl group.

[0522] In some embodiments of compounds of Formula (XII), R 26 for

[0523] In some embodiments of compounds of Formula (XII), R 26 for

[0524] 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.

[0525] Table 4:

[0526]

[0527]

[0528]

[0529] 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.

[0530] Table 5:

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538] **Arbitrary assignment of stereochemistry. Following chiral separation, a single stereoisomer is isolated, but the absolute configuration of the stereochemical center is unknown.

[0539] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents are chosen by one skilled in the art to provide stable moieties and compounds.

[0540] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0541] As used herein, "pharmaceutically acceptable" refers to a material (such as a carrier or diluent) that does not abrogate the biological activity or properties of the compound and is relatively nontoxic at the concentrations or amounts employed, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any component of a composition in which the material is contained.

[0542] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of a cationic form of the therapeutically active agent in combination with a suitable negative ion, or in alternative embodiments, a combination of an anionic form of the therapeutically active agent with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bigley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and CGWermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts are generally more soluble and more rapidly soluble in gastric and intestinal fluids than non-ionic species and are therefore suitable for solid dosage forms. Furthermore, because their solubility often varies with pH, ​​they may be selectively soluble in one part of the digestive tract or another, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Additionally, because salt-forming molecules can equilibrate with the neutral form, passage through biological membranes can be regulated.

[0543] In some embodiments, pharmaceutically acceptable salts are 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, the 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 reacts 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); acid); carbonic acid; cinnamic acid; citric acid; cyclohexanesulfonic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptanoic 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; propionic 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.

[0544] In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is prepared as a chloride salt, a sulfate salt, a bromide salt, a methanesulfonate salt, a maleate salt, a citrate salt, or a phosphate salt.

[0545] In some embodiments, pharmaceutically acceptable salts are 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, the 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 cases, the acidic protons of the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) are replaced with a metal ion, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein are coordinated with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming salts with compounds comprising 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.

[0546] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. 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 in the methods described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0547] 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 having the same type of activity.

[0548] In some embodiments, sites on the organic group (e.g., alkyl, 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. Incorporation of appropriate substituents on the organic group will reduce, minimize, or eliminate such metabolic pathways. In particular embodiments, appropriate substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are, for example, halogen, deuterium, alkyl, haloalkyl, or deuterated alkyl.

[0549] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioisotope) or labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0550] The compounds described herein include isotopically labeled compounds, which are identical to those depicted in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, e.g. 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 In one aspect, an isotopically labeled compound as described herein, for example one in which a radioactive isotope (e.g., 3 H and 14 C) compounds, which can be used in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0551] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) have one or more stereocenters, and each stereocenter independently exists in the R or S configuration. In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) exist in the R configuration. In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) exist in the S configuration. The compounds presented herein include all diastereoisomers, individual enantiomers, atropisomers, and epimeric forms, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, cis, trans, hetero (E), and homo (Z) isomers, as well as suitable mixtures thereof.

[0552] If necessary, individual stereoisomers are obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns or separation of diastereomers by achiral or chiral chromatographic columns or crystallization and recrystallization in appropriate solvents or solvent mixtures. In certain embodiments, compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII) are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, the resolution of individual enantiomers is performed 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, the separation of stereoisomers is performed 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.

[0553] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Because prodrugs are easier to administer than the parent drug in some cases, prodrugs are generally useful. For example, they can become bioavailable through oral administration, while the parent drug cannot. Additionally or alternatively, the prodrug can also have an improved solubility in the pharmaceutical composition that exceeds that of the parent drug. In some embodiments, the design of the prodrug increases effective water solubility. Examples of prodrugs are, but are not limited to, the compounds described herein, which are administered as esters ("prodrugs") and then metabolically hydrolyzed to provide the active entity. Another example of a prodrug is a short peptide (polyamino acid) bound to an acidic group, wherein the peptide is metabolized to reveal the active portion. In certain embodiments, upon in vivo administration, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized into the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0554] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkoxyacyl 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., eds.; 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, eds., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the 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 groups in the compounds disclosed herein are prodrugs wherein the hydroxyl groups are subsequently metabolized in vivo to provide carboxylic acid groups. In some embodiments, the carboxyl group is used to provide an ester or amide (ie, a prodrug), which is subsequently metabolized in vivo to provide the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0555] Prodrug forms of the compounds described herein are included within the scope of the claims, wherein 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) as described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0556] In some embodiments, any of the hydroxyl(s), amino(s), and / or carboxylic acid(s) groups are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0557] In additional or further embodiments, the compounds described herein are metabolized when administered to an organism in need thereof to produce metabolites, which are subsequently used to produce a desired effect, including a desired therapeutic effect.

[0558] A "metabolite" of a compound disclosed herein is a derivative of the 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 "metabolism" refers to the sum of processes (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions) by which an organism changes a particular substance. Thus, an enzyme can produce a specific structural change to 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 administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0559] In some cases, heterocycles can exist as tautomers. In such cases, it will be understood that the structure of the compound is described or named in one tautomeric form, but can be described or named in an alternative tautomeric form. Alternative tautomeric forms are explicitly included in the present disclosure, such as the structures shown below. For example, benzimidazole or imidazole can exist in the following tautomeric forms:

[0560]

[0561] Preparation of compounds

[0562] Compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) described herein are synthesized using standard synthetic techniques or using methods known in the art and the methods described herein.

[0563] Unless otherwise stated, conventional methods of mass spectrometry, NMR, and HPLC were employed.

[0564] The compounds can be prepared using standard organic chemistry techniques, for example, those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed, such as varying solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions.

[0565] In some embodiments, the compounds described herein are prepared as described in Scheme A.

[0566] Option A:

[0567]

[0568] a) Pd catalyst, base; b) removal of protecting group

[0569] An organometallic coupling reaction between intermediate A and an appropriate arylboronic acid or ester or organotrifluoroborate (BF3K) B, such as the Suzuki-Miyaura reaction, provides intermediate C. Removal of the protecting group using an appropriate deprotection method gives the final compound D.

[0570] In some other embodiments, the compounds described herein are prepared as described in Scheme B.

[0571] Option B:

[0572]

[0573] a) amine (R'NH2), AcOH, borohydride reagent; b) removal of protecting group

[0574] The ketone-containing intermediate E is reacted with an appropriate amine (R″′-NH2) under appropriate reductive amination conditions (e.g., treatment with a borohydride reagent: for example, NaBH4, NaCNBH3 or NaB(OAc)3H) to provide intermediate F. The protecting group is removed using an appropriate deprotection method to provide the final compound G.

[0575] In some embodiments, compounds are prepared as described in the Examples.

[0576] Certain terms

[0577] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes 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 a physical property, such as molecular weight, or a chemical property, such as a chemical formula, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or numerical range, the term "about" indicates that the number or numerical range referred to is an approximation of experimental variability (or within statistical experimental error), such that in some cases the number or numerical range will vary from 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, for example, embodiments of any composition of matter, composition, method or process, etc. described herein "consisting of" or "consisting essentially of the described features."

[0578] Unless otherwise indicated, the following terms used in this application have the definitions given below. The use of the term "including" and other forms such as "include," "includes," 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.

[0579] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are from one to six carbon atoms in the moiety, i.e., a group containing 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 one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0580] "Alkyl" refers to an aliphatic hydrocarbon group. An alkyl group is a branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10Alkyl. Whenever presented 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, but the present definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl. In some embodiments, the alkyl group is methyl.

[0581] "Alkylene" refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be converted to an alkylene group by extracting a second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a C1-C6 alkylene group. In other embodiments, the alkylene group is a C1-C4 alkylene group. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene group is -CH2-.

[0582] "Alkoxy" means an -O(alkyl) group where alkyl is as defined herein.

[0583] The term "alkylamine" refers to -N(alkyl) x H y A group wherein x is 0 and y is 2, or wherein x is 1 and y is 1, or wherein x is 2 and y is 0.

[0584] "Hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl group. In some embodiments, the hydroxyalkyl group is a C1-C4 hydroxyalkyl group. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like. In some embodiments, the hydroxyalkyl group is -CH2OH or -CH2CH2OH. In some embodiments, the hydroxyalkyl group is -CH2OH. In some embodiments, the hydroxyalkyl group is -CH2CH2OH.

[0585] "Aminoalkyl" refers to an alkyl group in which one hydrogen atom is replaced by an amino group. In some embodiments, the aminoalkyl group is a C1-C4 aminoalkyl group. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, etc. In some embodiments, the aminoalkyl group is -CH2NH2 or -CH2CH2NH2. In some embodiments, the hydroxyalkyl group is -CH2NH2. In some embodiments, the hydroxyalkyl group is -CH2CH2NH2.

[0586] The term "alkenyl" refers to an alkyl type in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR2, wherein R refers to the remainder of the alkenyl group, which may be the same or different. In certain embodiments, R is H or an alkyl group. In certain embodiments, the alkenyl group is selected from vinyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0587] The term "alkynyl" refers to an alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group 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.

[0588] The term "heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group in which one or two atoms are independently selected from O, NH, and S.

[0589] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aromatic ("aryl," e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups.

[0590] The term "carbocycle" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from a "heterocyclic" ring or "heterocycle" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl groups.

[0591] As used herein, the term "aryl" refers to an aromatic ring in which each atom 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 10 Depending on the structure, an aryl group is a monoradical or a diradical (ie, an arylene group).

[0592] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group, wherein each atom (i.e., skeleton atom) forming the ring is a carbon atom. In certain embodiments, cycloalkyl is a spirocyclic or bridged compound. In certain embodiments, 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 includes a group with 3 to 10 ring atoms. In certain embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro [2.2] pentyl, norbornyl and bicyclo [1.1.1] pentyl. In certain embodiments, cycloalkyl is C3-C6 cycloalkyl. In certain embodiments, cycloalkyl is C3-C4 cycloalkyl. In certain embodiments, cycloalkyl is cyclopropyl. In certain embodiments, cycloalkyl is cyclobutyl.

[0593] The term "halo" or alternatively, "halogen" or "halide" means fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluorine, chlorine, or bromine.

[0594] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is -CF3.

[0595] The term "heterocycle" or "heterocyclic ring" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S, and N, wherein each heterocyclyl group has 3 to 10 atoms in its ring system, and with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclyl groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclyl groups include rings having 5 to 10 atoms in their ring system. Heterocyclyl groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, diazepanyl, thiazepanyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolane, pyrazolyl, linoyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroisoquinolin-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 quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, 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, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Where possible, the aforementioned groups are C-attached (or C-linked) or N-attached. For example, groups derived from pyrrole include both pyrrol-1-yl (N-attached) and pyrrol-3-yl (C-attached). Additionally, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-attached). Heterocyclic groups include benzo-fused ring systems.The non-aromatic heterocycle is optionally substituted with one or two oxo (=O) moieties (e.g., pyrrolidin-2-one). In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0596] The term "heteroaryl" or alternatively, "heteroaromatic" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryl groups include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl groups contain 0-4 N atoms in the ring. In some embodiments, heteroaryl groups contain 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5-membered or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group.

[0597] "Heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group is fused to an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is oxazolidinone, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-one, pyrrolidine-2,5-dithione, pyrrolidine-2,5-diketone, pyrrolidinone, imidazolidinyl, imidazolidin-2-one, or thiazolidin-2-one. In one aspect, the heterocycloalkyl group is C2-C 10 In another aspect, the heterocycloalkyl group is C4-C 10Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is 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 is optionally substituted with one or two oxo (=O) moieties.

[0598] 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 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 form between the remaining identified groups.

[0599] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0600] 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 the group consisting of halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C02H, -C02alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, 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, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from the group consisting of halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, the substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0601] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R independently selected from the group consisting of: s Group substitution: 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)2; Each R 21 R is 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 group together with the nitrogen atom to which it is attached forms an N-containing heterocyclic ring; each R 22 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.

[0602] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0603] As used herein, the term "modulate" refers to interacting directly or indirectly with a target so as 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 extending the activity of the target.

[0604] 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 agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

[0605] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to achieve delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0606] As used herein, the terms "co-administered," "co-administered," and the like are intended to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0607] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. Results include alleviation and / or relief of the signs, symptoms, or causes of the disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Techniques such as dose escalation studies are optionally used to determine an appropriate "effective" amount in any individual case.

[0608] As used herein, the terms "enhance" or "enhancing" refer to increasing or prolonging, either in potency or duration, a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of another therapeutic agent on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0609] As used herein, the term "pharmaceutical combination" means a product that is mixed or combined with more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof and an adjuvant) are all administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof and an adjuvant) are administered to the patient simultaneously, concurrently or sequentially as separate entities without specific intervening time limits, wherein such administration provides effective levels of two compounds in the patient's body. The latter is also applicable to cocktail therapies, such as the administration of three or more active ingredients.

[0610] The terms "article of manufacture" and "kit" are used synonymously.

[0611] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and 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.

[0612] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing other symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating secondary conditions caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of the disease or condition.

[0613] Pharmaceutical composition

[0614] In certain embodiments, the heterocyclic LpxC inhibitory compounds described herein are administered as the pure chemical. In other embodiments, the heterocyclic LpxC inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically 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, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0615] Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, and 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 is not deleterious to the recipient of the composition (i.e., the subject or patient).

[0616] 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.

[0617] In certain embodiments, the heterocyclic LpxC-inhibiting compound described as Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is substantially pure in that it contains 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 synthesis byproducts produced, for example, during one or more steps of the synthetic method.

[0618] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0619] The dosage of the composition comprising at least one heterocyclic LpxC inhibitory compound as described herein will vary depending on the patient's condition, ie, stage of disease, general health, age, and other factors.

[0620] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). Suitable dosage, suitable duration and frequency of administration will be 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 method of administration. Typically, suitable dosage and treatment regimen provide compositions that are sufficient to provide treatment and / or prevention benefits (e.g., improved clinical results) or alleviate the amount of symptom severity. Optimal dose is typically determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0621] Oral dosages generally range from about 1.0 mg to about 1000 mg per day, one to four or more times.

[0622] Combination therapy

[0623] In certain instances, it is 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 additional therapeutic agents.

[0624] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit on its own, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by the administration of one of the compounds described herein and another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0625] In a specific 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.

[0626] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0627] For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with the one or more other therapeutic agents, or are administered sequentially.

[0628] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided, by way of example only, in a single, unified form or in multiple forms (e.g., in a single pill or in two separate pills).

[0629] The compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII), or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the time at which the compositions containing the compounds are administered varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to a subject with a propensity to develop a condition or disease in order to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject as soon as possible during or after the onset of symptoms. In specific embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the duration required to treat the disease. In some embodiments, the duration of treatment varies, and the duration of treatment is adjusted to meet the specific needs of each subject.

[0630] Other embodiments and uses will be apparent to those skilled in the art in light of this disclosure.The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0631] Examples

[0632] 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:

[0633] abbreviation:

[0634] ACN or MeCN: acetonitrile;

[0635] aq: aqueous solution;

[0636] Boc or BOC: tert-butoxycarbonyl;

[0637] DCM: dichloromethane;

[0638] DIAD: diisopropyl azodicarboxylate;

[0639] DMAP: 4-dimethylaminopyridine;

[0640] DMF: dimethylformamide;

[0641] DMP: Dess-Martin periodinane

[0642] DPPA: diphenylphosphoryl azide;

[0643] dr: diastereoisomer ratio

[0644] Eq. or equiv: equivalent;

[0645] EtOAc: ethyl acetate;

[0646] g: grams

[0647] h or hr: hours;

[0648] HPLC: high performance liquid chromatography;

[0649] LC-MS, LC MS, or LCMS: liquid chromatography-mass spectrometry;

[0650] LDA: lithium diisopropylamide;

[0651] M: Moore;

[0652] MeOH: methanol;

[0653] mg: milligram;

[0654] min: minute;

[0655] mL: milliliter;

[0656] mmol: millimole;

[0657] MsCl: methanesulfonyl (methylsulfonyl) chloride;

[0658] MTBE: methyl tert-butyl ether;

[0659] N: normal;

[0660] NBS: N-bromosuccinimide;

[0661] NMR: nuclear magnetic resonance;

[0662] Pet ether: petroleum ether;

[0663] PPTS: pyridinium p-toluenesulfonate;

[0664] p-TSA: p-toluenesulfonic acid

[0665] rt: room temperature;

[0666] SFC: supercritical fluid chromatography;

[0667] TEA: triethylamine (or Et3N);

[0668] TFA: trifluoroacetic acid;

[0669] THF: tetrahydrofuran;

[0670] THP: tetrahydropyran;

[0671] TLC: thin layer chromatography;

[0672] TsCl: p-Toluenesulfonyl (toluenesulfonyl) chloride.

[0673] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the technical solutions provided herein.

[0674] I. Chemical Synthesis

[0675] Unless otherwise stated, reagents and solvents received from commercial suppliers were used. Anhydrous solvents and oven-dried glassware were used for synthetic transformations that were sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and not optimized. Unless otherwise stated, column chromatography and thin-laye...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 1 is a C1-C4 alkyl group; R 2a and R 2b Each is 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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-,in: 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; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 2. -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. -NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: Each R 8 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R's attached to the same nitrogen 8 together form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 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 R 6 is a halogen; and (iii) R 7 The alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of 10 group substituted, and at least one R 10 It is a halogen.

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

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

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

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

6. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein at least two R 5 or R 6 is -F.

7. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein at least two R 10 is -F.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 1 It is -CH3.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 2a is hydrogen; and R 2b For hydrogen.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 4 For hydrogen.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 5 are independently -F, -Cl or -CH3.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 5 is -F.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 6 is -F.

14. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which has a structure of formula (IIa): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 5 is -F; and Each R 6 is -F.

15. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which has a structure of formula (IIIa): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 5 is -F; and Each R 6 is -F.

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is hydrogen or -(C1-C4 alkylene)-OH.

17. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is -(C1-C4 alkylene)-OH.

18. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is -CH2OH.

19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 9 For hydrogen.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 is a bond, -(C1-C4 alkylene)-, -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from the group consisting of: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NH)-.

21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from the group consisting of: -O-, -N(H)-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NH)-.

22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is selected from: -O-.

23. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 For -O-.

24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 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 substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 2. -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. -NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: Each R 8 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

25. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 )2. -NHSO2R 8 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and Each R 8 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl or 4- to 6-membered heterocycloalkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -CO2H, -C(=NH)NH2 and 5-membered monocyclic heteroaryl, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

26. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 are independently selected from: halogen, -OH, -OMe, -N(R 8 )2. -NHSO2R 8 and -CH2CN; and Each R 8 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

27. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: -F, -OH, -OCH3 and -NH2.

28. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 -R 7 for 29. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 1 -R 7 for 30. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 1 is -CH3; R 2a and R 2b Each is hydrogen; R 3 is hydrogen, -(C1-C4 alkylene)-OH or -(C1-C4 alkylene)-NH2; R 4 is hydrogen; Each R 5 and R 6 is a halogen; L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each is 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 substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 2. -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. -NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: Each R 8 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

31. The compound according to claim 30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 is hydrogen or -(C1-C4alkylene)-OH; L 1 -X 1 -or-X 2 -(C1-C4 alkylene)-, wherein: X 1 and X 2 Each selected from: -O-; R 7 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 are independently selected from: halogen, -OH, -OMe, -N(R 8 )2. -NHSO2R 8 and -CH2CN; and Each R 8 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

32. The compound according to claim 30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 is CH2OH; L 1 for -O-; R 7 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R 10 Group substitution, where: Each R 10 Independently selected from: -F, -OH, -OCH3 and -NH2.

33. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which has the structure of formula (IV): 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; 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)-, wherein: X 1 and X 2 Each selected from: -O-, -N(R 9 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 9 )-,in: R 9 is hydrogen or C1-C6 alkyl; Each R 10 Independently selected from: halogen, -OR 8 、-N(R 8 2. -CO2R 8 、-CON(R 8 )2、-CH2N(R 8 2. -NHCOR 8 、-NHSO2R 8 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: Each R 8 are 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.

34. The compound according to claim 33 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which has a structure of formula (V): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

35. A compound according to claim 33 or claim 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein s is 1 or 2; and at least one R 5 is -F.

36. A compound according to any one of claims 33 to 35, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein t is 1 or 2; and at least one R 6 is -F.

37. A compound according to any one of claims 33 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein u is 1 or 2; and at least one R 10 is -F.

38. A compound according to any one of claims 33 to 37, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is -(C1-C4 alkylene)-OH.

39. A compound according to any one of claims 33 to 37, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is -CH2OH.

40. The compound according to claim 1, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

41. The compound according to claim 1, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

42. A compound of formula (VI): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 is a C1-C4 alkyl group; R 12a and R 12b Each is 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 2. -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. -NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; wherein: Each R 18 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; or two R's attached to the same nitrogen 18 together form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; L 2 is a bond, -(C1-C6 alkylene)-, -X 3 -or-X 4 -(C1-C6 alkylene)-, wherein: X 3 and X 4 Each independently selected from: -O-, -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 )-,in: R 19 is hydrogen or C1-C6 alkyl; The condition is that when 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 a C1-C4 alkyl group, (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 disubstituted or trisubstituted cycloalkyl, or a -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 group; v is 0, 1, or 2; and w is 0, 1, or 2.

43. The compound according to claim 42, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 It is -CH3.

44. A compound according to claim 42 or claim 43, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 12a is hydrogen; and R 12b For hydrogen.

45. A compound according to any one of claims 42 to 44, wherein: R 14 For hydrogen.

46. ​​A compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 15 are independently -F, -Cl or -CH3.

47. A compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 15 Independently -F.

48. A compound according to any one of claims 42 to 47, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 16 are independently -F, -Cl or -CH3.

49. A compound according to any one of claims 42 to 47, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R 16 Independently -F.

50. A compound according to any one of claims 42 to 49, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, having a structure of formula (VIIa): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

51. A compound according to any one of claims 42 to 49, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, having a structure of formula (VIIIa): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

52. A compound according to any one of claims 42 to 50, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: v is 1 or 2.

53. A compound according to any one of claims 42 to 50, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: v is 0.

54. A compound according to any one of claims 42 to 53, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein w is 1 or 2.

55. A compound according to any one of claims 42 to 53, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: w is 0.

56. A compound according to any one of claims 42 to 55, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein L 2 -X 3 -or-X 4 -(C1-C6 alkylene)-; and X 3 and X 4 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 ).

57. The compound according to claim 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is hydrogen or -(C1-C4 alkylene)-OH.

58. The compound according to claim 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is -(C1-C4 alkylene)-OH.

59. The compound according to claim 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 3 It is -CH2OH.

60. A compound according to any one of claims 56 to 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 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 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 2. -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. -NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: Each R 18 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, oxo, phenyl, and monocyclic heteroaryl, wherein the monocyclic heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3.

61. A compound according to any one of claims 56 to 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: halogen, -OR 18 、-N(R 18 )2. -NHSO2R 18 , -CH2CN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl and C1-C4 methoxyalkyl; and Each R 18 independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl or 4- to 6-membered heterocycloalkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -CO2H, -C(=NH)NH2 and 5-membered monocyclic heteroaryl, wherein the 5-membered monocyclic heteroaryl is unsubstituted or substituted with 1 -CONH2 group.

62. A compound according to any one of claims 56 to 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 is a 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: halogen, -OH, -OMe, -N(R 8 )2. -NHSO2R 18 and -CH2CN; and Each R 18 independently hydrogen, C1-C2 alkyl or -C(=O)-C1-C2 alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

63. A compound according to any one of claims 56 to 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -OH, -OCH3 and -NH2.

64. The compound according to claim 42, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, having the structure of Formula (IX): 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; 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 Each independently selected from: -N(R 19 )-, -S-, -S(=O)-, -S(=O)2- and -S(=O)(=NR 19 ); R 19 is hydrogen or C1-C6 alkyl; Each R 20 Independently selected from: halogen, -OR 18 、-N(R 18 2. -CO2R 18 、-CON(R 18 )2、-CH2N(R 18 2. -NHCOR 18 、-NHSO2R 18 , -CH2CN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, C1-C4 aminoalkyl and oxo; in addition: 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.

65. The compound according to claim 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, having a structure of formula (X): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

66. A compound according to claim 64 or claim 65, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -(C1-C4 alkylene)-OH.

67. A compound according to any one of claims 64 to 66, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -CH2OH.

68. A compound according to any one of claims 64 to 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: w and v are each 0.

69. A compound according to any one of claims 42 to 55, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 2 is a bond, -(C1-C6 alkylene)-, -O- or -O-(C1-C6 alkylene)-; and (i)R 13 is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2; (ii) R 14 is a C1-C4 alkyl group, (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 disubstituted or trisubstituted cycloalkyl, or a -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 group.

70. The compound of claim 69, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -(C3-C6 cycloalkylene)-OH or -(C3-C6 cycloalkylene)-NH2.

71. The compound of claim 70, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -(cyclopropylene)-OH or -(cyclopropylene)-NH2.

72. The compound of claim 70, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 for 73. The compound of claim 69, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 14 It is a C1-C4 alkyl group.

74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 14 It is methyl.

75. The compound of claim 69, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 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 a -N(R 18 )2-substituted 4-membered heterocycloalkyl.

76. The compound of claim 75, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 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 substituted with at least one -N(R 18 ) substituted oxetane.

77. The compound of claim 76, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 for 78. A compound according to any one of claims 75 to 77, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 2 It is a bond, -CH2-, -O- or -O-CH2-.

79. The compound of claim 78, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: -L 2 -R 17 for 80. The compound of claim 69, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 2 is -O-(C1-C6 alkylene)-; and R 17 is an unsubstituted or substituted 5-membered heterocycloalkyl group.

81. The compound of claim 80, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 is unsubstituted or substituted tetrahydrofuranyl.

82. The compound of claim 81 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 17 for 83. A compound according to any one of claims 80 to 82, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L 2 It is -O-CH2-.

84. The compound of claim 83, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: -L 2 -R 17 for 85. The compound according to claim 42, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

86. The compound according to claim 42, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

87. A compound of formula (XI): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 is a C1-C4 alkyl group; R 12a and R 12b Each is 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 23 and R 24 Connect with R 23 To R 24 The middle carbon atoms of the ring A are taken together to form a ring A, wherein the ring A is a C3-C6 cycloalkyl group or a 4- to 8-membered heterocycloalkyl group, wherein the C3-C6 cycloalkyl group or the 4- to 8-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: 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; wherein: Each R 25 independently hydrogen or C1-C4 alkyl, wherein the 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's attached to the same nitrogen 25 together form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; v is 0, 1, or 2; and w is 0, 1, or 2.

88. The compound of claim 87, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -(C1-C4 alkylene)-OH.

89. A compound according to any one of claims 87 to 88, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -CH2OH.

90. A compound according to any one of claims 87 to 89, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 14 For hydrogen.

91. A compound according to any one of claims 87 to 90, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 12a and R 12b For hydrogen.

92. A compound according to any one of claims 87 to 91, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 It is -CH3.

93. A compound according to any one of claims 87 to 92, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: w is 0 and v is 0.

94. A compound according to any one of claims 87 to 93, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 23 and R 24 Connect with R 23 To R 24 The middle carbon atoms of the ring A are taken together to form a ring A, wherein the ring A 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 the following: 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.

95. A compound according to any one of claims 87 to 94, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 23 and R 24 Connect with R 23 To R 24 The middle carbon atoms of form ring A together, wherein ring A is a 5- to 6-membered heterocycloalkyl group, wherein the 5- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl and oxo.

96. A compound according to any one of claims 87 to 95, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 23 and R 24 Connect with R 23 To R 24 The middle carbon atoms of 97. The compound according to claim 87, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

98. A compound of formula (XII): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 is a C1-C4 alkyl group; R 12a and R 12b Each is 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-membered 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-membered to 6-membered heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: 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's attached to the same nitrogen 28 together form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, -SO2CH3 and oxo; y is 0, 1, or 2; v is 0, 1, or 2; and w is 0, 1, or 2.

99. The compound of claim 98, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -(C1-C4 alkylene)-OH.

100. A compound according to any one of claims 98 to 99, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 13 It is -CH2OH.

101. A compound according to any one of claims 98 to 100, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 14 For hydrogen.

102. A compound according to any one of claims 98 to 101, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 12a and R 12b For hydrogen.

103. A compound according to any one of claims 98 to 102, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 11 It is -CH3.

104. A compound according to any one of claims 98 to 103, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: w is 0 and v is 0.

105. A compound according to any one of claims 98 to 104, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 27 For hydrogen.

106. A compound according to any one of claims 98 to 105, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 27 It is -CH3.

107. A compound according to any one of claims 98 to 106, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 26 is 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; Each R 28 are independently hydrogen or -CH3; or two R's attached to the same nitrogen 28 Together they form a morpholinyl group.

108. A compound according to any one of claims 98 to 107, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 26 for 109. The compound according to claim 98, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

110. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

111. A pharmaceutical composition comprising a compound according to any one of claims 1 to 110 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

112. A method of treating or preventing a gram-negative bacterial infection in a patient in need thereof, the method comprising administering to the patient a compound according to any one of claims 1 to 110, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 111.

113. The method of claim 112, wherein the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

114. The method of claim 112, wherein the Gram-negative bacterial infection is a respiratory tract infection.

115. The method of claim 114, wherein the respiratory tract infection is pneumonia.

116. The method of claim 115, wherein the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof.

117. A method of treating or preventing a Pseudomonas aeruginosa infection in a patient in need thereof, the method comprising administering to the patient a compound according to any one of claims 1 to 110, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 111.

118. The method of any one of claims 112 to 117, wherein the patient has been identified as having a lung disease.

119. The method of claim 118, wherein the lung disease is a structural lung disease.

120. The method of claim 118 or claim 119, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease, or a combination thereof.

121. The method of any one of claims 112 to 120, wherein the administration is for treating an existing infection.

122. The method of any one of claims 112 to 120, wherein the administration is provided as prevention.

123. The method of any one of claims 112 to 122, wherein the compound of any one of claims 1 to 110 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition of claim 111 is administered in a solution by inhalation, intravenous injection or intraperitoneal injection.

124. A compound according to any one of claims 1 to 110 for use as therapeutically active substance.

125. A compound according to any one of claims 1 to 110 for use in the treatment or prevention of a Gram-negative bacterial infection.

126. The compound for use of claim 125, wherein the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

127. The compound for use according to claim 125, wherein the Gram-negative bacterial infection is a respiratory tract infection.

128. The compound for use according to claim 127, wherein the respiratory tract infection is pneumonia.

129. The composition for use according to claim 128, wherein the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof.

130. A compound according to any one of claims 1 to 110 for use in treating or preventing a Pseudomonas aeruginosa infection.

131. A compound for use according to any one of claims 124 to 130, wherein the patient has been identified as having a lung disease.

132. The compound for use of claim 131, wherein the lung disease is a structural lung disease.

133. A compound for use according to claim 131 or claim 132, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease, or a combination thereof.

134. Use of a compound according to any one of claims 1 to 110 for the preparation of a medicament for the treatment or prevention of Gram-negative bacterial infection.

135. Use of a compound according to any one of claims 1 to 110 for treating or preventing a Gram-negative bacterial infection.

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