TW202417437A - Antibacterial compounds - Google Patents

Abstract

Provided herein are heterocyclic compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting the growth of gram-negative bacteria. The subject compounds and compositions are useful for the treatment of bacterial infections, such as pneumonia.

Description

Antimicrobial compounds

There is a need in the medical field for effective treatments of diseases caused by bacterial infections.

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

In one embodiment, the present invention provides a compound of formula (I): Formula (I) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ¹ is C ₁ -C ₄ alkyl; R ^2a and R ^2b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or halogen; each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; each R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L wherein: ^X1 and ^X2 are independently selected from: -O-, -N(R10)-, ^-S- , -S(=O)-, _-S (=O) _2- and -S(=O)(= ^NR10 )-, wherein: ^R10 _is hydrogen or _{C1 -} ^C6 alkyl; ^R9 is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or ^{heterocycloalkyl} is unsubstituted or substituted with 1, 2 _or 3 ^R11 groups, wherein: each ^R11 _is independently selected from: halogen, ^-OR12 , -N( ^R12 ) ² _, -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pendooxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C ₆ cycloalkyl, and 4 to 6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, pendooxy, 4 to 6 membered heterocycloalkyl or C ₁ -C ₄ alkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ¹² attached to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendant oxygen; s is 0, 1 or 2; and t is 0, 1 or 2; and wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - or -S(=O)(=NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups; wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹² groups, and at least one R ¹⁰ is halogen.

In some embodiments, at least one R ⁷ , R ⁸ or R ¹² is -F. In some embodiments, at least one R ⁷ or R ⁸ is -F. In some embodiments, at least one R ¹² is -F. In some embodiments, at least two R ⁷ , R ⁸ or R ¹² are -F. In some embodiments, at least two R ⁷ or R ⁸ are -F. In some embodiments, at least two R ¹² are -F.

In some embodiments, R ¹ is -CH ₃ . In some embodiments, R ^2a is hydrogen; and R ^2b is hydrogen. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁵ is hydrogen or -F. In some embodiments, R ⁶ is hydrogen or -F. In some embodiments, each R ⁷ is -F. In some embodiments, each R ⁸ is -F.

In some embodiments, the compound is a compound of formula (IIa): Formula (IIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁶ is hydrogen or -F; each R ⁷ is -F; and each R ⁸ is -F.

In some embodiments, the compound is a compound of formula (IIIa): Formula (IIIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁶ is hydrogen or -F; each R ⁷ is -F; and each R ⁸ is -F

In some embodiments, R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ³ is -CH ₂ OH. In some embodiments, L ¹ is a bond, -(C ₁ -C ₄ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-. In some embodiments, L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-. In some embodiments, L ¹ is -O-.

In some embodiments, R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4 to 8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pendoxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C _6- membered cycloalkyl, and 4-6-membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, oxo, 4-6-membered heterocycloalkyl or C ₁ -C ₄ alkyl, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃

In some embodiments, R ⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ alkyl or a 4-6 membered heterocycloalkyl group, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -CN, -OH, -CO ₂ H, -C(=NH)NH ₂ and a 5-membered monocyclic heteroaryl which is unsubstituted or substituted with one -CONH ₂ group.

In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl, or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH, and oxadiazolyl.

In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -OH, -OCH ₃ , and -NH ₂

In some embodiments, L ¹ -R ⁹ are , or .

In some embodiments, L ¹ -R ⁹ are , or .

In some embodiments, R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ⁴ is hydrogen; each R ⁵ and R ⁶ is halogen; L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-; and R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ^{-C 2} R 12 ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pentooxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C ₆ cycloalkyl, and 4 to 6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, pentooxy, 4 to 6 membered heterocycloalkyl or C ₁ -C ₄ alkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ .

In some embodiments, R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-; R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

In some embodiments, R ³ is CH ₂ OH; L ¹ is -O-; R ⁹ is 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹² groups, wherein: each R ¹² is independently selected from: -F, -OH, -OCH ₃ and -NH ₂ .

In some embodiments, the compound is a compound of formula (IV): Formula (IV) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; each R ⁷ and R ⁸ is independently -F, -Cl or C ₁ -C ₄ alkyl; L ¹ is -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-, wherein: R ^{R 10} is hydrogen or C ₁ -C ₆ alkyl; each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ¹² is independently hydrogen or C ₁ -C ₄ alkyl; s is 0, 1 or 2; t is 0, 1 or 2; and u is 0, 1 or 2.

In some embodiments, the compound is a compound of formula (V): Formula (V) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, s is 1 or 2; and at least one R ⁵ is -F. In some embodiments, t is 1 or 2; and at least one R ⁶ is -F. In some embodiments, u is 1 or 2; and at least one R ¹⁰ is -F. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ³ is -CH ₂ OH.

In another aspect, the present invention provides a compound of formula (VI): Formula (VI) or a pharmaceutically acceptable salt, solvent or prodrug thereof, wherein: R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C _{1 -C6} heteroalkyl, _C3 - _C6 cycloalkyl or 4-8 membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: halogen, ^-OR30 , -N( ^R30 ) ₂ , _{-CO2R30 , -CON(R30)2, -CH2N(R30)2, -NHCOR30, -NHSO2R30, -CH2CN} ^{, C1} _- ^{C4 alkyl} _, ^C1 _{- C4 hydroxyalkyl , -C (} =O) _-C1 - _C4 hydroxyalkyl, _C1 - _C4 methoxyalkyl, _C1 - _C4 aminoalkyl and pendoxy; wherein: each ^R30 is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ 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, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R 2 groups connected to the same nitrogen ³⁰ are combined to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendant oxygen groups; L ² is a bond, -(C ₁ -C ₆ alkylene)-, -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; the proviso is that when L ² is a bond, -O- or -O-(C ₁ -C ₆ -membered alkyl)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments, R ²¹ is -CH ₃ . In some embodiments, R ^22a is hydrogen; and R ^22b is hydrogen. In some embodiments, R ²⁴ is hydrogen. In some embodiments, each R ²⁷ is independently -F, -Cl, or -CH ₃ . In some embodiments, each R ²⁷ is independently -F. In some embodiments, each R ²⁸ is independently -F, -Cl, or -CH ₃ . In some embodiments, each R ²⁸ is independently -F.

In some embodiments, the compound is a compound of formula (VIIa): Formula (VIIa), or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, the compound is a compound of formula (VIIIa): Formula (VIIIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

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 is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-; and X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ ).

In some embodiments, R ²³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ²³ is -CH ₂ OH.

In some embodiments, R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ .

In some embodiments, R ²⁹ 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 ¹¹ groups independently selected from the following: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ alkyl or a 4- to 6-membered heterocycloalkyl group, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -CO ₂ H, -C(=NH)NH ₂ and a 5-membered monocyclic heteroaryl which is unsubstituted or substituted with one -CONH ₂ group.

In some embodiments, R ²⁹ 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 halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl.

In some embodiments, R ²⁹ is 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from: -F, -OH, -OCH ₃ and -NH ₂ .

In some embodiments, the compound is a compound of formula (IX): Formula (IX) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; each R ²⁷ and R ²⁸ is independently -F, -Cl or C ₁ -C ₄ alkyl; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-; and X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ ). R ³¹ is hydrogen or C ₁ -C ₆ alkyl; each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy group; further wherein: each R ³⁰ is independently hydrogen or C ₁ -C ₄ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; and y is 0, 1 or 2.

In some embodiments, the compound is a compound of formula (X): Formula (X) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, L ² is -N(R ³¹ )- or -S-. In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ²³ is -CH ₂ OH. In some embodiments, w and v are each 0.

In some embodiments, ^L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-; and ^R29 is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7-8 membered heterocycloalkyl, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane, or an unsubstituted or substituted cyclohexyl.

In some embodiments, R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, R ²⁹ is an unsubstituted or substituted 5 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, R ²⁹ is an unsubstituted or substituted tetrahydrothiophene-1-oxide or an unsubstituted or substituted tetrahydropyran.

In some embodiments, R ¹⁷ is , or .

In some embodiments, ^L2 is -O-.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method for treating or preventing a Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), 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) or (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable formulation.

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. In some embodiments, the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof.

In another embodiment, the present invention provides a method for treating or preventing a Pseudomonas aeruginosa infection in a patient in need thereof, comprising administering to the patient a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), 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) or (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable formulation.

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 treatment of an existing infection. In some embodiments, administration is provided in a prophylactic form.

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

In some embodiments, the compound or salt is used as a therapeutic active substance. In some embodiments, the compound or salt is used to treat or prevent gram-negative bacterial infections. In some embodiments, gram-negative bacterial infections are 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), health care-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.

In another aspect, the present invention provides the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for preparing a medicament for treating or preventing Gram-negative bacterial infection.

In another embodiment, the present invention provides the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for treating or preventing Gram-negative bacterial infections.

For the specific purposes identified herein, all publications, patents, and patent applications mentioned in this specification are incorporated herein by reference.

Cross-references to related applications

This application claims the benefit of U.S. Provisional Patent Application No. 63/396,894, filed August 10, 2022, which is incorporated herein by reference in its entirety. Statement Regarding Federally Sponsored Research

This invention was made with government support under Agreement HHS0100201600038C awarded by HHS. The government may have certain rights in this invention. LpxC , lipid A , and Gram-negative bacteria

Metalloproteins affect a huge diversity 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 critical step in lipid A biosynthesis of Gram-negative bacteria. Lipid A is an essential component of the outer membrane of Gram-negative bacteria. LpxC is a zinc(II)-dependent metalloenzyme that has two histidine and aspartic acid residues bound to a zinc(II) ion. The structure of LpxC shows that the zinc(II) ion is bound to two water molecules, both of which have been implicated in the mechanism of the enzyme. LpxC is highly conserved among 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 .

In recent years, resistance and multidrug resistance of bacterial strains have increased. Therefore, new antibiotics are needed, especially with new mechanisms of action. There is still a need for metalloprotein modulators of LpxC that are suitable for use in therapeutics, diagnostics and research.

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).

In some embodiments, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable formulation.

Disclosed herein are methods for treating diseases in which inhibition of bacterial growth is indicated. Such diseases include Gram-negative bacterial infections. In some embodiments, Gram-negative bacterial infections are associated with Pseudomonas aeruginosa. In some embodiments, the method of treating Gram-negative bacterial infections in a patient in need thereof 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 some embodiments, the method of treating Pseudomonas aeruginosa infections in a patient in need thereof 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 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 Gram-negative bacterial infection is pneumonia. In some embodiments, the Gram-negative bacterial infection is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. In some embodiments, the Gram-negative bacterial infection is community-acquired pneumonia (CAP). In some embodiments, the Gram-negative bacterial infection is healthcare-associated pneumonia (HCAP). In some embodiments, the Gram-negative bacterial infection is hospital-acquired pneumonia (HAP). In some embodiments, the Gram-negative bacterial infection is ventilator-associated pneumonia (VAP).

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.

In some embodiments, administration is to treat an existing infection.

In some embodiments, administration is provided prophylactically.

In some embodiments, the LpxC inhibitory compounds described herein are used to treat or prevent conditions caused by bacterial production of endotoxins and, in particular, 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 formulation. 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 exacerbation of chronic bronchitis (AECB). In some embodiments, the method for 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 formulation, wherein the condition caused by endotoxin or LPS is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB).

In other embodiments, the compounds of the invention can be used to treat severe or chronic respiratory infections including severe lung and nosocomial infections, such as infections 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 , Alcaligenes xylosoxidans , Flavobacterium meningosepticum and Citrobacter freundi , Haemophilus influenzae , Kluyvera species , Legionella species , Moraxella catarrhalis , Enterobacter species , Acinetobacter species In some embodiments , the infection is associated with Pseudomonas . 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 invention do not inhibit the growth of Gram-positive bacteria such as Staphylococcus aureus.

In some embodiments, the LpxC inhibitory compounds described herein are used in a method for preventing the growth of Pseudomonas. In some embodiments, the Pseudomonas is Pseudomonas aureogenus.

In some cases, antibiotics have suboptimal concentrations in the lungs, resulting in ineffective treatment of lung infections. In some embodiments, the heterocyclic LpxC inhibitory compounds of Formula (I) have optimal concentrations in the lungs for use in treating or preventing Gram-negative bacterial infections in the lungs. In some embodiments, the compound is present in the lungs in a therapeutically effective amount after administration.

Disclosed herein, in some embodiments, is a compound described herein or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

In some embodiments, disclosed herein is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a Gram-negative bacterial infection. In some embodiments, the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the Gram-negative bacterial infection is a respiratory tract infection. In some embodiments, the respiratory tract infection is pneumonia.

In some embodiments, disclosed herein are uses of compounds described herein or pharmaceutically acceptable salts 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. LpxC Inhibitory Compounds

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

In some embodiments, the compound of formula (I) (including its pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvent complexes) is a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylases (LpxC) modulator. In some embodiments, the compound of formula (I) (including its pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvent complexes) is a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylases (LpxC) antagonist. In some embodiments, the compound of formula (I) (including its pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvent complexes) is a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitor.

One aspect of the present invention provides a compound having a structure of formula (I): Formula (I) or a pharmaceutically acceptable salt, solvent or prodrug thereof, wherein: R ¹ is C ₁ -C ₄ alkyl; R ^2a and R ^2b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or halogen; each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; each R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L wherein: ^X1 and ^X2 are independently selected from: -O-, -N(R10)-, ^-S- , -S(=O)-, _-S (=O) _2- and -S(=O)(= ^NR10 )-, wherein: ^R10 _is hydrogen or _{C1 -} ^C6 alkyl; ^R9 is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or ^{heterocycloalkyl} is unsubstituted or substituted with 1, 2 _or 3 ^R11 groups, wherein: each ^R11 _is independently selected from: halogen, ^-OR12 , -N( ^R12 ) ² _, -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pendooxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C ₆ cycloalkyl, and 4 to 6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, pendooxy, 4 to 6 membered heterocycloalkyl or C ₁ -C ₄ alkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ¹² connected to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and oxo; s is 0, 1 or 2; and t is 0, 1 or 2.

In some embodiments, for the compound of formula (I), when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - or -S(=O)(=NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) R The alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of ⁹ is substituted by 1, 2 or 3 R ¹² groups, and at least one R ¹¹ is halogen.

In some embodiments, for the compound of formula (I), R ¹ is C ₁ -C ₄ alkyl; R ^2a and R ^2b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ and R ⁶ are each independently hydrogen or halogen; each R ⁷ and R ⁸ are independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C 6 cycloalkylene)- ₆ alkylene)-, wherein: ^X1 and ^X2 are independently selected from: -O-, -N( ^R10 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR10 )-; ^R10 is hydrogen or _C1 - _C6 alkyl; ^R9 is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 ^R11 groups, wherein: each ^R11 is independently selected from: halogen, ^-OR12 , -N( ^R12 ) ₂ , _-CO2R12 , -CON( ^R12 ) ₂ , _-CH2N ( ^R12 ) ₂ , ^-NHCOR R ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 and _-SO2CH3 ; or two ^R12 connected to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, _{2 or 3 groups independently selected from the following: -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 conditions exists: (i) s is 1 or 2, and at least one ^R7 is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted by 1, 2 or 3 R ¹² groups, and at least one R ¹¹ is halogen.

In some embodiments, the compound of formula (I) is a compound of formula (Ia) or formula (Ib): Formula (Ia) Formula (Ib) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, for the compound of formula (I), R ¹ is C ₁ -C ₄ alkyl; R ^2a and R ^2b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ and R ⁶ are each independently hydrogen or halogen; each R ⁷ and R ⁸ are independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C 6 cycloalkylene)- ₆ alkylene)-, wherein: ^X1 and ^X2 are independently selected from: -O-, -N( ^R10 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR10 )-; ^R10 is hydrogen or _C1 - _C6 alkyl; ^R9 is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 ^R11 groups, wherein: each ^R11 is independently selected from: halogen, ^-OR12 , -N( ^R12 ) ₂ , _-CO2R12 , -CON( ^R12 ) ₂ , _-CH2N ( ^R12 ) ₂ , ^-NHCOR R ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ¹² connected to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and oxo; s is 0, 1 or 2; t is 0, 1 or 2; wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) _2- or -S(=O)(= ^NR10 )-, then ^R9 is further selected from _C1 - _C6 alkyl and _C1 - _C6 heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 ^R11 groups; and wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one ^R7 is halogen; (ii) t is 1 or 2, and at least one ^R8 is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of ^R9 is substituted with 1, 2 or 3 ^R12 groups, and at least one ^R11 is halogen.

In some embodiments of the compounds of formula (I), (Ia) or (Ib), ^R1 is _-CH3 ; ^R2a and ^R2b are each hydrogen; ^R3 is hydrogen, -( _C1 - _C4 alkylene)-OH or -( _C1 - _C4 alkylene) _-NH2 ; ^R4 is hydrogen; ^R5 and ^R6 are each independently hydrogen or -F; each ^R7 and ^R8 is -F; ^L1 is a bond, -( _C1 - _C6 alkylene)-, ^-X1- or ^-X2- ( _C1 - _C6 alkylene)-, wherein: ^X1 and ^X2 are each selected from: -O-, -N( ^R10 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR10 )-; ^R10 is hydrogen or _C1 -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4 to 8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH 2 , -SO 2 CH 3 , -C (= NH) NH 2 , ₂ and -SO ₂ CH ₃ ; and wherein at least one of the following conditions exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted by 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is halogen.

In some embodiments of compounds of Formula (I), (Ia) or (Ib), R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; R ⁴ is hydrogen; R ⁵ and R ⁶ are each independently hydrogen or -F; each R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH 2 , -SO 2 CH 3 , -C (= NH) NH 2 , ₂ and -SO ₂ CH ₃ ; wherein at least one of the following conditions exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted by 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is halogen.

In some embodiments of compounds of Formula (I), (Ia) or (Ib), R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; R ⁴ is hydrogen; R ⁵ and R ⁶ are each independently hydrogen or -F; each R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ^wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 R 9 is a _4- membered alkyl or a 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, -CO ₂ H, -C(═NH)NH ₂ and a 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

In some embodiments of compounds of Formula (I), (Ia) or (Ib), R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen or -CH ₂ OH; R ⁴ is hydrogen; R ⁵ and R ⁶ are each independently hydrogen or -F; each R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ⁸ ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl; wherein at least one of the following conditions exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) R The alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of ⁹ is substituted by 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

In some embodiments of the compounds of Formula (I), (Ia) or (Ib), R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen or -CH ₂ OH; R ⁴ is hydrogen; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -NH-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-; R ⁵ and R ⁶ are each independently hydrogen or -F; each R ⁷ and R ⁸ is -F; R ⁹ is a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R R 11 is substituted with a R ¹¹ group, wherein: each R ¹¹ is independently selected from: -F, -OH, -OCH ₃ and -NH ₂ ; s is 0, 1 or 2; t is 0, 1 or 2; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

For any and all embodiments, 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 unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ¹ is C ₁ -C ₂ alkyl. In some embodiments, R ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ . In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ¹ is -CH ₃ .

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ^2a and R ^2b are each independently hydrogen, halogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ^2a and R ^2b are each independently hydrogen, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -CH 2 CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH _{2 CH 3} , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH ₃ ) ₃ . In some embodiments, R ^2a and R ^2b are each independently hydrogen, -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ^2a is hydrogen. In some embodiments, R ^2b is hydrogen. In some embodiments, R ^2a and R ^2b are each hydrogen.

In some embodiments of compounds of Formula (I), (Ia) or (Ib), R ¹ is -CH ₃ ; R ^2a is hydrogen; and R ^2b is hydrogen.

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ⁴ is hydrogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ⁴ is hydrogen or C ₁ -C ₂ alkyl. In some embodiments, R ⁴ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH 2 CH ₃ , -CH(CH ₃ ) ₂ , -CH _{2 CH 2} CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ . In some embodiments, R ⁴ is hydrogen, -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ⁴ is hydrogen or -CH ₃ . In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is -CH ₃ .

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ⁵ and R ⁶ are each independently hydrogen or a halogen. In some embodiments, R ⁵ and R ⁶ are each independently hydrogen, -F or -Cl. In some embodiments, R ⁵ and R ⁶ are each independently hydrogen or -F. In some embodiments, R ⁵ and R ⁶ are each hydrogen. In some embodiments, R ⁵ and R ⁶ are each -F.

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ⁵ is hydrogen or a halogen. In some embodiments, R ⁵ is hydrogen, -F or -Cl. In some embodiments, R ⁵ is hydrogen or -F. In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is -F.

In some embodiments of compounds of formula (I), (Ia) or (Ib), ^R6 is hydrogen or a halogen. In some embodiments, ^R6 is hydrogen, -F or -Cl. In some embodiments, ^R6 is hydrogen or -F. In some embodiments, ^R6 is hydrogen. In some embodiments, ^R6 is -F.

In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (I) is a compound of formula (II): Formula (II) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, for the compound of formula (II), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁶ is hydrogen or halogen; each R ⁷ and R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ^{R 10} is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C _4- methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendooxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ 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 the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , pendooxy, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ or two R ^12s attached to the same nitrogen are combined 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, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendoxy groups; s is 0, 1 or 2; t is 0, 1 or 2; wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - or -S(=O)(=NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C 6 alkyl. ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups; and wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹² groups, and at least one R ¹¹ is halogen.

In some embodiments of the compound of formula (II), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ⁶ is hydrogen or -F; each of R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH 2 , -SO 2 CH 3 , -C (= NH) NH 2 , ₂ and -SO ₂ CH ₃ ; and wherein at least one of the following conditions exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted by 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is halogen.

In some embodiments of the compound of formula (II), each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; and each R ⁸ is independently halogen or C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently halogen; and each R ⁸ is independently halogen. In some embodiments, each R ⁷ is independently -F; and each R ⁸ is independently -F.

In some embodiments, the compound of formula (I) or (II) is a compound of formula (IIa) or formula (IIb): Formula (IIa) Formula (IIb) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, for the compound of formula (II), (IIa) or (IIb), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁶ is hydrogen or halogen; each R ⁷ and R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4 to 8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C _4- methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendooxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ 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 the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , pendooxy, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ or two R ^12s attached to the same nitrogen are combined 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, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendoxy groups; s is 0, 1 or 2; t is 0, 1 or 2; wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - or -S(=O)(=NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C 6 alkyl. ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups; and wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹² groups, and at least one R ¹¹ is halogen.

In some embodiments of the compounds of formula (II), (IIa) or (IIb), R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; R ⁶ is hydrogen or -F; each of R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ^wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 R 9 is a _4- membered alkyl or a 4- to 6-membered heterocycloalkyl group, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -CO ₂ H, -C(═NH)NH ₂ and a 5-membered monocyclic heteroaryl group, which is unsubstituted or substituted with 1 -CONH ₂ group; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

In some embodiments of compounds of formula (II), (IIa) or (IIb), each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; and each R ⁸ is independently halogen or C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently halogen; and each R ⁸ is independently halogen. In some embodiments, each R ⁷ is independently -F; and each R ⁸ is independently -F.

In some embodiments of compounds of Formula (II), (IIa) or (IIb), each R ⁷ is -F.

In some embodiments of compounds of Formula (II), (IIa) or (IIb), each R ⁸ is -F.

In some embodiments of compounds of formula (II), (IIa) or (IIb), s is 0; and each R ⁸ is -F. In some embodiments, each R ⁷ is -F; and t is 0. In some embodiments, R ⁷ is -F; and R ⁸ is -F.

In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (I) or (II) is a compound of formula (IIIa), formula (IIIb), formula (IIIc) or formula (IIId): Formula (IIIa) Formula (IIIb) Formula (IIIc) Formula (IIId) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments, for the compound of formula (IIIa), (IIIb), (IIIc) or (IIId), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁶ is hydrogen or halogen; each R ⁷ and R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ 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 the following: _{-F , -CN} , -OH, -NH ₂ , -OMe, -N(CH 3 ) ₂ , -CO 2 H, -CONH 2 , -SO 2 CH 3 , -C(═NH)NH 2 , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) 2 , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ , -C(═NH)NH ₂ , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ^12s attached to the same nitrogen are combined 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, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendoxy groups; s is 0, 1 or 2; t is 0, 1 or 2; wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(═O)-, -S(═O) ₂ - or -S(═O)(═NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C 6 alkyl. ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups; and wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹² groups, and at least one R ¹¹ is halogen.

In some embodiments of the compounds of Formula (IIIa), (IIIb), (IIIc) or (IIId), R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; R ⁶ is hydrogen or -F; each of R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ^wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 R 9 is a _4- membered alkyl or a 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, -CO ₂ H, -C(═NH)NH ₂ and a 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

In some embodiments of compounds of formula (IIIa), (IIIb), (IIIc) or (IIId), each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; and each R ⁸ is independently halogen or C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently halogen; and each R ⁸ is independently halogen. In some embodiments, each R ⁷ is independently -F; and each R ⁸ is independently -F.

In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc) or (IIId), each R ⁷ is -F.

In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc) or (IIId), each R ⁸ is -F.

In some embodiments of compounds of Formula (IIIa), (IIIb), (IIIc) or (IIId), s is 0; and each R ⁸ is -F. In some embodiments, each R ⁷ is -F; and t is 0. In some embodiments, R ⁷ is -F; and R ⁸ is -F.

In some embodiments, the compound is a compound of formula (IIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIc), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIId), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-, wherein: R ¹⁰ is hydrogen or C ₁ -C ₆ alkylene. In some embodiments, L ¹ is a bond, -(C ₁ -C ₃ alkylene)-, -X ¹ -, or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is a bond, -(C ₁ -C ₂ alkylene)-, -X ¹ -, or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is a bond, -CH ₂ -, -X ¹ -, or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, each R ¹⁰ is independently hydrogen or methyl. In some embodiments, R ¹⁰ is hydrogen.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ is -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is -CH ₂ -, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is a bond, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, R ¹⁰ is hydrogen.

In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, and -S(=O) ₂ -. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, and -S-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O- and -N(R ¹⁰ )-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O- and -S-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -N(R ¹⁰ )- and -S-. In some embodiments, R ¹⁰ is hydrogen.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-. In some embodiments, L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-. In some embodiments, L ¹ is -O-.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ is -O- or -O-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -N(R ¹⁰ )- or -N(R ¹⁰ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S- or -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O)- or -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O) ₂ - or -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O)(=NR ¹⁰ )- or -S(=O)(=NR ¹⁰ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -O-. In some embodiments, L ¹ is -N(R ¹⁰ )-. In some embodiments, L ¹ is -S-. In some embodiments, L ¹ is -S(=O)-. In some embodiments, L ¹ is -S(=O) ₂ -. In some embodiments, L ¹ is -S(=O)(=NR ¹⁰ )-. In some embodiments, L ¹ is -O-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -N(R ¹⁰ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -S(=O)(=NR ¹⁰ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ¹ is -O- or -O-(CH ₂ )-. In some embodiments, L ¹ is -N(H)- or -N(H)-(CH ₂ )-. In some embodiments, L ¹ is -S- or -S-(CH ₂ )-. In some embodiments, L ¹ is -S(=O)- or -S(=O)-(CH ₂ )-. In some embodiments, L ¹ is -S(=O) ₂ - or -S(=O) ₂ -(CH ₂ )-. In some embodiments, L ¹ is -S(=O)(=NH)- or -S(=O)(=NH)-(CH ₂ )-. In some embodiments, L ¹ is -O-(CH ₂ )-. In some embodiments, L ¹ is -N(H)-(CH 2 )-. In some embodiments, L ^{1 is -S-(CH 2 )-. In some embodiments, L 1} _is -S(=O)-(CH ₂ )-. In some embodiments, L ¹ is -S(=O)-(CH ₂ )-. In some embodiments, L ^{1 is -S(=O) 2 -(CH 2 )-. In some embodiments, L 1} is -S(=O) ₂ -(CH ₂ )-. In some embodiments, L ¹ is -S(=O)(=NH)-(CH ₂ )-.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), in some embodiments, R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C (= O) -C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendooxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which are unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ .

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(=NH)NH ₂ and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, R ⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, R ⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH.

In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl, or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH, and oxadiazolyl. In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ⁹ is a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, R ⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, R ⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 5-6 membered heterocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is a 5- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 5-6 membered heterocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R is a 5-6 membered heterocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, R ⁹ is a 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, R ⁹ is a 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH.

In some embodiments, R ⁹ is a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ⁹ is a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, R ⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, R ⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH.

In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OR ¹² , -N(R ¹² ) ₂ and -CH ₂ CN; and each R ¹² is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH. In some embodiments, R ⁹ is tetrahydrofuran substituted with 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH. In some embodiments, R ⁹ is tetrahydrofuran substituted with 1 R ¹¹ group selected from -OH.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is , , .

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is , , .

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), R ⁹ is , , , , , , , or .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ is -O-; and R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, L ¹ is -O-; and R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen and -OH. In some embodiments, L ¹ is -O-; and R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -Cl and -OH. In some embodiments, L ¹ is -O-; and R ⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH. In some embodiments, L ¹ is -O-; and R ⁹ is tetrahydrofuran substituted with 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F and -OH.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ -R ⁹ are , or .

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ -R ⁹ are , or .

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (IIId), L ¹ -R ⁹ are , , , , , , , or .

In some embodiments, the compound is a compound of formula (IIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIc), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIId), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (I) is a compound of formula (IV): Formula (IV) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (IV), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH, or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁶ is hydrogen or halogen; each R ⁷ and R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ -, or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-; R ^{R 10} is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C _4- methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendooxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ 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 the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , pendooxy, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ or two R ^12s attached to the same nitrogen are combined 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, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) u is 1 or 2, and at least one R ¹¹ is halogen.

In some embodiments of the compound of formula (IV), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ⁶ is hydrogen or -F; each of R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ^wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(═NH)NH ₂ and a 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) u is 1 or 2, and at least one R ¹¹ is -F.

In some embodiments of compounds of formula (IV), each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; and each R ⁸ is independently halogen or C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently halogen; and each R ⁸ is independently halogen. In some embodiments, each R ⁷ is independently -F; and each R ⁸ is independently -F. In some embodiments, each R ⁷ is -F; and t is 0. In some embodiments, R ⁷ is -F; and R ⁸ is -F.

In some embodiments of the compound of formula (IV), L ¹ is a bond, -(C ₁ -C ₂ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₂ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-, wherein: R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments, L ¹ is a bond, -(C ₁ -C ₂ alkylene)-, -X ¹ -, or -X ² -(C ₁ -C ₂ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NH)-. In some embodiments, L ¹ is a bond, -(CH ₂ )-, -X ¹ -, or -X ² -(CH ₂ )-, wherein: X ¹ and X ² are independently selected from: -O-, -N(R ⁹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ⁹ )-, wherein: R ⁹ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments, ^L1 is a bond, -( _CH2 )-, ^-X1- , or ^-X2- ( _CH2 )-, wherein: ^X1 and ^X2 are independently selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) _2- , and -S(=O)(=NH)-. In some embodiments, ^L1 is a bond, -( _CH2 )-, ^-X1- , or ^-X2- ( _CH2 )-, wherein: ^X1 and ^X2 are independently selected from: -O-, -N( ^R9 )-, and -S-. In some embodiments, ^L1 is a bond, -( _CH2 )-, ^-X1- , or ^-X2- ( _CH2 )-, wherein: ^X1 and ^X2 are independently selected from: -O-. In some embodiments, ^L1 is -O-.

In some embodiments, the compound of formula (I) is a compound of formula (V): Formula (V) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (IV), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH, or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁶ is hydrogen or halogen; each R ⁷ and R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ -, or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ¹⁰ )-; R ^{R 10} is hydrogen or C ₁ -C ₆ alkyl; R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C _4- methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendooxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ 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 the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , pendooxy, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ or two R ^12s attached to the same nitrogen are combined 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, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and oxo; s is 0, 1 or 2; t is 0, 1 or 2; and at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) u is 1 or 2, and at least one R ¹¹ is halogen.

In some embodiments of the compound of formula (IV), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ⁶ is hydrogen or -F; each of R ⁷ and R ⁸ is -F; L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-; R ¹⁰ is hydrogen; R ^wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(═NH)NH ₂ and a 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group; wherein at least one of the following situations exists: (i) s is 1 or 2; (ii) t is 1 or 2; and (iii) u is 1 or 2, and at least one R ¹¹ is -F.

In some embodiments of compounds of formula (V), each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; and each R ⁸ is independently halogen or C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently halogen; and each R ⁸ is independently halogen. In some embodiments, each R ⁷ is independently -F; and each R ⁸ is independently -F. In some embodiments, each R ⁷ is -F; and t is 0. In some embodiments, R ⁷ is -F; and R ⁸ is -F.

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.

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.

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.

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (V), each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, which 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 attached to the same nitrogen ¹² are combined together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of -F, -CN, -OH, _-NH2 , -OMe, _-CO2H , _-CONH2 , _-SO2CH3 and a _pendoxy group.

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (V), each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ¹² is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ¹² is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ¹² is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ , -CO ₂ H, -CONH ₂ , -CH ₂ CN, and C ₁ -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ , -CH ₂ CN, and C 1 -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: halogen, -OH, -NH ₂ , and C ₁ -C ₄ alkyl. In some embodiments, each R 11 is independently selected from: halogen, -OH, -NH 2, and C ₁ -C 4 alkyl. In some embodiments, each R ¹¹ is independently selected from: -F, -Cl, -OH, -NH ₂ , and C ₁ -C ₄ alkyl. In some embodiments, each R ¹¹ is independently selected from: -F, -Cl, -OH, -NH ₂ , and methyl. In some embodiments, each R ¹¹ is independently selected from: -F, -Cl, -OH, and -NH _2. In some embodiments, each R ¹¹ is independently selected from: -F, -OH, and -NH _2. In some embodiments, each R ¹¹ is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV) or (V), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ alkylene)-OH or -(C ₃ -C ₆ alkylene)-NH ₂ . In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ . In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH and -(C ₃ -C ₆ alkylene)-OH. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-NH ₂ or -(C ₃ -C ₆ alkylene)-OH.

In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV) or (V), R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(cyclopropylene)-OH or -(cyclopropylene)-NH _2. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(cyclopropylene)-OH or -(cyclopropylene)-NH _2. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH and -(cyclopropylene)-OH. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-NH ₂ or -(cyclopropylene)-OH.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R ³ is hydrogen. In some embodiments, R ³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ³ is -(C ₁ -C ₂ alkylene)-OH.

In some embodiments, ^R3 is _{-CH2OH , -CH2CH2OH} , -CH2CH2CH2OH, -CH2CH2CH2OH, -CH _{( CH3 ) OH} , -CH2CH _{( CH3 ) OH} , -CH( _{CH3 ) CH2OH} , _-CH2CH ( _CH2CH3 )OH, or -CH( _CH2CH3 ) _CH2OH . In some embodiments, ^R3 _{is -CH2OH} , _-CH2CH2OH , or _-CH ( _CH3 )OH. In some embodiments, ^R3 is _-CH2OH or _-CH2CH2OH . In some embodiments, ^R3 _{is -CH2OH .} In _some embodiments _, ^R3 is _{-CH2CH2OH .}

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R ³ is -(C ₁ -C ₄ alkylene)-NH ₂ . In some embodiments, R ³ is -(C ₁ -C ₂ alkylene)-NH ₂ . In some embodiments, ^R3 is _{-CH2NH2 , -CH2CH2NH2 , -CH2CH2CH2NH2 , -CH2CH2CH2NH2 ,} -CH2CH2CH2CH2NH2 _, -CH ₍ CH3) _{NH2, -CH2CH(CH3)NH2, -CH(CH3)CH2NH2 , -CH2CH ( CH2CH3 ) NH2 , or -CH ( CH2CH3 ) CH2NH2 . In some} embodiments, ^R3 is _{-CH2NH2 , -CH2CH2NH2 ,} or _-CH ( _{CH3 ) NH2 . In} some embodiments _, ^R3 _{is -CH2NH2 or -CH2CH2NH2} . In some embodiments, R ³ is -CH ₂ NH ₂ .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), ^R3 is hydrogen or -( _C1 - _C4 alkylene)-OH. In some embodiments, ^R3 is hydrogen or -( _C1 - _C2 alkylene ₎ -OH. In some embodiments, ^R3 is hydrogen _, -CH2OH, _{-CH2CH2OH , -CH2CH2CH2OH , -CH2CH2CH2OH , -CH2CH2CH2CH2OH ,} -CH( _CH3 )OH, _{-CH2CH ( CH3} )OH, _-CH ( _{CH3 )} CH2OH, -CH2CH( _CH2CH3 )OH, or -CH( _{CH2CH3 ) CH2OH} . In some embodiments, R ³ is hydrogen, -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH(CH ₃ )OH. In some embodiments, R ³ is hydrogen, -CH ₂ OH, or -CH ₂ CH ₂ OH. In some embodiments, R ³ is hydrogen or -CH ₂ OH.

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R ³ is hydrogen, -(C ₁ -C ₂ alkylene)-OH, or -(C ₁ -C ₂ alkylene)-NH _2. In some embodiments, R ³ is hydrogen, -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH ₂ NH _2. In some embodiments, R ³ is hydrogen, -CH ₂ OH, or -CH ₂ NH ₂ .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV) or (V), R ³ is -(C ₃ -C ₆ alkylene)-OH or -(C ₃ -C ₆ alkylene)-NH _2. In some embodiments, R ³ is -(C ₃ -C ₅ alkylene)-OH or -(C ₃ -C ₅ alkylene)-NH _2. In some embodiments, R ³ is -(C ₃ -C ₄ alkylene)-OH or -(C ₃ -C ₄ alkylene)-NH _2. In some embodiments, R ³ is -(cyclopropylene)-OH or -(cyclopropylene)-NH _2. In some embodiments, R ³ is or .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R ³ is -(C ₃ -C ₆ alkylene)-OH. In some embodiments, -(C ₃ -C ₅ alkylene)-OH. In some embodiments, R ³ is -(C ₃ -C ₄ alkylene)-OH. In some embodiments, R ³ is -(cyclopropylene)-OH. In some embodiments, R ³ is .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), R ³ is -(C ₃ -C ₆ alkylene)-NH ₂ . In some embodiments, R ³ is -(C ₃ -C ₅ alkylene)-NH ₂ . In some embodiments, R ³ is -(C ₃ -C ₄ alkylene)-NH ₂ . In some embodiments, R ³ is -(cyclopropylene)-NH ₂ . In some embodiments, R ³ is .

In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (V), ^R is hydrogen or a halogen. In some embodiments, ^R is hydrogen, -F, or -Cl. In some embodiments, ^R is hydrogen or -F. In some embodiments, ^R is hydrogen. In some embodiments, R is ^-F .

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 ⁷ and R ⁸ are independently halogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ and R ⁸ are independently -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH ₃ ) ₃ . In some embodiments, each R ⁷ and R ⁸ is independently -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In some embodiments, each R ⁷ and R ⁸ is independently -F, -Cl or -CH ₃ .

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 ⁷ is independently halogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, each R ⁷ is independently -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH ₃ ) ₃ . In some embodiments, each R ⁷ is independently -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In some embodiments, each R ⁷ is independently -F, -Cl or -CH ₃ .

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 ^R8 is independently halogen or unsubstituted _C1 - _C4 alkyl. In some embodiments, each ^R8 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 ⁸ is independently -F, -Cl, -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In some embodiments, each R ⁸ is independently -F, -Cl, or -CH ₃ .

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 ⁷ is independently -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH ₃ ) ₃ ; and t is 0. In some embodiments, each R ⁷ is independently -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and t is 0. In some embodiments, each R ⁷ is independently -F, -Cl, or -CH ₃ ; and t is 0.

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; and each R ⁷ is independently -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH ₃ ) ₃ . In some embodiments, s is 0; and each R ⁷ is independently -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In some embodiments, s is 0; and each R ⁷ is independently -F, -Cl or -CH ₃ .

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.

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.

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.

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.

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 is present: (i) s is 1 or 2, and at least one ^R is halogen; (ii) t is ¹ or ² , and at least one R is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl or ^{heterocycloalkyl} of R is substituted with 1, 2 or 3 R groups, and at least one R is ^halogen . In some embodiments, at least one of the following conditions exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen. In some embodiments, at least one of the following conditions exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁷ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is halogen. In some embodiments, at least one of the following is present: (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁷ is substituted with 1, 2, or 3 R ¹¹ groups, and at least one R ¹¹ is halogen. In some embodiments, s is 1 or 2, and at least one R ⁷ is halogen. In some embodiments, t is 1 or 2, and at least one R ⁸ is halogen. In some embodiments, the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁷ is substituted with 1, 2, or 3 R ¹¹ groups, and at least one R ¹¹ is halogen.

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 is present: (i) s is 1 or 2 and R ⁷ is halogen; (ii) t is 1 or 2 and R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups and R ¹¹ is halogen. In some embodiments, at least one of the following is present: (i) s is 1 or 2 and R ⁷ is halogen; and (ii) t is 1 or 2 and R ⁸ is halogen. In some embodiments, at least one of the following is present: (i) s is 1 or 2, and R ⁷ is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and R ¹¹ is halogen. In some embodiments, at least one of the following is present: (ii) t is 1 or 2, and R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and R ¹¹ is halogen. In some embodiments, s is 1 or 2, and R ⁷ is halogen. In some embodiments, t is 1 or 2, and R ⁸ is halogen. In some embodiments, the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and R ¹¹ is halogen.

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 is present: (i) s is 1 or 2, and at least one R ⁷ is -F; (ii) t is 1 or 2, and at least one R ⁸ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F. In some embodiments, at least one of the following is present: (i) s is 1 or 2, and at least one R ⁷ is -F; and (ii) t is 1 or 2, and at least one R ⁸ is -F. In some embodiments, at least one of the following is present: (i) s is 1 or 2, and at least one R ⁷ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and at least one R ¹¹ is -F. In some embodiments, at least one of the following is present: (ii) t is 1 or 2, and at least one R ⁸ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and at least one R ¹¹ is -F. In some embodiments, s is 1 or 2, and at least one R ⁷ is -F. In some embodiments, t is 1 or 2, and at least one R ⁸ is -F. In some embodiments, the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and at least one R ¹¹ is -F.

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 is present: (i) s is 1 or 2, and R ⁷ is -F; (ii) t is 1 or 2, and R ⁸ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and R ¹¹ is -F. In some embodiments, at least one of the following is present: (i) s is 1 or 2, and R ⁷ is -F; and (ii) t is 1 or 2, and R ⁸ is -F. In some embodiments, at least one of the following is present: (i) s is 1 or 2, and R ⁷ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and R ¹¹ is -F. In some embodiments, at least one of the following is present: (ii) t is 1 or 2, and R ⁸ is -F; and (iii) the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of R ⁹ is substituted with 1, 2, or 3 R ¹¹ groups, and R ¹¹ is -F. In some embodiments, s is 1 or 2, and R ⁷ is -F. In some embodiments, t is 1 or 2, and R ⁸ is -F. In some embodiments, the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹¹ groups, and R ¹¹ is -F.

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 ⁷ , R ⁸ , or R ¹¹ is -F. In some embodiments, at least one R ⁷ or R ⁸ is -F. In some embodiments, at least one R ⁷ or R ¹¹ is -F. In some embodiments, at least one R ¹¹ or R ⁸ is -F. In some embodiments, at least one R ⁷ is -F. In some embodiments, at least one R ⁸ is -F. In some embodiments, at least one R ¹¹ is -F. In some embodiments, at least two R ⁷ , R ⁸ , or R ¹¹ are -F. In some embodiments, at least two R ⁷ or R ⁸ are -F. In some embodiments, at least two R ⁷ or R ¹¹ are -F. In some embodiments, at least two R ¹¹ or R ⁸ are -F. In some embodiments, at least two R ⁷ are -F. In some embodiments, at least two R ⁸ are -F. In some embodiments, at least two R ¹¹ are -F.

In some embodiments, the compound is selected from: , , and .

In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a non-mirror isomer of a compound of Table 1, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. Table 1 : Compound No. Structure IUPAC name 1** (3R,4R)-4-((2-fluoro-4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol 2** (3S,4S)-4-((2-fluoro-4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol 3** (3R,4R)-4-((3-fluoro-4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol 4** (3S,4S)-4-((3-fluoro-4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol 5 (3R,4S)-5,5-difluoro-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol 6 (3S,4R)-2,2-difluoro-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol **Arbitrary assignment of stereochemistry. After chiral separation, individual stereoisomers are isolated, but the absolute configuration of the stereochemical center is unknown.

In another aspect, the present invention provides a compound having a structure of formula (VI): Formula (VI) or a pharmaceutically acceptable salt, solvent or prodrug thereof, wherein: R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C _{1 -C6} heteroalkyl, _C3 - _C6 cycloalkyl or 4-8 membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: halogen, ^-OR30 , -N( ^R30 ) ₂ , _{-CO2R30 , -CON(R30)2, -CH2N(R30)2, -NHCOR30, -NHSO2R30, -CH2CN} ^{, C1} _- ^{C4 alkyl} _, ^C1 _{- C4 hydroxyalkyl , -C (} =O) _-C1 - _C4 hydroxyalkyl, _C1 - _C4 methoxyalkyl, _C1 - _C4 aminoalkyl and pendoxy; wherein: each ^R30 is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ 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, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R 2 groups connected to the same nitrogen wherein: R ^{31 is} hydrogen or C _{1 -C 6} alkyl; v ^is ₀ ^, _{1 or 2 ; and w} ^{is 0 ,} _{1 or} ^{2 .}

In some embodiments, for the compound of formula (VI), when ^L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-, then ^R29 is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7-8 membered heterocycloalkyl, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl.

In some embodiments of the compound of formula (VI), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ ; L ² is a bond, -(C ₁ -C ₆ alkylene)-, -X ³ -, or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -O-, -N(R ³¹ )-, -S-, -S(═O)-, -S(═O) ₂ -, and -S(═O)(═NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; with the proviso that when L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VI), R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ ... _6- membered cycloalkyl or 4-8-membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C 1 -C 4 ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R attached to the same nitrogen wherein ^L2 is -X3- or _-X4- (C1-C6 alkylene)-, wherein ^X3 and ^X4 are independently selected from: -N(R31)-, ^-S- , -S(=O ₎ -, -S(=O)2- and -S _{( =} ^O )(= ^NR31 )-, wherein: ^R31 is hydrogen or _C1 - _{C6 alkyl} ; v is ⁰ _{, 1} or ₂ ; and w is 0 ^, 1 or 2.

In some embodiments of the compound of formula (VI), R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-; R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2.

In another aspect, the present invention provides a compound having a structure of formula (VIa) or (VIb): Formula (VIa) Formula (VIb) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (VI), (VIa) or (VIb), R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C 6 cycloalkylene _{C 6-} membered heteroalkyl, C ₃ -C ₆ -membered 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C -C(=O)-C ₁ -C ₄ alkyl, or a 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, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R 2 groups connected to the same nitrogen ³⁰ are combined to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, _-NH2 , -OMe, _-CO2H , _-CONH2 , _-SO2CH3 and _pendoxy groups; ^L2 is a bond, -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(=NR31)-, wherein: R31 is hydrogen or _C1 - _C6 alkyl; the proviso is that when L2 is a bond, -O- or -O-(C1-C6 alkylene ⁾ -, the proviso is that when ^L2 is a bond, -O- or -O-(C1-C6 alkylene)-, the proviso is that when ^L2 is a bond, -O- or -O-( _C1 -C6 ₆ -membered alkyl)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compounds of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(═O)-C ₁ -C ₄ 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 following groups: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(═NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ ; L ² is a bond, -(C _{1 -C 6} alkylene)-, -X ³ -, or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -O-, -N(R ³¹ )-, -S-, -S(═O)-, -S(═O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; with the proviso that when L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VI), (VIa) or (VIb), R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C 6 cycloalkylene _{C 6-} membered heteroalkyl, C ₃ -C ₆ -membered 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C -C(=O)-C ₁ -C ₄ alkyl, or a 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, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R 2 groups connected to the same nitrogen wherein ^L2 is -X3- or _-X4- (C1-C6 alkylene)-, wherein ^X3 and ^X4 are independently selected from: -N(R31)-, ^-S- , -S(=O ₎ -, -S(=O)2- and -S _{( =} ^O )(= ^NR31 )-, wherein: ^R31 is hydrogen or _C1 - _{C6 alkyl} ; v is ⁰ _{, 1} or ₂ ; and w is 0 ^, 1 or 2.

In some embodiments of the compounds of formula (VI), (VIa) or (VIb), R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; L ² is a bond, -O- or -O-(C ₁ -C R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted ₅ membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or fluorine; each R ²⁷ and R ²⁸ are independently -F; R ²⁹ is a 4-8 membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; each R ³⁰ is independently hydrogen, C _{1 -C 4 alkylene)-OH, -(C 1} -C 4 alkylene)-NH 2 -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl _is unsubstituted or substituted by 1 or 2 groups independently selected from -CN, -OH and oxadiazole; L ² is a bond, -(C ₁ -C ₆ alkylene)-, -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; with the proviso that when L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, then R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group, v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; R ²⁹ is a 4-8 membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; each R ³⁰ is independently hydrogen, C _{1 -C 4 alkylene)-OH, -(C 1} -C 4 alkylene)-NH 2 _L2 is ^-X3- or -X4-( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -N( ^R31) -, -S-, -S(=O)-, -S(=O) ^2- and -S(=O)(= ^NR31 )-, wherein: ^R31 is ^hydrogen or _C1 - _{C6 alkyl} ; v is 0 _, 1 or 2; and w is 0, 1 or ₂ .

In some embodiments of the compounds of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen or -CH ₂ OH; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-; R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group, each of which, when substituted, is substituted by 1, 2 or 3 groups independently selected from the following: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C 2 _2- alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of compounds of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen or -CH ₂ OH; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or -F; each R ²⁷ and R ²⁸ are independently -F; R ²⁹ is a 4- to 6-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of -F, -OH, -OCH ₃ and -NH; L ² is a bond, -(C ₁ -C ₆ alkylene)-, -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from the group consisting of: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; with the proviso that when L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, then R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group, each of which, when substituted, is substituted with 1, 2 or 3 groups independently selected from the following groups: -F, -OH, _-OCH3 and -NH; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of compounds of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen or -CH ₂ OH; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; R ²⁹ is a 4- to 6-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of -F, -OH, -OCH ₃ and -NH; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O)- ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compounds of formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a and R ^22b are each hydrogen; R ²³ is hydrogen or -CH ₂ OH; R ²⁴ is hydrogen; R ²⁵ and R ²⁶ are each independently hydrogen or halogen; each R ²⁷ and R ²⁸ are independently halogen; L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-; R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group, each of which, when substituted, is substituted with 1, 2 or 3 groups independently selected from the following groups: -F, -OH, _-OCH3 and -NH; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments, the compound is a compound of formula (VIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

For any and all embodiments, substituents are selected from a subset of the listed alternatives. For example, in some embodiments of compounds of Formula (VI), (VIa) or (VIb), R ²¹ is unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ²¹ is C ₁ -C ₂ alkyl. In some embodiments, R ²¹ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ . In some embodiments, R ²¹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ²¹ is -CH ₃ .

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (VI), (VIa) or (VIb), R ^22a and R ^{22b are} each independently hydrogen, halogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ^22a and R ^22b are each independently hydrogen, -F, -Cl, -Br, -CH ₃ , -CH 2 ^CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) or -C(CH _{3 ) 3} . In some embodiments, R ^22a and R ^22b are each independently hydrogen, -F, -Cl, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (VI), (VIa) or (VIb), R ^22a is hydrogen. In some embodiments, R ^22b is hydrogen. In some embodiments, R ^22a and R ^22b are each hydrogen.

In some embodiments of the compound, salt, solvate or stereoisomer of Formula (VI), (VIa) or (VIb), R ²¹ is -CH ₃ ; R ^22a is hydrogen; and R ^22b is hydrogen.

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (VI), (VIa) or (VIb), R ²⁴ is hydrogen or unsubstituted C ₁ -C ₄ alkyl. In some embodiments, R ²⁴ is hydrogen or C ₁ -C ₂ alkyl. In some embodiments, R ²⁴ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH _{2 CH 3} , -CH(CH ₃ ) ₂ , -CH ₂ CH 2 CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ . In some embodiments, R ²⁴ is hydrogen, -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ²⁴ is hydrogen or -CH ₃ . In some embodiments, R ²⁴ is hydrogen. In some embodiments, R ²⁴ is -CH ₃ .

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ²⁵ and R ²⁶ are each independently hydrogen or halogen. In some embodiments, R ²⁵ and R ²⁶ are each independently hydrogen, -F or -Cl. In some embodiments, R ²⁵ and R ²⁶ are each independently hydrogen or -F. In some embodiments, R ²⁵ and R ²⁶ are each hydrogen. In some embodiments, R ²⁵ and R ²⁶ are each -F.

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ²⁵ is hydrogen or a halogen. In some embodiments, R ²⁵ is hydrogen, -F or -Cl. ^In some embodiments, R ^{25 is hydrogen or -F. In some embodiments, R 25} is hydrogen. In some embodiments, R ²⁵ is -F.

In some embodiments of compounds of formula (I), (Ia) or (Ib), R ²⁶ is hydrogen or a halogen. In some embodiments, R ²⁶ is hydrogen, -F or -Cl. In some embodiments, R ²⁶ is hydrogen or -F. In some embodiments, R ²⁶ is hydrogen. In some embodiments, R ²⁶ is -F.

In some embodiments, the compound is a compound of formula (VII), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VII): Formula (VII) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (VII), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , _-CO2R30 ^, -CON( ^R30 ) ₂ , _-CH2N ( ^R30 ) ₂ , ^-NHCOR30 , -NHSO2R30, _-CH2CN , _C1 - _C4 alkyl, C1- _C4 hydroxyalkyl _, -C(=O)-C1- _{C4 hydroxyalkyl} , _C1 - _C4 methoxyalkyl, _C1 - _C4 aminoalkyl and pendoxy; wherein: ^each _R30 is independently hydrogen, _C1 - _C4 alkyl, -C(=O) _-C1 - _C4 alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 ^, 3 or 4 groups independently selected from the following: -F, -CN, -OH, _-CH2OH , _-NH2 , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ ; or two R ³⁰ connected to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , and a pendoxy group; L ² is a bond, -(C ₁ -C 1 _-X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkylene; with the proviso that when L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, then R ²⁹ is an unsubstituted or substituted 3-6-membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8-membered heterocycloalkyl group, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VII), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO 2 R 30 , -CON(R 30 ) 2 , -CH 2 N(R 30 ) 2 , -NHCOR 30 , -OR 30 , -N(R 30 ) 2 , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR R ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 and _-SO2CH3 ; ^L2 is a bond, -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- (C1- _C6 alkylene)-, wherein: X3 ^{and X4} are each independently selected from: -O-, -N( ^R31 )-, -S-, _-S (=O)-, -S(=O _)2- and -S(=O)(=NR31)-, wherein: R31 is hydrogen or _C1 - ^C6 alkyl; the limiting condition is that when L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-, the substituted aryl group is substituted with -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) ^2- and -S( ₌ O)(= ^NR31 )-. ₆ -membered alkyl)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VII), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , _-CO2R30 ^, -CON( ^R30 ) ₂ , _-CH2N ( ^R30 ) ₂ , ^-NHCOR30 , -NHSO2R30, _-CH2CN , _C1 - _C4 alkyl, C1- _C4 hydroxyalkyl _, -C(=O)-C1- _{C4 hydroxyalkyl} , _C1 - _C4 methoxyalkyl, _C1 - _C4 aminoalkyl and pendoxy; wherein: ^each _R30 is independently hydrogen, _C1 - _C4 alkyl, -C(=O) _-C1 - _C4 alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 ^, 3 or 4 groups independently selected from the following: -F, -CN, -OH, _-CH2OH , _-NH2 -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ³⁰ connected to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and oxo; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VII), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; L ² is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-; R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7-8 membered heterocycloalkyl group, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VIIa) or formula (VIIb): Formula (VIIa) Formula (VIIb) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (VIIa) or (VIIb), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl or 4-8 membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C (= O) -C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 and _-SO2CH3 ; ^L2 is a bond, -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- (C1- _C6 alkylene)-, wherein: X3 ^{and X4} are each independently selected from: -O-, -N( ^R31 )-, -S-, _-S (=O)-, -S(=O _)2- and -S(=O)(=NR31)-, wherein: R31 is hydrogen or _C1 - ^C6 alkyl; the limiting condition is that when L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-, the substituted aryl group is substituted with -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) ^2- and -S( ₌ O)(= ^NR31 )-. ₆ -membered alkyl)-, then R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VII), (VIIa) or (VIIb), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C (= O) -C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _{-CONH2 and -SO2CH3} ; ^L2 is ^-X3- or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are each independently selected from: -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR31 )-, v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compound of formula (VII), (VIIa) or (VIIb), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, unsubstituted or substituted 7-8 membered heterocycloalkyl, unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, unsubstituted or substituted aziridinyl, unsubstituted or substituted oxirane or unsubstituted or substituted cyclohexyl, each of which, when substituted, is substituted with 1, 2 or 3 groups independently selected from the following: halogen, -OR ^{R 30} , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ alkyl or 4-6 membered heterocycloalkyl, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the following groups: -F, -CN, -OH, -CH ₂ OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 , _-SO2CH3 , -C(=NH) _NH2 , a pendoxy group, a phenyl group, and a monocyclic _heteroaryl group, which are unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 , and _-SO2CH3 ; ^L2 is a bond, -O-, or -O-( _C1 - _{C6 alkylene} )-; v is 0, 1, or 2; and w is 0, 1, or 2.

In some embodiments, the compound is a compound of formula (VIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (VI) or (VII) is a compound of formula (VIIIa), formula (VIIIb), formula (VIIIc) or formula (VIIId): Formula (VIIIa) Formula (VIIIb) Formula (VIIIc) Formula (VIIId) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compounds of Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(═O)-C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ ; L ² is a bond, -(C _{1 -C 6} alkylene)-, -X ³ -, or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; the proviso is that when L When ^{R 2} is a bond, -O- or -O-(C ₁ -C ₆ alkylene)-, R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compounds of Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 group consisting of halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(═O)-C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendooxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, v is 0, 1 or 2; and w is 0, 1 or 2.

In some embodiments of the compounds of Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently -F; R ²⁹ is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group, each of which, when substituted, is substituted by 1, 2 or 3 groups independently selected from the following groups: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C 4 alkyl, wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C _{1 -C 4} alkyl or a 4- to _{6 -} membered heterocycloalkyl group, wherein the alkyl or _{heterocycloalkyl} group is unsubstituted or substituted _{with 1} , ₂ , 3 or 4 groups independently selected from the following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , oxo, phenyl and monocyclic heteroaryl, which are unsubstituted or substituted with 1 or 2 groups selected from the following groups: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 and _-SO2CH3 , _L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-; v is 0, 1 or ² ; and w is 0, 1 or 2.

In some embodiments, the compound is a compound of formula (VIIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIIc), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIId), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), ^L2 is a bond, -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR31 )-, wherein: ^R31 is hydrogen or _C1 - _C6 alkyl. In some embodiments, ^L2 is a bond, -( _C1 - _C3 alkylene)-, ^-X3- , or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- , and -S(=O)(= ^NR31 )-. In some embodiments, ^L2 is a bond, -( _C1 - _C2 alkylene)-, ^-X3- , or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- , and -S(=O)(= ^NR31 )-. In some embodiments, ^L2 is a bond, _-CH2- , ^-X3- , or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are each selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- , and -S(=O)(= ^NR31 )-. In some embodiments, each ^R31 is independently hydrogen or methyl. In some embodiments, ^R31 is hydrogen.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), ^L2 is -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR31 )-. In some embodiments, L ² is -CH ₂ -, -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-. In some embodiments, L ² is a bond, -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-. In some embodiments, R ³¹ is hydrogen.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(R ³¹ )-, -S-, -S(=O)- and -S(=O) ₂ -. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -O-, -N(R ³¹ )-, and -S-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -O- and -N(R ³¹ )-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -O- and -S-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -N(R ³¹ )- and -S-. In some embodiments, R ³¹ is hydrogen.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -O-. In some embodiments, L ² is -O-.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is -O- or -O-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -N(R ³¹ )- or -N(R ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S- or -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)- or -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O) ₂ - or -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)(=NR ³¹ )- or -S(=O)(=NR ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -O-. In some embodiments, L ² is -N(R ³¹ )-. In some embodiments, R ³¹ is hydrogen. In some embodiments, L ² is -S-. In some embodiments, L ² is -S(=O)-. In some embodiments, L ² is -S(=O) ₂ -. In some embodiments, L ² is -S(=O)(=NR ³¹ )-. In some embodiments, L ² is -O-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -N(R ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)(=NR ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -O- or -O-(CH ₂ )-. In some embodiments, L ² is -N(H)- or -N(H)-(CH ₂ )-. In some embodiments, L ² is -S- or -S-(CH ₂ )-. In some embodiments, L ² is -S(=O)- or -S(=O)-(CH ₂ )-. In some embodiments, L ² is -S(=O) ₂ - or -S(=O) ₂ -(CH ₂ )-. In some embodiments, L ² is -S(=O)(=NH)- or -S(=O)(=NH)-(CH ₂ )-. In some embodiments, L ² is -O-(CH ₂ )-. In some embodiments, L ² is -N(H)-(CH ₂ )-. In some embodiments, L ^{2 is -S-(CH 2 )-. In some embodiments, L 2} is -S(=O)-(CH ₂ )-. In some embodiments, L ² is -S(=O)-(CH ₂ )-. In some embodiments, L 2 is -S(=O) 2 -(CH 2 )-. In some embodiments, L ² is -S(=O) ₂ -(CH ₂ )-. In some embodiments, L ² is -S(=O)(=NH)-(CH ₂ )-.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl or 4 to 8 membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R 32 groups, wherein: each R 32 is independently selected from: halogen, -OR 30 , -N(R 30 ) 2 , -CO 2 R 30 , -CON(R ³⁰ ) _{2 , -CH 2 N(R 30 ) 2} , -NHCOR 30 , -NHSO ₂ R ³⁰ , -CH 2 CN, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4 to 8 membered heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R 30 , -CON(R 30 ) 2 , -CH 2 N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C C _{1 -C 4} alkyl, -C (= O) -C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which are unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is C ₃ -C ₆ cycloalkyl, wherein the C ₃ -C ₆ cycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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 and -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(=NH)NH ₂ and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ²⁹ 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 ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ²⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ²⁹ is a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, R ²⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, R ²⁹ is a 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments, R ²⁹ 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 ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ , and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl, or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH, and oxadiazolyl. In some embodiments, R ²⁹ 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 ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ²⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ²⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, R ²⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, R ²⁹ is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ²⁹ 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 ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ²⁹ is a 5- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 5-6 membered heterocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ²⁹ is a 5-6 membered heterocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, R ²⁹ is a 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, R ²⁹ is a 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl. In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, R ²⁹ is a 5-membered heterocycloalkyl group, wherein the 5-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OMe, -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C ₂ alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl. In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -OR ³⁰ , -N(R ³⁰ ) ₂ and -CH ₂ CN; and each R ³⁰ is independently hydrogen or C ₁ -C ₂ alkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH. In some embodiments, R ²⁹ is tetrahydrofuran substituted with 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ¹⁹ )-, -S-, -S(=O)- and -S(=O) ₂ -. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -N(R ³¹ )- and -S-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -S- and -N(R ¹⁹ )-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -S(=O) ₂ - and -N(R ³¹ )-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -S(=O)(=NR ³¹ )- and -N(R ³¹ )-. In some embodiments, R ³¹ is hydrogen.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, L ² is selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2, or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2, or 3 R ³² groups ^, wherein: each R ³² is independently selected from: -F, -Cl, and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2, or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ -, and -S(=O)(=NR ³¹ )-; and R ²⁹ is tetrahydrofuran substituted with 1, 2, or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is selected from: -N(R ³¹ )- and -S-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen, -OH, -NH ₂ and -CH ₂ CN. In some embodiments, L ² is selected from: -N(R ³¹ )- and -S-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: halogen and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )- and -S-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F, -Cl and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )- and -S-; and R ²⁹ is tetrahydrofuran, wherein the tetrahydrofuran is unsubstituted or substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH. In some embodiments, L ² is selected from: -N(R ³¹ )- and -S-; and R ²⁹ is tetrahydrofuran substituted with 1, 2 or 3 R ³² groups, wherein: each R ³² is independently selected from: -F and -OH.

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² -R ²⁹ is or .

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² -R ²⁹ is .

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² -R ²⁹ is or .

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² -R ²⁹ is , , , , or .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L is ^a bond, -( _Ci - _C6 alkylene)-, -O- or -O-(Ci _{-C6 alkylene} )-; and R is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7-8 membered heterocycloalkyl, an unsubstituted or substituted ⁵ membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxiranealkyl or an unsubstituted or substituted cyclohexyl. In some embodiments, L ² is -O- or -OC ₁ -C ₆ alkylene-; and R ²⁹ is unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, unsubstituted or substituted 7-8 membered heterocycloalkyl, unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, unsubstituted or substituted aziridinyl, unsubstituted or substituted oxirane, or unsubstituted or substituted cyclohexyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L ² is a bond, -CH ₂ -, -O- or -O-CH ₂ -; and R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, an unsubstituted or substituted 7-8 membered heterocycloalkyl, an unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, an unsubstituted or substituted aziridinyl, an unsubstituted or substituted oxirane or an unsubstituted or substituted cyclohexyl. In some embodiments, L ² is -O- or -O-CH ₂ -; and R ²⁹ is unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, unsubstituted or substituted 7-8 membered heterocycloalkyl, unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, unsubstituted or substituted aziridinyl, unsubstituted or substituted oxirane, or unsubstituted or substituted cyclohexyl. In some embodiments, ^L2 is -O-; and ^R29 is unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl, unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl, unsubstituted or substituted 7-8 membered heterocycloalkyl, unsubstituted or substituted 5 membered nitrogen-containing heterocycloalkyl, unsubstituted or substituted aziridinyl, unsubstituted or substituted oxirane, or unsubstituted or substituted cyclohexyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L is ^a bond, -(C ₁ -C ₆ alkylene)-, -O- or -O-(C ₁ -C ₆ alkylene)-; and R is an unsubstituted or substituted ^3-6 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, L is ^-O- or -OC ₁ -C ₆ alkylene-; and R ^is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, L ² is a bond, -(C ₁ -C ₆ alkylene)-, -O- or -O-(C ₁ -C ₆ alkylene)-; and R ²⁹ is an unsubstituted or substituted 5-membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl. In some embodiments, L ² is -O- or -OC ₁ -C ₆ alkylene-; and R ²⁹ is an unsubstituted or substituted 5-membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² is a bond, -CH ₂ -, -O-, or -O-CH ₂ -; and R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, L ² is -O- or -O-CH ₂ -; and R ²⁹ is an unsubstituted or substituted 3-6 membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6 membered oxygen-containing heterocycloalkyl. In some embodiments, ^L2 is a bond, _-CH2- , -O-, or -O- _CH2- ; and ^R29 is an unsubstituted or substituted 5-membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl. In some embodiments, ^L2 is -O- or -O- _CH2- ; and ^R29 is an unsubstituted or substituted 5-membered sulfur-containing heterocycloalkyl or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), L is ^a bond, -(C ₁ -C ₆ alkylene)-, -O- or -O-(C ₁ -C ₆ alkylene)-; and ^R is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, ^L is -O- or -OC ₁ -C ₆ alkylene-; and R ^is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, ^L2 is a bond, -( _C1 - _C6 alkylene)-, -O- or -O-( _C1 - _C6 alkylene)-; and ^R29 is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, ^L2 is -O- or -OC1 _{- C6} alkylene-; and ^R29 is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² is a bond, -CH ₂ -, -O-, or -O-CH ₂ -; and R ²⁹ is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, L ² is -O- or -O-CH ₂ -; and R ²⁹ is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, L ² is a bond, -CH ₂ -, -O-, or -O-CH ₂ -; and R ²⁹ is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. In some embodiments, L ² is -O- or -O-CH ₂ -; and R ²⁹ is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran.

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), L ² -R ²⁹ is , or .

In some embodiments of the compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), ^L2 - ^R29 is , , , , , , , or .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ alkylene)-OH or -(C ₃ -C ₆ alkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH and -(C ₃ -C ₆ alkylene)-OH. In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-NH ₂ or -(C ₃ -C ₆ alkylene)-OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(cyclopropylene)-OH or -(cyclopropylene)-NH ₂ . In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(cyclopropylene)-OH or -(cyclopropylene)-NH ₂ . In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH and -(cyclopropylene)-OH. In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-NH ₂ or -(cyclopropylene)-OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R ²³ is hydrogen. In some embodiments, R ²³ is -(C ₁ -C ₄ alkylene)-OH. In some embodiments, R ²³ is -(C ₁ -C ₂ alkylene)-OH.

In some embodiments, R ²³ is -CH ₂ OH, -CH _{2 CH 2 OH ,} -CH 2 CH 2 CH 2 OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₍ CH ₃ )OH, -CH ₂ CH(CH ₃ )OH, -CH(CH ₃ )CH ₂ OH, -CH ₂ CH(CH ₂ CH ₃ )OH, or -CH(CH ₂ CH ₃ )CH ₂ OH. In some embodiments, R ²³ is -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH(CH ₃ )OH. In some embodiments, R ²³ is -CH ₂ OH or -CH ₂ CH ₂ OH. In some embodiments, R ²³ is -CH ₂ OH. In some embodiments, R ²³ is -CH ₂ CH ₂ OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), ^R23 is -( _C1 - _C4 alkylene) _-NH2 . In some embodiments, ^R23 is -( _C1 - _C2 alkylene) _-NH2 . In some embodiments, R ²³ is -CH ₂ NH ₂ , -CH ₂ CH ₂ NH _{2, -CH 2 CH 2 CH 2 NH 2 , -CH 2} CH ₂ CH _{2 CH 2 NH 2} , -CH(CH ₃ )NH ₂ , -CH ₂ CH(CH ₃ )NH _{2 ,} -CH(CH ₃ )CH ₂ NH ₂ , -CH ₂ CH(CH ₂ CH ₃ )NH ₂ , or -CH(CH ₂ CH ₃ )CH ₂ NH _2. In some embodiments, R ²³ is -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , or -CH(CH ₃ )NH _2. In some embodiments, R ²³ is -CH ₂ NH ₂ or -CH ₂ CH ₂ NH ₂ . In some embodiments, R ²³ is -CH ₂ NH ₂ .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), ^R23 is hydrogen or -( _C1 - _C4 alkylene)-OH. In some embodiments, ^R23 is hydrogen or -( _C1 - _C2 alkylene)-OH. In some embodiments, ^R23 is hydrogen, _{-CH2OH , -CH2CH2OH ,} -CH2CH2CH2OH _{, -CH2CH2CH2OH} , _{-CH2CH2CH2CH2OH ,} -CH( _CH3 )OH, _-CH2CH ( _{CH3 ) OH} , _{-CH ( CH3 )} CH2OH, -CH2CH( _CH2CH3 )OH _, or -CH( _CH2CH3 ) _CH2OH . In some embodiments, R ²³ is hydrogen, -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH(CH ₃ )OH. In some embodiments, R ²³ is hydrogen, -CH ₂ OH, or -CH ₂ CH ₂ OH. In some embodiments, R ²³ is hydrogen or -CH ₂ OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), or (VIIId), R ²³ is hydrogen, -(C ₁ -C ₂ alkylene)-OH, or -(C ₁ -C ₂ alkylene)-NH ₂ . In some embodiments, R ²³ is hydrogen, -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH ₂ NH ₂ . In some embodiments, R ²³ is hydrogen, -CH ₂ OH, or -CH ₂ NH ₂ .

In some embodiments of compounds of (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc) or (VIIId), ^L2 is ^-X3- or ^-X4- ( _C1 - _C4 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -N(H)-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(=NH)-.

In some embodiments, the compound is a compound of formula (VIIIa), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIIb), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIIc), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a compound of formula (VIIId), or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof.

In some embodiments, the compound of formula (VI) is a compound of formula (IX): Formula (IX) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (IX), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ alkylene)-NH ₂ ; R ²⁶ is hydrogen or -F; each of R ²⁷ and R ²⁸ is -F; each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ 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 following: _-F , _-CN , -OH, -CH ₂ OH, -NH _{2 , -OMe, -N(CH 3 ) 2 , -CO 2 H, -CONH 2 , -SO 2 CH 3 , -C(=NH)NH 2 , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH 2 , -OMe, -N(CH 3 ) 2 , -CO 2 H, -CONH 2 , -SO 2 CH 3 , -C} (=NH)NH ₂ , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO 2 ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

In some embodiments of the compound of formula (IX), R ²³ is -CH ₂ -OH, CH ₂ -NH ₂ , (cyclopropylene)-OH; or -(cyclopropylene)-NH ₂ ; R ²⁶ is hydrogen or -F; each of R ²⁷ and R ²⁸ is -F; each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH 2 , -SO 2 CH 3 , -C (= NH) NH 2 , ₂ and -SO ₂ CH ₃ ; L ² is X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

In some embodiments, the compound of formula (VI) is a compound of formula (X): Formula (X) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof.

In some embodiments of the compound of formula (X), R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ alkylene)-NH ₂ ; R ²⁶ is hydrogen or -F; each of R ²⁷ and R ²⁸ is -F; each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C 6 hydroxyalkyl, wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ 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 following: _-F , _-CN , -OH, -CH ₂ OH, -NH _{2 , -OMe, -N(CH 3 ) 2 , -CO 2 H, -CONH 2 , -SO 2 CH 3 , -C(=NH)NH 2 , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH 2 , -OMe, -N(CH 3 ) 2 , -CO 2 H, -CONH 2 , -SO 2 CH 3 , -C} (=NH)NH ₂ , a pendoxy group, a phenyl group and a monocyclic heteroaryl group, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO 2 ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

In some embodiments of the compound of formula (X), R ²³ is -CH ₂ -OH, CH ₂ -NH ₂ , (cyclopropylene)-OH; or -(cyclopropylene)-NH ₂ ; R ²⁶ is hydrogen or -F; each of R ²⁷ and R ²⁸ is -F; each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C 4 ₄ aminoalkyl and pendant oxygen; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , pendant oxygen, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH 2 , -SO 2 CH 3 , -C (= NH) NH 2 , ₂ and -SO ₂ CH ₃ ; L ² is X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-, wherein: X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ )-, wherein: R ³¹ is hydrogen or C ₁ -C ₆ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; y is 0, 1 or 2.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX) or (X), R ²³ is -(C ₃ -C ₆ alkylene)-OH or -(C ₃ -C ₆ alkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₃ -C ₅ alkylene)-OH or -(C ₃ -C ₅ alkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₃ -C ₄ alkylene)-OH or -(C ₃ -C ₄ alkylene)-NH ₂ . In some embodiments, R ²³ is -(cyclopropylene)-OH or -(cyclopropylene)-NH ₂ . In some embodiments, R ²³ is or .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R ²³ is -(C ₃ -C ₆ alkylene)-OH. In some embodiments, -(C ₃ -C ₅ alkylene)-OH. In some embodiments, R ²³ is -(C ₃ -C ₄ alkylene)-OH. In some embodiments, R ²³ is -(cyclopropylene)-OH. In some embodiments, R ²³ is .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R ²³ is -(C ₃ -C ₆ alkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₃ -C ₅ alkylene)-NH ₂ . In some embodiments, R ²³ is -(C ₃ -C ₄ alkylene)-NH ₂ . In some embodiments, R ²³ is -(cyclopropylene)-NH ₂ . In some embodiments, R ²³ is .

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX) or (X), L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(H)-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(H)-, -S-, -S(=O)- and -S(=O) ₂ -. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(H)-, -S-, -S(=O)-, and -S(=O)(=NH)-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(H)-, -S-, -S(=O) ₂ -, and -S(=O)(=NH)-. In some embodiments, L ² is -X ³ - or -X ⁴ -(C ₁ -C ₄ alkylene)-, wherein: X ³ and X ⁴ are independently selected from: -N(H)- and -S-.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX) or (X), L ² is -N(R ³¹ )- or -N(R ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S- or -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)- or -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O) ₂ - or -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)(=NR ³¹ )- or -S(=O)(=NR ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -N(R ³¹ )-. In some embodiments, R ³¹ is hydrogen. In some embodiments, L ^{2 is -S-. In some embodiments, L 2 is} -S(=O)-. In some embodiments, L ² is -S(=O) ₂ -. In some embodiments, L ² is -S(=O)(=NR ³¹ ). In some embodiments, L ² is -N(R ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O) ₂ -(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -S(=O)(=NR ³¹ )-(C ₁ -C ₆ alkylene)-. In some embodiments, L ² is -N(H)- or -N(H)-(CH ₂ )-. In some embodiments, L ² is -S- or -S-(CH ₂ )-. In some embodiments, L ² is -S(=O)- or -S(=O)-(CH ₂ )-. In some embodiments, L ² is -S(=O) ₂ - or -S(=O) ₂ -(CH ₂ )-. In some embodiments, ^L2 is -S(=O)(=NH)- or -S(=O)(=NH)-(CH ₂ )-. In some embodiments, ^L2 is -N(H)-(CH ₂ )-. In some embodiments, ^L2 is -S-(CH ₂ )-. In some embodiments, L2 is -S(=O)-(CH ₂ )-. In some embodiments, ^L2 is -S(=O) _{2-(CH 2 )-. In some embodiments, L2 is -S(=O)2-} ⁽ CH ₂ )-. In some embodiments, ^L2 is -S(=O)(=NH)-(CH ₂ )-.

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.

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.

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.

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.

In some embodiments of the compounds, salts, solvates or stereoisomers of formula (IX) or (X), each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, which 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 attached to the same nitrogen ³⁰ are combined together to form a 4- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of -F, -CN, -OH, _-NH2 , -OMe, _-CO2H , _-CONH2 , _-SO2CH3 and a _pendoxy group.

In some embodiments of the compound, salt, solvate or stereoisomer of formula (IX) or (X), each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ³⁰ is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ³⁰ is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CH ₂ CN and C ₁ -C ₄ alkyl, further wherein: each R ³⁰ is independently hydrogen or C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: halogen, -OH, -NH ₂ , -CO ₂ H, -CONH ₂ , -CH ₂ CN, and C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: halogen, -OH, -NH ₂ , -CH ₂ CN, and C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: halogen, -OH, -NH ₂ , and C ₁ -C ₄ alkyl. In some embodiments, each R 32 is independently selected from: halogen, -OH, -NH 2, and C 1 -C 4 alkyl. In some embodiments, each R ³² is independently selected from: -F, -Cl, -OH, -NH ₂ , and C ₁ -C ₄ alkyl. In some embodiments, each R ³² is independently selected from: -F, -Cl, -OH, -NH ₂ , and methyl. In some embodiments, each R ³² is independently selected from: -F, -Cl, -OH, and -NH _2. In some embodiments, each R ³² is independently selected from: -F, -OH, and -NH _2. In some embodiments, each R ³² is independently selected from: -F and -OH. In some embodiments, each R ³² is -OH.

In some embodiments of compounds of Formula (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IX), or (X), R ²⁶ is hydrogen or a halogen. In some embodiments, R ²⁶ is hydrogen, -F, or -Cl. In some embodiments, R ²⁶ is hydrogen or -F. In some embodiments, R ²⁶ is hydrogen. In some embodiments, R ²⁶ is -F.

In some embodiments, the compound is selected from: , , , , and .

In some embodiments, the compound is a compound of Table 2, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a non-mirror isomer of a compound of Table 2, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. Table 2 : Compound No. Structure IUPAC name 7** * Racemic-trans (rac-trans)-3-hydroxy-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrothiophene 1-oxide 8 1-Hydroxy-4-(4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)butan-2-one 9 (3R,4R)-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)thio)tetrahydrofuran-3-ol 10 (3S,4R)-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)amino)tetrahydrofuran-3-ol 11 (3R,4R)-3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-4-ol 12 (3R,4R)-4-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-3-ol 13 2-((3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)amino)cyclobutyl)amino)acetonitrile 14 * Racemic-cis 2-(((rac-cis)-3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)amino)cyclobutyl)amino)acetonitrile 15 * Racemic-trans 2-(((rac-trans)-3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)amino)cyclobutyl)amino)acetonitrile **Arbitrary assignment of stereochemistry. After chiral separation, individual stereoisomers are isolated, but the absolute configuration of the stereochemical center is unknown.

In some embodiments, the compound is a compound of Table 3, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. In some embodiments, the compound is a non-mirror isomer of a compound of Table 3, or a pharmaceutically acceptable salt, solvent complex or stereoisomer thereof. Table 3 : Compound No. Structure IUPAC name 16 * Racemic-trans N-((rac-trans)-3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)cyclobutyl)methanesulfonamide 17 2-(3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)azinecyclobut-1-yl)acetonitrile 18 3-((4-(4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)methyl)cyclobutan-1-ol 19 * Racemic-cis (S,E)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)-4-(4'-((rac-cis)-3-methoxycyclobutyl)-[1,1'-biphenyl]-4-yl)but-3-en-1-ol 20 * Racemic-trans (S,E)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)-4-(4'-(((rac-trans)-4-(trifluoromethoxy)tetrahydrofuran-3-yl)oxy)-[1,1'-biphenyl]-4-yl)but-3-en-1-ol twenty one * Racemic-trans (S,E)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)-4-(4'-((rac-trans)-3-methoxycyclobutyl)-[1,1'-biphenyl]-4-yl)but-3-en-1-ol twenty two 3-(4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)-1-methylcyclobutan-1-ol twenty three * Racemic-trans 2-(((rac-trans)-3-((4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)oxy)cyclobutyl)amino)acetonitrile twenty four** (S,E)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)-4-(4'-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-[1,1'-biphenyl]-4-yl)but-3-en-1-ol 25** (S,E)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)-4-(4'-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-[1,1'-biphenyl]-4-yl)but-3-en-1-ol 26** (3S,4R)-4-(4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)tetrahydrofuran-3-ol 27** (3R,4S)-4-(4'-((S,E)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-en-1-yl)-[1,1'-biphenyl]-4-yl)tetrahydrofuran-3-ol **Arbitrary assignment of stereochemistry. After chiral separation, individual stereoisomers are isolated, but the absolute configuration of the stereochemical center is unknown.

Any combination of the groups described above for the various variables is encompassed herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Likewise, active metabolites of such compounds having the same type of activity are included within the scope of the present invention. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

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 concentration or amount employed, i.e., the substance can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

The term "pharmaceutically acceptable salt" refers to a form of the therapeutically active agent consisting of a cationic form of the therapeutically active agent in combination with a suitable anion, or in the alternative, a form of the therapeutically active agent consisting of an anionic form of the therapeutically active agent in combination 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 Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal juices than nonionic species and are therefore suitable for solid dosage forms. Moreover, since their solubility generally varies with pH, selective dissolution in one part of the digestive tract or another is possible, and this ability can be manipulated as a function of delayed and sustained release characteristics. Furthermore, because salt-forming molecules can be equilibrated in neutral form, delivery through biological membranes can be regulated.

In some embodiments, the pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) with an acid. In some embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) (i.e., the free base form) is alkaline 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 (+); caprylic acid (decanoic acid); caprylic acid (caproic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclohexylamine sulfonic acid; dodecyl sulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentian Acid; glucoheptanoic acid (D); gluconic acid (D); glucuronic acid (D); glutaric acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; dodecanoic acid; cis-butenedioic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; niacin; oleic acid; oxalic acid; palmitic acid; bis(hydroxynaphthoic acid); phosphoric acid; propionic acid; pyroglutamine (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) 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.

In some embodiments, the pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) with a base. In some embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) is acidic and reacts with a base. In these cases, the acidic protons of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium or aluminum ions. In some cases, the compounds described herein are coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, sulfamethoxazole, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming salts with compounds that include 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.

It should be understood that references to pharmaceutically acceptable salts include solvent addition forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of a solvent and is formed during a crystallization process with a pharmaceutically acceptable solvent 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 preferably prepared or formed during the processes described herein. In addition, the compounds provided herein exist in non-solvated as well as solvated forms as appropriate.

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) or (X) and active metabolites of these compounds having the same type of activity.

In some embodiments, sites on the organic groups (e.g., alkyl groups, aromatic rings) of compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic groups will reduce, minimize, or eliminate such metabolic pathways. In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogens, deuterium, alkyl groups, halogenalkyl groups, or deuterated alkyl groups.

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.

The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but in which 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, such as, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ³² P, and ³³ P. In one aspect, isotopically labeled compounds described herein (e.g., those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated) are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium confers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

In some embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) has one or more stereocenters, and each stereocenter exists independently in the R or S configuration. In some embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) exists in the R configuration. In some embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) exists in the S configuration. The compounds presented herein include all non-mirror isomers, single mirror isomers, hysteresis isomers and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, para, iso (E) and syn (Z) isomers and appropriate mixtures thereof.

If desired, a single stereoisomer is obtained by stereoselective synthesis and/or separation of stereoisomers by chiral chromatography columns, or separation of non-mirror image isomers by crystallization and recrystallization on non-chiral or chiral chromatography columns or in an appropriate solvent or mixture of solvents. In certain embodiments, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) is prepared as a single stereoisomer thereof by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of non-mirror image isomers/salts, separating the non-mirror image isomers and recovering the optically pure single mirror image isomer. In some embodiments, a single mirror image isomer is resolved using a covalent non-mirror image derivative of a compound described herein. In another embodiment, non-mirror image isomers are separated by separation/resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by forming non-mirror image isomer 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, 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, the compounds described herein are prepared in the form of prodrugs. "Prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally applicable because they are easier to administer than the parent drug in some cases. It is bioavailable, for example, by oral administration, while the parent drug is not. Additionally or alternatively, compared to the parent drug, the prodrug also has improved solubility in a pharmaceutical composition. In some embodiments, the design of the prodrug increases effective water solubility. Examples of prodrugs, but not limited to, are compounds described herein, which are administered in the form of esters ("prodrugs"), but then undergo metabolic hydrolysis to obtain an active entity. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, wherein the peptide undergoes metabolism to display an active portion. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

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, e.g., 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" 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 group in the compounds disclosed herein is a prodrug, wherein the hydroxyl group is subsequently metabolized in vivo to give the carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is subsequently metabolized in vivo to give the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

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) or (X) as described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

In some embodiments, any of the hydroxyl, amine and/or carboxylic acid groups are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

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

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 a specific substance is changed by an organism. Thus, an enzyme can produce a specific structural change in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while UDP-glucuronyl transferase 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 identified by administering the compounds to a subject and analyzing tissue samples from the subject, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds, as appropriate. In some cases, heterocycles may exist in tautomeric forms. In such cases, it is understood that the structures of the compounds are shown or named in one tautomeric form, but may be shown or named in an alternative tautomeric form. Alternative tautomeric forms are expressly included in the present invention, such as the structures described below. For example, benzimidazole or imidazole may exist in the following tautomeric forms: Preparation of compounds

Compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

Unless otherwise indicated, known methods of mass spectrometry, NMR, and HPLC were used.

The compounds are prepared using standard organic chemistry techniques such as those described in, for example, 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 variations in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions.

In some embodiments, the compounds described herein are prepared as described in Scheme A. Scheme A :

Intermediate A is reacted with an appropriate aromatic An organometallic coupling reaction such as Suzuki-Miyaura reaction is carried out between the organic acid or its ester or organic trifluoroborate (BF ₃ K) B to obtain intermediate C. The protecting group is removed by an appropriate deprotection method to obtain the final compound D.

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

The ketone-containing intermediate E is reacted with a suitable amine (R'''-NH ₂ ) under appropriate reductive amination conditions (such as treatment with a borohydride reagent: for example NaBH ₄ , NaCNBH ₃ or NaB(OAc) ₃ H) to afford intermediate F. The protecting group is removed using an appropriate deprotection method to afford the final compound G .

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

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "an agent" includes a plural number of such agents, and reference to "the cell" includes reference to one or more cells (or reference to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein in reference to physical properties such as molecular weight, or chemical properties such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. Reference to the term "about" in reference to a number or numerical range means that the number or numerical range is an approximation within experimental variability (or within experimental error), and thus in some cases the number or numerical range may vary between 1% and 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 in certain other embodiments, for example, embodiments in which any composition of matter, composition, method or process described herein, or the like, "consists of" or "consists essentially of" the described features.

Unless otherwise stated, the following terms used in this application have the definitions given below. The term "including" and other forms such as "include", "includes" and "included" are used without limitation. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

As used herein, _C1 - _Cx includes _C1 - _C2 , _C1 - _C3 ... _C1 - _Cx . By way of example only, a group designated as " _C1 - _C6 " indicates that there are 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 one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, and tertiary butyl.

"Alkyl" refers to an aliphatic hydrocarbon group. Alkyl groups are branched or straight chain. In some embodiments, "alkyl" has 1 to 10 carbon atoms, i.e., _C1 - _C10 alkyl. Whenever it appears in this article, 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 this definition also covers the existence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is _C1 - _C6 alkyl. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl or tertiary butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dibutyl, tertiary butyl, pentyl, neopentyl or hexyl. In some embodiments, the alkyl group is methyl.

"Alkylene" refers to a divalent alkyl group. Any of the above monovalent alkyl groups may be an alkylene group formed by extracting a second hydrogen atom from an alkyl group. In some embodiments, the alkylene group is a C ₁ -C ₆ alkylene group. In other embodiments, the alkylene group is a C ₁ -C ₄ alkylene group. Typical alkylene groups include, but are not limited to: -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and the like. In some embodiments, the alkylene group is -CH ₂ -.

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

The term "alkylamine" refers to a -N(alkyl) _x H _y radical, 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.

"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 C ₁ -C ₄ hydroxyalkyl group. Typical hydroxyalkyl groups include, but are not limited to: -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ CH ₂ OH, and the like. In some embodiments, the hydroxyalkyl group is -CH ₂ OH or -CH ₂ CH ₂ OH. In some embodiments, the hydroxyalkyl group is -CH ₂ OH. In some embodiments, the hydroxyalkyl group is -CH ₂ CH ₂ OH.

"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 C ₁ -C ₄ aminoalkyl group. Typical aminoalkyl groups include, but are not limited to: -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH _{2 CH 2 NH 2} , -CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ , and the like. In some embodiments, the aminoalkyl group is -CH ₂ NH ₂ or -CH ₂ CH 2 NH _2. In some embodiments, the hydroxyalkyl group is -CH ₂ NH _2. In some embodiments, the hydroxyalkyl group is -CH ₂ CH ₂ NH ₂ .

The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR ₂ , where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ , and -CH ₂ CH=CH ₂ .

The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon reference 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≡CCH ₃ , -C≡CCH ₂ CH ₃ , -CH ₂ C≡CH.

The term "heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C ₁ -C ₆ heteroalkyl group. In some embodiments, the heteroalkyl group is a C ₁ -C ₆ heteroalkyl group in which one or two atoms are independently selected from O, NH, and S.

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

The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the main chain of the ring are all carbon atoms. The term thus distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the main chain of the ring contains at least one atom different from 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.

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, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is phenyl, naphthyl, dihydroindenyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is _C6 - _C10 aryl. Depending on the structure, the aryl group is a monoradical or a diradical (i.e., an aryl radical).

The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group in which each of the atoms forming the ring (i.e., backbone atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norinyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl group is C ₃ -C ₆ cycloalkyl. In some embodiments, the cycloalkyl group is C ₃ -C ₄ cycloalkyl. In some embodiments, the cycloalkyl group is cyclopropyl. In some embodiments, the cycloalkyl group is cyclobutyl.

The term "halogen", or alternatively "halogen" or "halogen" means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine or bromine.

The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, the fluoroalkyl group is a C ₁ -C ₆ fluoroalkyl group. In some embodiments, the fluoroalkyl group is -CF ₃ .

The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S and N, wherein each heterocycloalkyl has 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocycloalkyls (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocycloalkyls include rings having 5 to 10 atoms in their ring system. Heterocycloalkyls include benzofused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, oxolinyl, thiooxolinyl, thioxocyclohexyl, piperidine, aziridinyl, azidocyclobutanyl, oxocyclobutanyl, thiocyclobutanyl, homopiperidinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexanyl, 1,3-dioxolane, pyrrolyl, oxazolinyl, dithianyl, dithiothiophene, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indolin-2-one, isoindol-1-one, isoindol-1,3- dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindoline-1,3-disulfinyl, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazol-2(3H)-one, benzo[d]thiazol-2(3H)-one and quininyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazolyl, tetrazolyl, furanyl, thienyl, isoozolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, indazolyl, indolizyl, oxazolyl, pyrimidinyl, triazolyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, oxadiazolyl and furopyridinyl. The aforementioned radicals are C-linked (or C-bonded) or N-linked where possible. For example, radicals derived from pyrrole include both pyrrole-1-yl ( N -linked) or pyrrole-3-yl (C-linked). In addition, radicals derived from imidazole include imidazole-1-yl or imidazole-3-yl (both N -linked) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (all C-linked). Heterocyclic groups include benzofused ring systems. Non-aromatic heterocyclic rings are optionally substituted with one or two pendant oxy groups (=O), such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocyclic ring is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The term "heteroaryl" or "heteroaromatic" refers to an aryl group including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl groups and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrimidinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, triazolyl, oxadiazolyl, thiadiazolyl and furazanyl. Monocyclic heteroaryl groups include indole, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolone, quinoline, isoquinoline, benzophenone, quinolone, quinazoline, quinoxaline, 1,8-oxadiazole and pteridine. In some embodiments, the heteroaryl group contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 1 to 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 to 4 N atoms, 0 to 1 O atoms and 0 to 1 S atoms in the ring. In some embodiments, the heteroaryl group is a C ₁ -C ₉ heteroaryl group. In some embodiments, the monocyclic heteroaryl is a C ₁ -C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C ₆ -C ₉ heteroaryl.

"Heterocycloalkyl" refers to a cycloalkyl group including at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl group is fused with an aryl group or a heteroaryl group. In some embodiments, the heterocycloalkyl group is azolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidine, piperidin-2-one, pyrrolidine-2,5-disulfinyl, pyrrolidine-2,5-dione, pyrrolidone, imidazolidinyl, imidazolidin-2-one or thiazolidin-2-one. In one aspect, the heterocycloalkyl group is a _C2 - _C10 heterocycloalkyl group. In one embodiment, the heterocycloalkyl group is a C ₄ -C ₁₀ heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group. In some embodiments, the heterocycloalkyl group is a monocyclic group and is a 3, 4, 5, 6, 7 or 8-membered ring. In some embodiments, the heterocycloalkyl group is a monocyclic group and is a 3, 4, 5 or 6-membered ring. In some embodiments, the heterocycloalkyl group is a monocyclic group and is a 3 or 4-membered ring. In some embodiments, the heterocycloalkyl group contains 0 to 2 N atoms in the ring. In some embodiments, the heterocycloalkyl group contains 0 to 2 N atoms, 0 to 2 O atoms and 0 to 1 S atoms in the ring. The heterocycloalkyl group is optionally substituted with one or two pendant oxy groups (=O) moieties.

The term "bond" or "single bond" refers to a chemical bond between two atoms or moieties when the atoms joined 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 not present, thereby forming a bond between the remaining identified groups.

The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a generally recognized chemical entity embedded in or attached to a molecule.

The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups selected individually and independently from the group consisting of halogen, -CN, _-NH2 , -NH(alkyl), -N(alkyl) ₂ , -OH, _-CO2H , _-CO2alkyl , -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, alkylsulfonyl, arylsulfonyl, alkylsulfonyl, and arylsulfonyl. In some other embodiments, the substituents selected as appropriate are independently selected from: halogen, -CN, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), -C(=O)NH ₂ , -C(=O)NH(C ₁ -C ₄ alkyl), -C(=O)N(C ₁ -C ₄ alkyl) ₂ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NH(C ₁ -C ₄ alkyl), -S(=O) ₂ N(C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C 4 In some embodiments, the optional substituents are independently selected from halogen _{, -CN} , _{-NH 2} , -OH _, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -CH 2 CH ₃ , -CHF ₂ , -CF _{3 ,} -OCH ₃ , -OCHF ₂ and _{-OCF 3} . In some embodiments, the substituted groups are substituted _with one or both of the previous groups _. In some embodiments, the optional substituents on aliphatic carbon atoms (non- _cyclic or cyclic) include pendoxy (=O).

In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^groups independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ²¹ , -CO ₂ R ²¹ , -C(═O)N(R 21 ) ₂ , -N(R ²¹ ) ₂ , -NR ²¹ C(═O)R ²² , -SR ^{21 ,} -S(═O)R ²² , -SO ₂ R ²² , and -SO ₂ N(R ²¹ ) ₂ ; each R ²¹ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C 6 or two R ²¹ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ²² is independently selected from C _{1 -C 6} alkyl, _{C 1 -C 6} fluoroalkyl, C ₁ -C _{6 heteroalkyl} , C ₃ -C ₆ cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the individual being treated.

As used herein, the term "modulate" means to interact directly or indirectly with a target so as to change 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.

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 of agonists, partial agonists, inverse agonists, antagonists, downregulators, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

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 a desired biological site of action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the term "co-administration" or its analogs is meant to encompass administration of selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same time or at different times.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an agent or compound administered that is sufficient to reduce to some extent one or more symptoms of the disease or condition being treated. Results include reduction and/or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to achieve a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined, as appropriate, using techniques such as dose escalation studies.

As used herein, the terms "enhance" and "enhancing" mean to increase or prolong the potency or duration of 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 the potency or duration of the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount that adequately enhances the effect of another therapeutic agent in a desired system.

As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously, concurrently or consecutively in separate entities without specific time intervals, wherein such administration provides an effective level of both compounds in the patient's body. The latter also applies to mixture therapy, such as administration of three or more active ingredients.

The terms "product" and "set" are used synonymously.

The term "individual" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (such as chimpanzees and other apes and monkey species); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents (such as rats, mice and guinea pigs) and the like. In one aspect, the mammal is a human.

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

In certain embodiments, the heterocyclic LpxC inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the heterocyclic LpxC inhibitory compounds described herein are 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 on the basis of the selected route of administration and standard medical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub Company, Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitory compound described herein or a stereoisomer thereof, a 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 harmful to the recipient of the composition (i.e., individual or patient).

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

In certain embodiments, the heterocyclic LpxC inhibitory compounds described by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis byproducts formed in one or more steps of the synthesis method.

Suitable oral dosage forms include tablets, pills, sachets or capsules of, for example, 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, which include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. (See, for example, Remington : The Science and Practice of Pharmacy (Gennaro, 21st edition. Mack Pub. Company, Easton, PA (2005)).

The dosage of the composition comprising at least one heterocyclic LpxC inhibitory compound described herein varies depending on the condition of the patient (ie, disease stage, general health, age, and other factors).

The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or to be prevented). The appropriate dosage and the appropriate 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. In general, the appropriate dosage and treatment regimen provides an amount of the composition sufficient to provide a therapeutic and/or preventive benefit (e.g., improved clinical outcome) or a reduction in the severity of symptoms. Experimental models and/or clinical trials are generally used to determine the optimal dosage. The optimal dosage depends on the patient's body mass, weight, or blood volume.

Oral dosages are generally in the range of about 1.0 mg to about 1000 mg, one to four or more times per day.

In certain instances, it is appropriate to administer at least one compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

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

In a particular embodiment, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) 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) or (X) 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 better overall benefit compared to administration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply the addition of the two treatments, or the patient experiences a synergistic benefit.

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 additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

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, for example, in a single unified form or in multiple forms (e.g., in a single pill or in two separate pills).

The compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds varies. Thus, in one embodiment, the compounds described herein are used prophylactically and are administered continuously to a subject prone to developing a condition or disease in order to prevent the disease or condition from occurring. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In specific embodiments, the compounds described herein are administered as soon as practicable after the onset of a detected or suspected disease or condition, and are continued for as long as necessary to treat the disease. In some embodiments, the length of treatment required varies, and the duration of treatment is adjusted to suit the specific needs of each individual.

Other embodiments and uses will be apparent to those skilled in the art based on the present invention. The following examples are provided only to illustrate various embodiments and should not be considered to limit the present invention in any way.

As used above and throughout the specification of the present invention, unless otherwise indicated, the following abbreviations should be understood to have the following meanings: Abbreviations: ACN or MeCN: acetonitrile; aq: aqueous solution; Boc or BOC: tert-butyloxycarbonyl; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMP: Dess-Martin periodinane dr: non-imagery isomer ratio DPPA: diphenylphosphatidyl azide; Eq. or equiv: equivalent; EtOAc: ethyl acetate; g: gram h or hr: hour; HPLC: high performance liquid chromatography; LC-MS, LC MS or LCMS: liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; M: molar concentration; MeOH: methanol; mg: milligram; min: minute; mL: milliliter; mmol: millimole; MsCl: methanesulfonyl (methylsulfonyl) chloride; MTBE: methyl tert-butyl ether; N: equivalent concentration; NBS: N -bromosuccinimide; NMR: nuclear magnetic resonance; Pet ether: petroleum ether; PPTS: pyridinium p-toluenesulfonate; p-TSA: p-toluenesulfonic acid rt: room temperature; SFC: supercritical fluid chromatography; TEA: triethylamine (or Et ₃ N); TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran; TLC: thin layer chromatography; TsCl: p-toluenesulfonyl chloride.

The following examples are provided for illustrative purposes only and do not limit the scope of the patent applications provided herein. I. Chemical Synthesis

Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. For synthetic transformations sensitive to moisture and/or oxygen, anhydrous solvents and oven-dried glassware were used. Yields were not optimized. Reaction times were approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. For proton spectra, the solvent peak was used as reference peak. Example A1 : Chemical Synthesis of Compounds 1 and 2 Preparation of 4- Isomer -1 and 4- Isomer -2 Step -1 :

To a stirred solution of 4-bromo- ₃ -fluorophenol ( 1 , 9 g, 47.1 mmol) in 1,4-dioxane (100 mL) were added 3,4-ethoxytetrahydrofuran ( 2 , 4.06 g, 47.1 mmol), _Cs2CO3 (23.03 g, 70.7 mmol) and benzyltriethylammonium chloride (2.141 g, 9.42 mmol) (room temperature). The reaction mixture was heated at 120 °C for 16 h. After the reaction was completed, the inorganic solid was filtered through a celite pad and washed with EtOAc (2 x 200 mL). The filtrate was concentrated under reduced pressure, and the resulting crude residue was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 30% EtOAc/hexane) to afford 3 as a light yellow liquid. Yield = 9.5 g (73%). The mirror isomers of 3 (8.2 g) were separated by SFC (column: Amylose 1 (250*30) mm, 5 μm; solvent: CO2: 0.5% IPAm/MeOH [80:20]). The fraction was concentrated under reduced pressure to afford 3- isomer -1 (tR = 1.92 min) and 3- isomer -2 (tR = 2.58 min). Yield = 3- isomer -1 : 2.2 g (%ee = 100) and 3- isomer -2 : 1.9 g (%ee = 100) Step -2 : (4-isomer-1)

To a stirred solution of 3- isomer -1 (2.2 g, 7.94 mmol) in 1,4-dioxane (40 mL) were added KOAc (2.338 g, 23.82 mmol) and bis(pinacolato)diboron (3.02 g, 11.91 mmol) (room temperature), and the reaction mixture was degassed with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (0.581 g, 0.794 mmol) and degassed for 2 min. The reaction mixture was stirred at 100 °C for 16 h. After the reaction was completed, the inorganic solid was filtered through a celite pad. The pad was washed with DCM (150 mL), the filtrate was combined and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 38% EtOAc/hexane) to obtain 4- isomer -1 as a light yellow gum. Yield: 2.1 g (78%) Step -2 : (4-isomer-2)

To a stirred solution of 3- isomer -2 (1.9 g, 6.86 mmol) in 1,4-dioxane (20 mL) were added KOAc (2.019 g, 20.57 mmol) and bis(pinacolato)diboron (2.61 g, 10.29 mmol) (room temperature), and the reaction mixture was degassed with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (0.502 g, 0.686 mmol) and degassed for 2 min. The reaction mixture was stirred at 100 °C for 16 h. After the reaction was completed, the inorganic solid was filtered through a diatomaceous earth pad. The pad was washed with DCM (500 mL), and the filtrate was combined and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by MPLC (manually packed filter cartridge; SiO2 230-400 mesh; 16% EtOAc/hexane) to obtain 4- isomer -2 as a light brown liquid. Yield: 1.8 g (73%) Preparation of compound 1 step -1 :

To a solution of 2 (2.0 g, 4.27 mmol) in acetonitrile (20 mL) and water (20 mL) was added Ester 4- isomer -1 (2.07 g, 6.41 mmol) and potassium carbonate (1.77 g, 12.81 mmol) were added and the mixture was purged with nitrogen for 15 min. PdCl2(dtbpf) (0.27 g, 0.42 mmol) was added to the reaction mixture and purging was continued for 5 min. The reaction mixture was stirred at 80°C for 16 h. The reaction was cooled to ambient temperature, water (50 mL) was added and extracted with 10% MeOH/DCM (300 mL×2). The combined organic extracts were washed with brine (100 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 6% MeOH/DCM) to give 3- isomer -1 as a light brown solid. Yield: 1.4 g (46%). LC-MS: Calcd. for C30H35FN2O6: 538.61, Observed: 539.2 [M+1] ⁺ Step -2 :

To a stirred solution of 3- isomer -1 (1.4 g, 2.60 mmol) in MeOH (90 mL) was added p-toluenesulfonic acid monohydrate (1.48 g, 7.80 mmol) (at 0°C). The reaction mixture was warmed to 25°C and stirred for 4 h. The volatiles were evaporated under reduced pressure, and the resulting residue was alkalized with 10% NaHCO ₃ solution and extracted with 10% MeOH/DCM (100 mL×2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 10% MeOH/DCM) to give 290 mg of compound 1 as a light brown solid. ¹ H NMR showed the presence of aliphatic impurities. In addition, the product was re-purified by reverse phase preparative HPLC (10 mM ammonium bicarbonate in water and ACN) to give compound 1 as a white solid. Yield: 120 mg (40%) LC-MS: Calculated for C25H27FN2O5: 454.49; Observed: 455.2 [M+1] ⁺

Compound 1: 1H-NMR (400 MHz, DMSO-d6): δ 7.52-7.45 (m, 5H), 7.30 (app d, J = 0.80 Hz, 1H), 7.01 (dd, J = 2.40, 12.80 Hz, 1H), 6.92 (dd, J = 2.40, 8.80 Hz, 1H), 6.83 (app d, J = 0.80 Hz, 1H), 6.58 (dd, J = 6.80, 16.00 Hz, 1H), 6.47 (d, J = 16.00 Hz, 1H), 5.55 (d, 1H, exchanged with D2O), 5.30-5.22 (m, 3H, 2 protons exchanged with D2O), 4.89 (t, 1H), 4.73 (d, J = 3.60 Hz, 1H), 4.24 (d, 1H), 4.07 (dd, J = 4.00, 10.20 Hz, 1H), 3.92 (dd, J = 4.40, 9.60 Hz, 1H), 3.84-3.78 (m, 3H), 3.60 (dd, J = 2.00, 9.40 Hz, 1H), 1.50 (d, J = 6.80 Hz, 3H). 19F (376MHz, DMSO-d6): δ -115.349 SFC purity = 100% (tR = 2.81 min; single isomer; column: LUX-A1; solvent: 0.5% IPAm/MeOH) Preparation of compound 2 Step -1 :

To a solution of 2 (2.0 g, 4.27 mmol) in acetonitrile (20 mL) and water (20 mL) was added Ester 4- isomer -2 (2.07 g, 6.41 mmol) and potassium carbonate (1.77 g, 12.81 mmol) were added and the mixture was purged with nitrogen for 15 min. PdCl2(dtbpf) (0.27 g, 0.42 mmol) was added to the reaction mixture and purging was continued for 5 min. The reaction mixture was stirred at 80°C for 16 h. The reaction was cooled to ambient temperature, water (50 mL) was added and extracted with 10% MeOH/DCM (300 mL×2). The combined organic extracts were washed with brine (100 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 6% MeOH/DCM) to give 3- isomer -2 as a light brown solid. Yield: 0.85 g (30%). LC-MS: Calcd. for C30H35FN2O6: 538.62, Observed: 539.4 [M+1] ⁺ Step -2 :

To a stirred solution of 3- isomer -2 (0.85 g, 2.60 mmol) in MeOH (90 mL) was added p-toluenesulfonic acid monohydrate (0.76 g, 7.65 mmol) (at 0°C). The reaction mixture was warmed to 25°C and stirred for 4 h. The volatiles were evaporated under reduced pressure, and the resulting residue was alkalized with 10% NaHCO3 solution and extracted with 10% MeOH/DCM (100 mL×2). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 10% MeOH/DCM) to give 188 mg of compound 2 as a light brown solid. The compound contained some aliphatic impurities. The compound was re-purified by reverse phase preparative HPLC (0.1% HCCOH in water and ACN) to give compound 2 ( formate salt ) as a white gum. Yield: 108 mg (55%). LC-MS: calcd. for C25H27FN2O5: 454.49; observed: 455.2 [M+1] ⁺ 1H-NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.52-7.45 (m, 5H), 7.30 (d, J = 1.20 Hz, 1H), 7.01 (dd, J = 2.40, 13.20 Hz, 1H), 6.92 (dd, J = 2.40, 8.80 Hz, 1H), 6.83 (d, J = 1.20 Hz, 1H), 6.58 (dd, J = 6.80, 16.00 Hz, 1H), 6.47 (d, J = 16.00 Hz, 1H), δ 5.54-5.53 (m, 1H, exchanged with D2O), 5.29-5.22 (m, 3H, 2 protons exchanged with D2O), 4.89-4.86 (m, 1H), 4.73 (d, J = 4.00 Hz, 1H), 4.23 (br s, 1H), 4.07 (dd, J = 4.40, 10.20 Hz, 1H), 3.92 (dd, J = 4.40, 9.20 Hz, 1H), 3.84-3.78 (m, 3H), 3.60 (dd, J = 1.60, 9.40 Hz, 1H), 1.50 (d, J = 6.40 Hz, 3H). 19F (376MHz, DMSO-d6): δ -115.349. SFC purity = 100% (tR = 4.29 min; single isomer; column: LUX-A1; solvent: 0.5% IPAm/MeOH) Example A2 : Chemical synthesis of compound 7 Scheme 1 Step 1

To a stirred solution of (-)-1,4-di- O -tosyl-2,3- O -isopropylidene-L-threitol ( A-1 , 10.0 g, 21.25 mmol; CAS # 37002-45-2) in methanol (100 mL) was added HCl (0.5 N aqueous solution; 6.38 mL, 3.19 mmol) (at 25 °C). The reaction mixture was heated at 70 °C for 6 h. The progress of the reaction was monitored by TLC, showing the formation of polar spots and unreacted starting material. To this reaction mixture was added HCl (0.5 N aqueous solution; 6.38 mL, 3.19 mmol) (at 25 °C). The reaction mixture was heated at 70 °C for another 6 h. The reaction was monitored by TLC, showing complete consumption of the starting material. The reaction mixture was cooled to room temperature. The volatiles were distilled off. Water (200 mL) was added to the obtained crude material and extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain A-2 as an off-white solid. The crude material was used in the next step without any purification. Yield: 9.0 g (98%). Step 2

To a stirred solution of A-2 (4.5 g, 10.45 mmol) in ethanol (45 mL) was added Na2S·9H2O (6.28 g, 26.1 mmol) (at 25°C). The reaction mixture was heated at 90°C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature. The solid was filtered through a celite bed, and the filtrate was concentrated under reduced pressure. DCM (100 mL) was added to the obtained crude product and the precipitated solid was filtered and washed with DCM (200 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO ₂ , 230-400 mesh; 10% MeOH/DCM) to obtain A-3 as a yellow liquid. Yield: 970 mg (77%). Step 3

To a stirred solution of A-3 (1.9 g, 15.95 mmol) in DMF (7.5 mL) was added sodium hydride (0.638 g, 15.95 mmol) (at 0°C). After the addition, the reaction mixture was stirred for 30 min. To this reaction mixture was added a solution of A-4 (1.5 g, 10.63 mmol) in DMF (7.5 mL). The reaction mixture was heated at 110°C for 16 h. The reaction was monitored by TLC, showing a new polar spot. The reaction mixture was quenched by adding ice water (50 mL). The aqueous layer was extracted with EtOAc (40 mL×2). The combined organic layers were washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2 100-200 mesh; 30% EtOAc/hexane) to afford A-5 as a light yellow solid. Yield: 1.05 mg (77%). Step 4

To a stirred solution of A-5 (1.05 g, 4.35 mmol) in THF:MeOH:H2O (1:1:1; 15.0 mL) were added iron (2.43 g, 43.5 mmol) and ammonium chloride (2.33 g, 43.5 mmol) (at 25°C). The reaction mixture was heated at 90°C for 2 h. The reaction was monitored by TLC. The reaction was quenched by adding water (50 mL) and EtOAc (50 mL). This was filtered through a celite pad; the filtrate was extracted with EtOAc (50 mL×2). The combined EtOAc layers were washed with cold water (50 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford A-6 as an off-white solid. The crude material was used in the next step without any purification. Yield: 800 mg (74%). LCMS: Calcd. for C ₁₀ H ₁₃ NO ₂ S: 211.28, Observed: 212.2 [M+H] ⁺ . Step 5

To a stirred solution of A-6 (0.8 g, 3.79 mmol) in acetonitrile (24 mL) were added copper (II) bromide (1.015 g, 4.54 mmol) and tributyl nitrite (0.676 ml, 5.68 mmol) (at 0°C). The reaction mixture was stirred at 65°C for 16 h. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature. To this mixture were added water (20 mL) and EtOAc (20 mL). The suspension was filtered through a celite pad. The filtrate was extracted with 10% methanol/DCM (200 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude material. The crude material was purified by flash column chromatography (SiO2 100-200 mesh; 5-10% methanol/DCM) to obtain A-7 as a brown solid. Yield: 500 mg (30%). LCMS: Calcd. for C ₁₀ H ₁₁ BrO ₃ S: 291.16, Observed: 291.1 [M] ⁺ and 293.1 [M+2] ⁺ . Step 6

To a stirred solution of A-7 (200 mg, 0.687 mmol) in 1,4-dioxane (8 mL) were added potassium acetate (135 mg, 1.374 mmol) and bis(pinacolato)diboron (262 mg, 1.030 mmol) (room temperature). The reaction mixture was degassed with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf).DCM complex (56.1 mg, 0.069 mmol) and degassed for 5 min. The reaction mixture was heated at 100 °C for 16 h. The reaction was monitored by LCMS. The reaction mixture was diluted with 10% methanol in DCM (30 mL), filtered through a celite bed, and the bed was washed with 10% methanol in DCM (20 mL). The filtrate was washed with water (30 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO ₂ 230-400 mesh; 5-10% MeOH/DCM) to give A-8 as a brown solid. The purity of the product was 50% according to LCMS. The product was used as is in the next step without further purification. Yield: 200 mg (43%). LCMS: Calcd. for C ₁₆ H ₂₃ BO ₅ S: 338.2, Observed: 339.2 [M+1] ⁺ . Step 7

To a stirred solution: A-9 (80 mg, 0.208 mmol) and A-8 (176 mg, 0.521 mmol) in acetonitrile (4 mL) were added K ₂ CO ₃ (57.6 mg, 0.416 mmol), water (1.0 mL) and degassed with nitrogen. To this reaction mixture was added PdCl 2 (dtbpf) (13.57 mg, 0.021 mmol). The reaction mixture was irradiated at 80 °C in a microwave reactor for 2 h. The reaction was monitored by LCMS. The reaction mixture was diluted with 10% methanol in DCM (20 mL), filtered through a celite bed, and the bed was washed with 10% methanol in DCM (10 mL). The filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC (0.1% ammonium bicarbonate in MQ water and acetonitrile) to give compound 7 as a white solid. Yield: 12 mg (12%). LCMS: Calcd. for C ₂₅ H ₂₈ N ₂ O ₅ S: 468.57, Observed: 469.1 [M+1] ⁺ . Example A3 : Synthesis of Compounds 13 , 14 , and 15 Step 1 :

To a stirred solution of tributyl (3-hydroxycyclobutyl)carbamate ( 1 , 20 g, 108 mmol) in AcOH (100 mL) was added 4-bromoaniline ( 2 , 24.15 g, 140 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. Sodium cyanoborohydride (20.36 g, 324 mmol) was added portionwise to the reaction mixture cooled to 0 °C. After the addition was complete, the resulting reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was quenched with saturated _NaHCO3 solution (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine solution (3×90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiO ₂ cartridge, 100-200 mesh: 20% EtOAc/hexanes) to give 3 as a white solid. 1HNMR showed the presence of cis and trans isomers; the product was used as is in the next step without further separation of the isomers. Yield: 8 g (20%). LCMS: Calcd. for C15H21BrN2O2: 340.25, Observed: 341.2 [M] ⁺ and 343.2 [M+2] ⁺ Step 2 :

To the following solution: 3 (4 g, 11.72 mmol) in 1,4-dioxane (60 mL) were added bis(pinacolato)diboron (4.46 g, 17.58 mmol) and potassium acetate (3.45 g, 35.2 mmol) (room temperature). The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf) (0.858 g, 1.172 mmol) and heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (90 mL), and filtered through a celite pad. The celite pad was washed with EtOAc (90 mL×2). The combined filtrate was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by MPLC (using a manually packed SiO2 cartridge; 230-400 mesh; 20% EtOAc/hexanes) to give 4 as an off-white solid. Yield: 3.8 g (74%). LCMS: Calcd. for C21H33BN2O4: 388.31, Observed: 389.2 [M+1] ⁺ Step 3 :

To a stirred solution of 4 (3.73 g, 9.61 mmol) in acetonitrile (40 mL) and water (40 mL) were added 5 (3 g, 6.41 mmol) and potassium carbonate (2.213 g, 16.01 mmol) (room temperature). The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture was added PdCl2(dtbpf) (0.417 g, 0.641 mmol) and the resulting reaction mixture was heated to 80 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×90 mL). The combined organic extracts were washed with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed _SiO2 cartridge, 230-400 mesh; 4% MeOH/DCM) to give 6 as a brown gum. Yield: 1.9 g (40%). LCMS: Calcd. for C35H46N4O5: 602.78, Observed: 603.2 [M+1] ⁺ Step 4 :

To a stirred solution of 6 (300 mg, 0.498 mmol) in 2,2,2-trifluoroethanol (5 mL) was added trimethylsilyl chloride (0.140 mL, 1.095 mmol) (at 0 °C). The reaction was allowed to reach room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the resulting brown gum was triturated with DCM (8 mL x 3). The solid was further co-distilled with toluene and dried under reduced pressure to give 7 as a brown solid. Yield: 200 mg (79%). LCMS: Calculated for C35H46N4O5: 602.35, Observed: 603.2 [M+1] ⁺ Step 5 :

To a stirred solution of 7 (200 mg, 0.440 mmol) in DMF (5 mL) was added Et3N (0.460 mL, 3.30 mmol) and 2-bromoacetonitrile (0.057 mL, 0.824 mmol) (at 0 °C). The reaction was stirred at room temperature for 5 h. The reaction was quenched with water (20 mL) and extracted with 10% MeOH/DCM (3×50 mL). The combined organic extracts were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (column: YMC C18 250*20 mm, 5 μm; solvent: 10 mM ammonium bicarbonate in water and acetonitrile) to give compound 13 as an off-white solid. Yield: 38 mg (19%). LCMS: Calculated for C27H31N5O2: 457.25, Observed: 458.4 [M+H] ⁺ . 1H-NMR (400 MHz, DMSO-d6) of the major isomers: δ 7.52 (d, J = 8.00 Hz, 2H), 7.44-7.40 (m, 4H), 7.30 (app d, J = 0.80 Hz, 1H), 6.83 (s, 1H), 6.59-6.48 (m, 3H), 6.43 (d, J = 16.00 Hz, 1H), 6.03 (d, J = 6.40 Hz, 1H, exchanged with D2O), 5.29-5.26 (m, 2H, 1H exchanged with _D2O ), 5.22 (t, J = 5.20 Hz, 1H, exchanged with D2O), 4.89-4.86 (m, 1H), 3.91-3.89 (m, 1H), 3.82 (t, J = 5.60 Hz, 2H), 3.59-3.43 (m, 3H), 3.05-3.03 (m, 1H), 2.72-2.66 (m, 1H), 2.17-2.13 (m, 1H), 2.08-2.04 (m, 1H), 1.64-1.57 (m, 1H), 1.50 (d, J = 6.40 Hz, 3H). SFC: LUX-I-Amylose3_0.5% IPAm/ACN_MeOH_45; tR = 4.66 min (45.2%) and 6.70 min (54.7%). The cis- and trans-mixture at the tail; the ratio of SFC data (unidentified) is 45.29:54.7. SFC separation

32 g of 3 ( mixture of cis and trans ) was separated by SFC (column: RR WHELK (250*30) mm, 5 μm; solvent: CO2: 100% 2-propanol [85:15] to obtain 3- cis isomer (tR = 5.38 min) and 3- trans isomer (tR = 4.65 min) as off-white solids. Yield: 3 -cis isomer = 15 g and 3- trans isomer = 10 g. SFC purity = 3- cis isomer : 99.73% (de = 99.7%) and 3- trans isomer : 99.15% (de = 99.1%)

The synthesis of compound 15 was carried out by using the same procedures as outlined in step-2 to step-5 of compound 13 .

Yield = 55 mg (15%). LCMS: Calcd. for C27H31N5O2 457.25, Observed: 458.4 [M+H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 7.52 (d, J = 8.40 Hz, 2H), 7.45-7.40 (m, 4H), 7.30 (app d, J = 1.20 Hz, 1H), 6.83 (app d, J = 0.80 Hz, 1H), 6.55-6.48 (m, 3H), 6.43 (d, J = 16.00 Hz, 1H), 6.14 (d, J = 6.00 Hz, 1H, exchanged with D2O), 5.27-5.21 (m, 3H, 2H exchanged with D2O), 4.90-4.84 (m, 1H), 3.92-3.88 (m, 1H), 3.82 (t, J = 5.20 Hz, 2H), 3.58 (d, J = 6.80 Hz, 2H), 3.44-3.43 (m, 1H), 2.90-2.85 (m, 1H), 2.19-2.13 (m, 2H), 2.08-2.04 (m, 2H), 1.50 (d, J = 6.40 Hz, 3H). SFC purity = 100%; tR = 4.95 min (column: LUX Amylose-3; solvent: 0.5% isopropylamine in acetonitrile and MeOH).

The synthesis of compound 14 was carried out by using the same procedures as outlined in step-2 to step-5 of compound 13 .

Yield = 55 mg (18%). LCMS: Calcd. for C27H31N5O2 457.25, Observed: 458.4 [M+H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 7.52 (d, J = 8.40 Hz, 2H), 7.44-7.40 (m, 4H), 7.30 (app d, J = 1.20 Hz, 1H), 6.83 (app d, J = 1.20 Hz, 1H), 6.58 (d, J = 8.80 Hz, 2H), 6.53-6.48 (m, 1H), 6.43 (d, J = 16.00 Hz, 1H), 6.03 (d, J = 6.40 Hz, 1H, exchanged with D2O), 5.28-5.21 (m, 3H, 2H exchanged with D2O), 4.89-4.86 (m, 1H), 3.82 (t, J = 5.60 Hz, 2H), 3.56-3.52 (m, 3H), 3.05-3.03 (m, 1H), 2.78-2.66 (m, 3H), 1.64-1.57 (m, 2H), 1.50 (d, J = 6.40 Hz, 3H). SFC purity = 99.3%; tR = 7.11 min (column: LUX Amylose-3; solvent: 0.5% isopropylamine in acetonitrile and MeOH). Example A4 : Synthesis of Compound 16 Step -1 :

To a stirred solution of 1 (8.0 g, 23.38 mmol) in DCM (250 mL) was added HCl (4 M in dioxane, 276 mL, 304 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure to obtain a crude residue. To the residue was added hexane (15 mL) at room temperature and stirred for 5 min. The obtained precipitate was filtered to obtain 2 as a white solid. Yield: 4.6 g (76%). LC-MS: Calcd. for C ₁₀ H ₁₂ BrNO: 242.116, Observed: 242.0 [M] ⁺ and 244.0 [M+2] ⁺ Step -2 :

To a stirred solution of 2 (4.6 g, 19.00 mmol) in DCM (150 mL) were added triethylamine (6.63 mL, 47.5 mmol) and methanesulfonyl chloride (2.206 mL, 28.5 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 2 h. The reactant was quenched with water (50 mL) and extracted with DCM (100 mL×2). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3 as a white solid. Yield: 5.6 g (70%) Step -3 :

To a stirred solution of 3 (5.6 g, 17.49 mmol) in dioxane (40 mL) were added potassium acetate (5.15 g, 52.5 mmol) and bis(pinacolato)diboron (6.66 g, 26.2 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (1.280 g, 1.749 mmol) and purging was continued for 2 min. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh; 70% EtOAc/hexane) to give Ester 4 , yellow liquid. Yield: 5.5 g (64%) Step -4 :

To a solution of 5 (1.5 g, 3.20 mmol) in acetonitrile (50 mL) and water (8 mL) was added Ester 4 (1.412 g, 3.84 mmol) and K2CO3 (0.885 g, 6.41 mmol) were added and the mixture was purged with nitrogen for 5 min. PdCl2(dtbpf) (0.209 g, 0.320 mmol) was added to the reaction mixture and purging was continued for another 2 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction was cooled to ambient temperature, water (30 mL) was added and extracted with 10% MeOH/DCM (50 mL×3). The combined organic extracts were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed filter cartridge; SiO2 230-400 mesh; 15% MeOH/DCM) to give 6 as a brown solid. Yield: 1.0 g (51%). LC-MS: Calcd. for C ₃₁ H ₃₉ N ₃ O ₆ S: 581.73, Observed: 582.6 [M+1] ⁺ Step -5 :

To the following solution: 6 (0.6 g, 1.031 mmol) in MeOH (60 mL) was added p-toluenesulfonic acid monohydrate (0.6 g, 3.15 mmol) (at 0 °C). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The volatiles were removed under reduced pressure, and the resulting residue was alkalized with 10% NaHCO ₃ solution and extracted with 10% MeOH/DCM (100 mL×2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC (column: C18-reverse phase SiO ₂ , solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 16 as a white solid. Yield: 0.130 g (25%). LC-MS: Calcd. for C ₂₆ H ₃₁ N ₃ O ₅ S: 497.61, Observed: 498.0 [M+1] ⁺ Example A5 : Synthesis of Compound 17 Step -1 :

To a stirred solution of tributyl 3-oxazolidinone-1-carboxylate ( 1 , 15 g, 88 mmol) in MeOH (150 mL) was added sodium borohydride (4.97 g, 131 mmol) dropwise (at 0°C). The reaction mixture was stirred at room temperature for 3 h. The volatiles in the reaction mixture were removed under reduced pressure. The reactant was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (250 mL×2). The combined organic layers were washed with brine (100 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed cartridge; SiO2 100-200 mesh; 10-20% EtOAc/hexane) to afford 2 as a yellow liquid. Yield = 11 g (67%) Step -2 :

To a stirred solution of 2 (10 g, 57.7 mmol) in DCM (120 mL) were added DIPEA (25.2 mL, 144 mmol), DMAP (1.763 g, 14.43 mmol) and p-toluenesulfonyl chloride (16.51 g, 87 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 3 h. The reactant was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (50 mL×2). The combined organic extracts were washed with brine solution (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3 as a yellow liquid. Yield: 18 g (95%) Step -3 :

To the following solution: 4-bromophenol ( 4 , 9.51 g, 55.0 mmol) in DMF (150 mL) was added cesium carbonate (29.9 g, 92 mmol) and 3 (15 g, 45.8 mmol) (room temperature). The reaction mixture was stirred at 90 °C for 16 h. The reaction was cooled to room temperature, quenched with saturated ammonium chloride solution (400 mL) and extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude material was purified by MPLC (manually packed filter cartridge; SiO2 100-200 mesh; 10-20% EtOAc/hexane) to afford 5 as a white solid. Yield: 10 g (64%). LC-MS: Calcd. for C14H18BrNO3: 328.21; Observed: 227.9 [M-Boc] ⁺ and 230 [M-Boc+2] ⁺ Step -4 :

To a stirred solution of 5 (4 g, 12.19 mmol) in dioxane (40 mL) was added potassium acetate (2.392 g, 24.37 mmol) and bis(pinacolato)diboron (3.71 g, 14.62 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (0.892 g, 1.219 mmol) and purging was continued for 2 min. The reaction mixture was stirred at 100 °C for 16 h. The reaction was cooled to ambient temperature and filtered through a celite bed. The celite bed was washed with EtOAc (500 mL). The combined filtrate was washed with saline solution (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by MPLC (manually packed filter cartridge; SiO 2 230-400 mesh; 5-10% EtOAc/hexane) to obtain Ester 6 was obtained as a white solid. Yield: 4 g (61%). LC-MS: Calcd. for C ₂₀ H ₃₀ BNO ₅ : 375.2, Observed: 276.2 [M-Boc] ⁺ Step -5 :

To a stirred solution of 7 (1 g, 2.135 mmol) in dioxane (7.5 mL) and water (3 mL) was added Ester 6 (0.962 g, 2.56 mmol) and K2CO3 (0.590 g, 4.27 mmol). The reaction mixture was purged with nitrogen for 5 min. PdCl2(dppf) (0.312 g, 0.427 mmol) was added to the reaction mixture and purging was continued for another 2 min. The reaction mixture was stirred at 85 °C for 16 h. TLC analysis (10% EtOAc/MeOH/detection with KMnO4) showed product formation (Rf=0.3). The reaction was cooled to ambient temperature and filtered through a celite bed. The bed was washed with EtOAc (150 mL). The combined filtrate was concentrated under reduced pressure to give a crude residue. The crude material was purified by MPLC (manually packed filter cartridge; SiO ₂ , 230-400 mesh; 90-100% EtOAc/hexanes) to give 8 as a brown liquid. Yield: 0.5 g (34%). LC-MS: Calcd. for C ₃₄ H ₄₃ N ₃ O ₆ : 589.73, Observed: 590.2 [M+1] ⁺ . Four more batches were performed to give 1.6 g of 8. ((330 mg), (330 mg), (500 mg) and (0.5)). All batches were mixed together and used in the next step. Step -6 :

To a stirred solution of 8 (1 g, 1.696 mmol) in 2,2,2-trifluoroethanol (20 mL) was added TMSCl (0.325 mL, 2.54 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 1 h. The volatiles in the reaction mixture were removed under reduced pressure to give 9 as a brown liquid. Yield = 1.20 g (73%). LC-MS: Calculated for C ₂₄ H ₂₇ N ₃ O ₃ : 405.49 (for parent compound), Observed: 406.2 [M+1] ⁺ Step -7 :

To the following solution: 9 (1 g, 2.466 mmol) in DMF (15 mL) were added triethylamine (2.080 mL, 14.80 mmol) and 2-bromoacetonitrile ( 10 , 0.258 mL, 3.70 mmol) (room temperature). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with aqueous brine (100 mL). The aqueous layer was extracted with 10% MeOH/EtOAc (250 mL×2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1.8 g of crude material. Another batch was carried out with 400 mg of 9 to give 400 mg of crude material. The two batches were combined and purified by reverse phase preparative HPLC (column: Zorbax 150 mm; solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 17 as a white solid. Yield: 184 mg (combined yield of two batches). LC-MS: Calcd. for C ₂₆ H ₂₈ N ₄ O ₃ : 444.53, Observed: 445.0 [M+1] ⁺ Example A6 : Synthesis of compound 18 Step -1 :

To a stirred solution of 3-oxocyclobutane-1-carboxylic acid ( 1 , 15 g, 131 mmol) in THF (90 mL) was added CDI (25.6 g, 158 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 1 h, after which benzylamine (16.25 mL, 158 mmol) was added and stirring was continued at room temperature for 16 h. The volatiles were removed by reduced pressure. The resulting residue was purified by column chromatography ( _SiO2 , 100-200 mesh; solvent: 0-20% MeOH/DCM) to give 2 as a white solid. Yield: 11 g (39%). LC-MS: Calcd. for C ₁₂ H ₁₃ NO ₂ : 203.24, Observed: 204.0 [M+1] ⁺ Step -2 :

To a stirred solution of 2 ( 3.0 g, 14.76 mmol) in THF (40 mL) was added LiAlH4 (1 M in THF, 29.5 mL, 29.5 mmol) dropwise (at 0 °C). The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was cooled at 0 °C, quenched with 10% NaOH solution (15 mL) and water (40 mL). The reaction mixture was filtered through a celite bed and the bed was washed with THF (2×50 mL). The combined filtrate was concentrated under reduced pressure to give 3 as a yellow liquid, which was used in the next step without further purification. Yield: 2.5 g (71%). LC-MS: Calcd. for C ₁₂ H ₁₇ NO: 191.27, Observed: 192.4 [M+1] ⁺ . Note: One more batch was performed to give 2.6 g 3 . Both batches were combined and used in the next step. Step - 3

To a solution of 3 (5.1 g, 26.7 mmol) in MeOH (70 mL) was added 20% Pd(OH)2 (wetted with H2O; 5.0 g, 7.12 mmol) and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction mixture was filtered through a celite bed. The celite bed was washed with MeOH (200 mL). The combined filtrate was concentrated under reduced pressure to give the crude product 4 as a brown gum, which was taken to the next step without further purification. Yield: 3.25 g (95%) Step - 4

To a stirred solution of 4 (2.7 g, 26.7 mmol) in MeOH (150 mL) were added potassium carbonate (11.07 g, 80 mmol), 1H-imidazole-1-sulfonylazide hydrochloride ( 5 , 6.71 g, 32.0 mmol) and copper (II) sulfate pentahydrate (0.667 g, 2.67 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 6 as a brown liquid, which was used in the next step without further purification. (The crude product contains EtOAc). Yield: 7.5 g Step 5 :

To a stirred solution: 1-bromo-4-ethynylbenzene ( 7 , 8.54 g, 47.2 mmol) and 6 ( 3.0 g, 23.59 mmol) in tert-butyl alcohol (6 mL) and water (6.00 mL) were added sodium ascorbate (0.934 g, 4.72 mmol) and copper sulfate pentahydrate (0.588 g, 2.359 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (25 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude product was purified by using MPLC (manually packed filter cartridge, SiO ₂ 230-400 mesh; 80% EtOAc/hexane) to give 8 as an off-white solid. Yield: 3.6 g (49%). LC-MS: Calcd. for C ₁₃ H ₁₄ BrN ₃ O: 308.18, Observed: 308.3 [M] ⁺ and 310.3 [M+2] ⁺ . One more batch was carried out to give 0.3 g of 8 . Both batches were combined and used in the next step. Step -6 :

To a stirred solution of 8 (3.9 g, 12.65 mmol) in 1,4-dioxane (60 mL) were added potassium acetate (3.73 g, 7 38.0 mmol) and bis(pinacolato)diboron (4.82 g, 18.98 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this mixture was added PdCl2(dppf) (0.926 g, 1.265 mmol) and degassing was continued for another 2 min. The reaction mixture was then heated at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a crude residue which was purified by MPLC (manually packed filter cartridge, SiO2 230-400 mesh; 100% EtOAc) to give 9 as a pink solid. Yield: 3.5 g (49%). LC-MS: Calcd. for C ₁₉ H ₂₆ BN ₃ O ₃ : 355.25, Observed: 356.3 [M+1] ⁺ Step -7 :

To a stirred solution of 10 (1.3 g, 2.78 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added 9 (1.479 g, 4.16 mmol) and tripotassium phosphate (1.768 g, 8.33 mmol) (room temperature). The reaction mixture was degassed with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf) (0.203 g, 0.278 mmol) and degassed for another 2 min. The resulting reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with water (60 mL) and extracted with 10% MeOH/DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by MPLC (manually packed filter cartridge, SiO2 230-400 mesh; 20% MeOH/DCM) to give 11 as a brown solid. Yield: 1.2 g (66%). LC-MS: Calculated for C ₃₃ H ₃₉ N ₅ O ₄ : 569.70, Observed: 570.0 [M+1] ⁺ Step -8 :

To a stirred solution of 11 (1.4 g, 2.457 mmol) in MeOH (25 mL) was added p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with 10% NaHCO ₃ solution (10 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude material, which was purified by reverse phase preparative HPLC (column: YMC, C18, 250*mM); solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 18 as a white solid. Yield: 350 mg (29%). LC-MS: Calculated for C ₂₈ H ₃₁ N ₅ O ₃ : 485.58, Observed: 486.2 [M+1] ⁺ Example A7 : Synthesis of Compound 19 Step -1 :

To a stirred solution of 2 (800 mg, 1.708 mmol) in ACN (10 mL) and water (10 mL) was added Ester 1 (738 mg, 2.56 mmol) and K ₂ CO ₃ (708 mg, 5.12 mmol) (room temperature). The reaction mixture was purged with nitrogen for 5 min. PdCl 2 (dtbpf) (0.111 g, 0.171 mmol) was added to the reaction mixture and purging was continued for 2 min. The resulting reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH / DCM (50 mL × 2). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by MPLC (manually packed filter cartridge, SiO2 230-400 mesh; 5% MeOH/DCM) to give 3 as a light brown solid. Yield: 500 mg (53%). LC-MS: Calcd. for C31H38N2O4: 502.65, Observed: 503.5 [M+1] ⁺ Step -2 :

To a stirred solution of 3 (0.5 g, 0.995 mmol) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (0.568 g, 2.98 mmol) (at 0°C). The reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the resulting residue was alkalized with 10% NaHCO ₃ solution (20 mL) and extracted with 10% MeOH/DCM (50 mL×2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC (column: Zorbax C18 (150*21.2 mm) 5 μm; solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 19 as a white solid. Yield = 200 mg (48%). LC-MS: Calculated for C26H30N2O3: 418.54, Observed: 419.0 [M+1] ⁺ Example A8 : Synthesis of compound 20 Step -1 :

To a stirred solution of 3-oxocyclobutane-1-carboxylic acid ( 1 , 15 g, 131 mmol) in THF (90 mL) was added CDI (25.6 g, 158 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 1 h, after which benzylamine (16.25 mL, 158 mmol) was added and stirring was continued at room temperature for 16 h. The volatiles were removed by reduced pressure. The resulting residue was purified by column chromatography ( _SiO2 , 100-200 mesh; solvent: 0-20% MeOH/DCM) to give 2 as a white solid. Yield: 11 g (39%). LC-MS: Calcd. for C ₁₂ H ₁₃ NO ₂ : 203.24, Observed: 204.0 [M+1] ⁺ Step -2 :

To a stirred solution of 2 ( 3.0 g, 14.76 mmol) in THF (40 mL) was added LiAlH4 (1 M in THF, 29.5 mL, 29.5 mmol) dropwise (at 0 °C). The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was cooled at 0 °C, quenched with 10% NaOH solution (15 mL) and water (40 mL). The reaction mixture was filtered through a celite bed and the bed was washed with THF (2×50 mL). The combined filtrate was concentrated under reduced pressure to give 3 as a yellow liquid, which was used in the next step without further purification. Yield: 2.5 g (71%). LC-MS: Calcd. for C ₁₂ H ₁₇ NO: 191.27, Observed: 192.4 [M+1] ⁺ . One more batch was carried out to give 2.6 g 3 . Both batches were combined and used in the next step. Step - 3

To a solution of 3 (5.1 g, 26.7 mmol) in MeOH (70 mL) was added 20% Pd(OH)2 (wetted with H2O; 5.0 g, 7.12 mmol) and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction mixture was filtered through a celite bed. The celite bed was washed with MeOH (200 mL). The combined filtrate was concentrated under reduced pressure to give the crude product 4 as a brown gum which was used in the next step without further purification. Yield: 3.25 g (95%) Step - 4

To a stirred solution of 4 (2.7 g, 26.7 mmol) in MeOH (150 mL) were added potassium carbonate (11.07 g, 80 mmol), 1H-imidazole-1-sulfonylazide hydrochloride ( 5 , 6.71 g, 32.0 mmol) and copper (II) sulfate pentahydrate (0.667 g, 2.67 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 6 as a brown liquid, which was used in the next step without further purification. (The crude product contains EtOAc). Yield: 7.5 g Step 5 :

To a stirred solution: 1-bromo-4-ethynylbenzene ( 7 , 8.54 g, 47.2 mmol) and 6 ( 3.0 g, 23.59 mmol) in tert-butyl alcohol (6 mL) and water (6.00 mL) were added sodium ascorbate (0.934 g, 4.72 mmol) and copper sulfate pentahydrate (0.588 g, 2.359 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (25 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude product was purified by using MPLC (manually packed filter cartridge, SiO ₂ 230-400 mesh; 80% EtOAc/hexane) to give 8 as an off-white solid. Yield: 3.6 g (49%). LC-MS: Calcd. for C ₁₃ H ₁₄ BrN ₃ O: 308.18, Observed: 308.3 [M] ⁺ and 310.3 [M+2] ⁺ . One more batch was carried out to give 0.3 g of 8 . Both batches were combined and used in the next step. Step -6 :

To a stirred solution of 8 (3.9 g, 12.65 mmol) in 1,4-dioxane (60 mL) were added potassium acetate (3.73 g, 7 38.0 mmol) and bis(pinacolato)diboron (4.82 g, 18.98 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this mixture was added PdCl2(dppf) (0.926 g, 1.265 mmol) and degassing was continued for another 2 min. The reaction mixture was then heated at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a crude residue which was purified by MPLC (manually packed filter cartridge, SiO2 230-400 mesh; 100% EtOAc) to give 9 as a pink solid. Yield: 3.5 g (49%). LC-MS: Calcd. for C ₁₉ H ₂₆ BN ₃ O ₃ : 355.25, Observed: 356.3 [M+1] ⁺ Step -7 :

To a stirred solution of 10 (1.3 g, 2.78 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added 9 (1.479 g, 4.16 mmol) and tripotassium phosphate (1.768 g, 8.33 mmol) (room temperature). The reaction mixture was degassed with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf) (0.203 g, 0.278 mmol) and degassed for another 2 min. The resulting reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with water (60 mL) and extracted with 10% MeOH/DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by MPLC (manually packed filter cartridge, SiO2 230-400 mesh; 20% MeOH/DCM) to give 11 as a brown solid. Yield: 1.2 g (66%). LC-MS: Calcd. for C ₃₃ H ₃₉ N ₅ O ₄ : 569.70, Observed: 570.0 [M+1] ⁺ Step -8 :

To a stirred solution of 11 (1.4 g, 2.457 mmol) in MeOH (25 mL) was added p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with 10% NaHCO ₃ solution (10 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material, which was purified by reverse phase preparative HPLC (column: YMC, C18, 250*mM; solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 20 as a white solid. Yield: 350 mg (29%). LC-MS: Calculated for C ₂₈ H ₃₁ N ₅ O ₃ : 485.58, Observed: 486.2 [M+1] ⁺ Example A9 : Synthesis of Compound 21 Step 1 :

To a stirred solution of 1 (1 g, 2.028 mmol) in MeCN (4 mL) and water (4 mL) were added K ₂ CO ₃ (0.841 g, 6.09 mmol) and 2 (0.818 g, 2.84 mmol) (room temperature). The resulting reaction mixture was purged with nitrogen for 2 min. To this reaction mixture was added PdCl ₂ (dtbpf) (0.132 g, 0.203 mmol) and the resulting reaction mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was diluted with ice-cold water (8 mL) and extracted with 5% MeOH/DCM (16 mL×3). The combined organic extracts were washed with brine (8 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by MPLC (manually packed filter cartridge; SiO2 230-400 mesh; 5% MeOH/DCM) to afford 3 as a brown viscous solid. Yield: 500 mg (41%) LC MS: Calcd. for C31H38N2O4: 502.65, Observed: 503.2 [M+1] ⁺ Step 7 :

To a stirred solution of 3 (125 mg, 0.249 mmol) in MeOH (30 mL) was added toluene-4-sulfonic acid monohydrate (142 mg, 0.746 mmol) (at 0 °C). The resulting reaction mixture was allowed to warm to room temperature and stirred for 3 h. Three more batches were performed with 125 mg of 3. After the reaction was complete, all batches were quenched with saturated NaHCO3 solution at 0 °C. Subsequently, all reaction mixtures were combined for work-up and purification. The combined aqueous layers were extracted with DCM (100 mL×3). The combined organic extracts were washed with saturated NaHCO ₃ solution (2×6 mL), saline solution (6 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude residue, which was purified by reverse phase preparative HPLC to obtain compound 21 as a white solid. Yield: 140 mg (combined yield of four batches). LC MS: Calculated value for C26H30N2O3: 418.23, Observed value: 419.0 [M+1] ⁺ . SFC purity: 97.9%. The product is a mixture of trans non-mirror isomers at the tail. Example A10 : Synthesis of compound 22 Step 1 :

To a stirred solution of 1 (0.5 g, 1.068 mmol) in acetonitrile (3 mL) and water (2 mL) were added 2 (0.400 g, 1.388 mmol) and K2CO3 (0.443 g, 3.20 mmol) (room temperature). The resulting reaction mixture was purged with nitrogen for 5 min. To this reaction mixture was added _PdCl2 (dtbpf) (0.070 g, 0.107 mmol) at room temperature and the resulting reaction mixture was stirred at 85°C for 16 h. The reaction was cooled to room temperature, diluted with water (10 mL) and extracted with 10% MeOH/DCM (25 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed filter cartridge; SiO ₂ 230-400 mesh; 3% MeOH/DCM) to afford 3 as a light red solid. Yield: 0.2 g (33%). LCMS: Calcd. for C ₃₁ H ₃₈ N ₂ O ₄ : 502.66, Observed: 503.4 [M+1] ⁺ Step 2 :

To a stirred solution of 3 (0.15 g, 0.298 mmol) in MeOH (25 mL) was added p-toluenesulfonic acid monohydrate (0.170 g, 0.895 mmol) (at 0 °C). The resulting reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO ₃ solution (10 mL) (at 0 °C). Two more batches were made using 150 mg and 100 mg of 3. All batches were combined for work-up and purification. All batches were combined and extracted with 5% MeOH/DCM (100 mL×3). The combined organic extracts were washed with saturated NaHCO ₃ solution (3×10 mL), brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue which was purified by preparative HPLC to give compound 22 as a white solid. Three combined batches of 3×150 mg were used for removal of protecting groups for workup and preparative HPLC purification. Yield: 120 mg (combined yield of three batches). LCMS: Calcd. for C ₂₆ H ₃₀ N ₂ O ₃ : 418.23, Observed: 419.4 [M+1] ⁺ Example A11 : Synthesis of compound 23 Step -1 :

To a stirred solution of 2 (1.7 g, 3.63 mmol) in acetonitrile (50 mL) and water (10 mL) was added Ester 1 (2.120 g, 5.44 mmol) and K2CO3 (1.505 g, 10.89 mmol) were added. The mixture was purged with nitrogen for 10 min. PdCl2(dtbpf) (0.237 g, 0.363 mmol) was added to the reaction mixture and purging was continued for another 2 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with water (30 mL) and extracted with 10% MeOH/DCM (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed filter cartridge; SiO2 230-400 mesh; 15% MeOH/DCM) to afford 3 as a brown solid. Yield: 1.5 g (66%) LC-MS: Calcd. for C ₃₅ H ₄₅ N ₃ O ₆ : 603.76, Observed: 604.2 [M+1] ⁺ Step -2 :

To a stirred solution of 3 (1.5 g, 2.484 mmol) in DCM (30 mL) was added HCl (2 M in ether, 29.8 mL, 59.6 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure to afford 4 as a brown solid. Yield: 1.2 g (93%). LC-MS: Calcd. for C ₂₅ H ₂₉ N ₃ O ₃ : 419.52 (for parent compound), Observed: 420.0 [M+1] ⁺ Step -3 :

To a stirred solution of 4 (1.5 g, 3.29 mmol) in DMF (25 mL) were added triethylamine (3.33 g, 32.9 mmol) and iodoacetonitrile (0.824 g, 4.93 mmol) (room temperature). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/DCM (100 mL×2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (column: Shimpack, C18 (250*20 mm), 5 µm; solvent: 10 mM ammonium bicarbonate in water and ACN) to give compound 23 as a white solid. Yield: 0.172 g (11%). LC-MS: Calcd. for C ₂₇ H ₃ 0N ₄ O ₃ : 458.56, Observed: 459.0 [M+1] ⁺ . The tail has a trans geometry. Example A12 : Synthesis of Compounds 24 and 25 Step -3 : ( ± ) -4 SFC separation

( ± ) -4 isomers (14 g) were separated by SFC (column: LUXA1-(250*30) mm, 5 μm; solvent: CO ₂ : 0.5% isopropylamine/MeOH [95:05]). The eluted fraction was concentrated under reduced pressure to give 4- isomer -1 (retention time = 3.08 min) and 4- isomer -2 (retention time = 3.25 min). Yield = 4- isomer -1 : 3.5 g (ee = 100%) and 4- isomer -2 : 2.7 g (ee = 90%). Both isomers were used separately for further transformation. Compound 24: Step -4 :

To the following solution: 4- isomer -1 (3.5 g, 12.81 mmol) in dioxane (30 mL) were added potassium acetate (2.52 g, 25.6 mmol) and bis(pinacolato)diboron (4.88 g, 19.22 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (0.47 g, 0.641 mmol) and purged for another 2 min. The reaction mixture was stirred at 100 °C for 3 h. The inorganic solid was filtered through a celite pad and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a crude residue. The crude residue was purified by MPLC (manually packed _SiO2 cartridge, 100-200 mesh; 10% EtOAc/hexanes) to afford 5 -isomer- 1 as an off-white solid. Yield: 4 g (88%) Step -5 : To the following solution: 5- isomer -1 (2 g, 6.41 mmol) in ACN (15 mL) and water (10 mL) were added 6 (2 g, 4.27 mmol) and K2CO3 (1.77 g, 12.81 mmol) (room temperature). The reaction mixture was purged with nitrogen for 10 min. To this reaction mixture was added PdCl2(dtbpf) (0.28 g, 0.427 mmol) and purging was continued for another 2 min. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with 10% MeOH/DCM (50 mL×2). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by MPLC (manually packed SiO ₂ cartridge, 100-200 mesh; 5% MeOH/DCM) to give 7- isomer -1 as a brown solid. Yield: 1.3 g (53%). LC-MS: Calculated for C31H38N2O6: 534.65, Observed: 535.2 [M+1] ⁺ Step 6 :

To a stirred solution of 7- isomer -1 (0.3 g, 0.56 mmol) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (0.32 g, 1.68 mmol) (at 0 °C). The reaction mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure, and the resulting residue was alkalized with 10% NaHCO ₃ solution and extracted with 10% MeOH/DCM (20 mL×2). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (manually packed 100 g cartridge; SiO 2 230-400 mesh; 6% MeOH/DCM) to give compound 24 as an off-white solid. Yield = 0.12 g (46%) SFC : t _R = 3.82 min. LC-MS: Calcd. for C26H30N2O5: 450.535, Observed: 451.2 [M+1] ⁺ 1H-NMR (400 MHz, DMSO-d6): δ 7.64 (d, J = 8.80 Hz, 2H), 7.61 (d, J = 8.80 Hz, 2H), 7.48 (d, J = 8.40 Hz, 2H), 7.32 (app d, J = 1.20 Hz, 1H), 7.06 (d, J = 8.80 Hz, 2H), 6.85 (s, 1H), 6.56 (dd, J = 6.40, 16.00 Hz, 1H), 6.47 (d, J = 16.00 Hz, 1H), 5.26-5.22 (m, 3H, 2 protons exchanged with D2O), 4.95-4.94 (m, 1H), 4.90-4.87 (m, 1H), 4.05-3.95 (m, 2H), 3.84-3.81 (m, 1H), 3.83 (t, J = 5.60 Hz, 2H), 3.78-3.74 (m, 2H), 3.35 (s, 3H, combined with solvent water), 1.50 (d, J = 6.40 Hz, 3H). SFC showed dr = 95.4: 2.2; the stereochemistry of the tail is unknown. Compound 25 : Step -4 :

To the following solution: 4- isomer -2 (2.7 g, 9.89 mmol) in dioxane (30 mL) was added potassium acetate (1.94 g, 19.77 mmol) and bis(pinacolato)diboron (3.77 g, 14.83 mmol) (room temperature). The resulting mixture was purged with nitrogen for 10 min. To this reaction mixture was added PdCl2(dppf) (0.36 g, 0.49 mmol) and purging was continued for another 2 min. The reaction mixture was stirred at 100 °C for 3 h. The inorganic solid was filtered through a celite pad and washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and the resulting crude residue was purified by MPLC (manually packed _SiO2 cartridge, 100-200 mesh; 30% EtOAc/hexanes) to afford 5 -isomer- 2 as an off-white solid. Yield: 3.7 g (97%) Step -5 :

To the following solution: 5- isomer -2 (2 g, 6.41 mmol) in ACN (15 mL) and water (10 mL) were added 6 (2 g, 4.27 mmol) and K2CO3 (1.77 g, 12.81 mmol) (room temperature). The reaction mixture was purged with nitrogen for 10 min. PdCl2(dtbpf) (0.28 g, 0.427 mmol) was added to this reaction mixture and purging was continued for another 2 min. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH/DCM (100 mL×2). The combined organic layers were washed with saline solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by MPLC (manually packed SiO ₂ cartridge, 100-200 mesh; 5% MeOH/DCM) to give 7- isomer -2 as a light brown solid. Yield: 1.3 g (55%). LC-MS: Calculated for C 31 H 38 N 2 O 6: 534.65, Observed: 535.2 [M+1] ⁺ Step 6 :

To a stirred solution of 7- isomer -2 (0.3 g, 0.56 mmol) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (0.32 g, 1.68 mmol) (at 0 °C) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, and the resulting residue was alkalized with 10% NaHCO ₃ solution (15 mL) and extracted with 10% MeOH/DCM (50 mL×2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (manually packed 100 g cartridge; SiO2 230-400 mesh; 8% MeOH/DCM) to give compound 25 as an off-white solid. SFC: t _R =4.25 min. Yield = 80 mg (32%). LC-MS: Calcd. for C26H30N2O5: 450.535, Observed: 451.2 [M+1] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 7.64 (d, J = 8.80 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.48 (d, J = 8.40 Hz, 2H), 7.32 (app d, J = 0.80 Hz, 1H), 7.06 (d, J = 8.80 Hz, 2H), 6.85 (app d, J = 0.80 Hz, 1H), 6.56 (dd, J = 6.40, 16.00 Hz, 1H), 6.47 (d, J = 15.60 Hz, 1H), 5.35-5.22 (m, 3H, 2 protons exchanged with D2O), 4.95-4.94 (m, 1H), 4.90-4.85 (m, 1H), 4.05-3.99 (m, 2H), 3.95-3.91 (m, 1H), 3.83 (t, J = 5.60 Hz, 2H), 3.78-3.74 (m, 2H), 3.35 (s, 3H, combined with solvent water), 1.50 (d, J = 6.40 Hz, 3H). SFC showed dr = 89.5 : 4.4; the stereochemistry of the tail is unknown Example A13 : Synthesis of compounds 26 and 27 Step 1 :

To the following solution: 1 (1 g, 2.135 mmol) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (1.218 g, 6.41 mmol) (at 0°C) and the resulting reaction mixture was stirred at room temperature for 2 h. The volatiles in the reactant were concentrated under reduced pressure. The resulting crude residue was alkalized with saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with 10% MeOH/DCM (15 mL×2). The combined organic extracts were dried over _{anhydrous Na2SO4} , filtered and concentrated to give 2 as a brown solid. Yield: 0.7 g (74%). LC-MS: Calculated for C15H17IN2O2: 384.2, Observed: 385.2 [M+1] ⁺ Synthesized 4- isomer -1 and 4- isomer -2 Step 1a :

To a stirred solution of 1-bromo-4-iodobenzene (2, 32.9 g, 116 mmol) in THF (340 mL), isopropylmagnesium chloride (58.1 mL, 116 mmol) (at 0°C) was added dropwise, and stirred at 0°C for 2 h. To a stirred solution of 3,4-ethoxytetrahydrofuran ( 1 , 5 g, 58.1 mmol) in THF (60 mL) was added copper (I) iodide (1.106 g, 5.81 mmol) (at 0°C). To this reaction mixture was added the above solution dropwise at -78°C. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL) and extracted with EtOAc (250 mL×2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (using a hand-packed filter cartridge, SiO ₂ 230-400 mesh; 20% EtOAc/hexane) to give racemic (±)- 3 as a white solid. Yield: 10 g (70 %) Step 2a :

10 g (±) -3 was separated by SFC (column: LUX I_A3 (250×30) mm, 5 μm; solvent: CO2: 0.5% isopropylamine/MeOH [60:40]) to give 3- isomer -1 ( t _R = 3.0 min) and 3- isomer - 2 ( t _R = 4.7 min) as off-white solids. Yield: 3- isomer -1 = 4 g and 3- isomer -2 = 3.4 g. SFC purity = 3 -isomer -1: 97.5% (ee = 95%) and 3- isomer -2: 98.5% (ee = 97%). The two isomers ( 3- isomer -1 and 3- isomer -2 ) were used independently for further transformations. Step 3a :

To a stirred solution of 3- isomer -1 (1 g, 4.11 mmol) in 1,4-dioxane (20 mL) were added bis(pinacolyl)diboron (1.567 g, 6.17 mmol) and potassium acetate (1.211 g, 12.34 mmol) (room temperature). The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf) (0.301 g, 0.411 mmol). The mixture was stirred at 100 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product. The crude residue was purified by MPLC (manually packed filter cartridge, SiO 2 230-400 mesh; 30% EtOAc/hexane) to give 4- isomer -1 as a light yellow gum. Step 2

To a stirred solution of 2 (250 mg, 0.651 mmol) in acetonitrile (3 mL) and water (3 mL) were added 4- isomer -1 (283 mg, 0.976 mmol) and K2CO3 (270 mg, 1.952 mmol) (room temperature). The resulting mixture was purged with nitrogen for 5 min. PdCl2(dtbpf) (42.4 mg, 0.065 mmol) was added to the reaction mixture and purging was continued for another 2 min. The resulting reaction mixture was irradiated with microwaves at 80 °C for 1 h. The volatiles in the reaction were concentrated under reduced pressure. The reaction mixture was quenched with water (20 mL) and extracted with 10% MeOH/DCM (10 mL×2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: SHIMPAK (C18 X 150 mm) 5 µm; solvent: 10 mM ammonium bicarbonate in water and acetonitrile) to give compound 26 as a white solid. Yield: 60 mg (22%). LC-MS: Calculated for C25H28N2O4: 420.5, Observed: 421.2 [M+1] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 7.64-7.62 (m, 4H), 7.50 (d, J = 8.00 Hz, 2H), 7.35 (d, J = 8.40 Hz, 2H), 7.30 (app d, J = 1.20 Hz, 1H), 6.83 (app d, J = 0.80 Hz, 1H), 6.58 (dd, J = 6.80, 16.00 Hz, 1H), 6.47 (d, J = 16.00 Hz, 1H), 5.28-5.22 (m, 4H, 3 protons exchanged with D2O), 4.89-4.86 (m, 1H), 4.26-4.24 (m, 1H), 4.17 (t, J = 7.20 Hz, 1H), 3.98 (dd, J = 5.60, 9.20 Hz, 1H), 3.83 (t, J = 5.60 Hz, 2H), 3.75 (dd, J = 6.00, 8.40 Hz, 1H), 3.58 (dd, J = 4.00, 9.00 Hz, 1H), 3.33-3.21 (m, 1H), 1.50 (t, J = 6.40 Hz, 3H). Stereochemistry of tail unknown; dr = 90.3 : 1.1 (based on retention time of non-mirror isomer; Lux Amylose-1_0.5% IPAm/MeOH t _R = 8.43 min)

Compound 27 was prepared using 4- isomer -2 by the same procedure as compound 26 to give a white solid. LC-MS: Calcd. for C25H28N2O4: 420.5, Observed: 421.2 [M+1] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 7.64-7.62 (m, 4H), 7.50 (d, J = 8.00 Hz, 2H), 7.35 (d, J = 8.40 Hz, 2H), 7.30 (app d, J = 1.20 Hz, 1H), 6.83 (app d, J = 0.80 Hz, 1H), 6.58 (dd, J = 6.40, 16.00 Hz, 1H), 6.47 (d, J = 16.00 Hz, 1H), 5.30 (m, 3H, exchanged with D2O), 5.23 (t, J = 5.60 Hz, 1H), 4.89-4.86 (m, 1H), δ 4.24 (m, 1H), 4.17 (dd, J = 7.20, 8.40 Hz, 1H), 3.98 (dd, J = 5.60, 9.20 Hz, 1H), 3.83 (t, J = 5.60 Hz, 2H), 3.75 (dd, J = 6.00, 8.80 Hz, 1H), 3.58 (dd, J = 3.60, 9.20 Hz, 1H), 3.25-3.21 (m, 1H), 1.50 (t, J = 6.40 Hz, 3H). The stereochemistry of the tail is unknown; dr = 96.8:0.2 (based on the retention time of the non-mirror isomer; Lux Amylose-1_0.5% IPAm/MeOH t _R = 11.27 min). Example B-1 : Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound of formula (I) or a pharmaceutically acceptable salt or solvent thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer and an acid or base are added as appropriate to adjust the pH. The mixture is incorporated into a unit dosage form suitable for administration by injection. Example B-2 : Oral solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is added to water (and optionally a solubilizer, optionally a buffer and a taste-masking formulation) to provide a 20 mg/mL solution. Example B-3 : Oral Tablets

Tablets are prepared by mixing 20-50% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose and 1-10% by weight of magnesium stearate or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablet is maintained at 100 to 500 mg. Example B-4 : Oral Capsules

To prepare a pharmaceutical composition for oral delivery, 10 to 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with starch or other suitable powder blends. The mixture is incorporated into oral dosage units such as hard gelatin capsules, which are suitable for oral administration.

In another embodiment, 10 to 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is placed in a No. 4 capsule or a No. 1 capsule (hydroxypropyl methylcellulose or hard gelatin) and the capsule is closed. II. Bioassessment Example C-1 : In vitro analysis of screening compounds and metalloprotein modulators Bacterial susceptibility test

Minimum inhibitory concentrations (MICs) were determined by culture medium microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Briefly, organism suspensions were adjusted to a final inoculum between 3 × 10 ⁵ and 7 × 10 ⁵ colony forming units (CFU) /mL. Drug dilutions and inoculum were made in sterile, cation-adjusted Miller-Hinton broth (Beckton Dickinson). In a well, a 100 μL volume of inoculum was mixed with a 2-fold serial dilution of drug in 2 μL DMSO. All inoculated microdilution plates were incubated at 35°C in ambient air for 18-24 h. After incubation, the lowest drug concentration that prevented visible growth (OD600 nm < 0.05) was recorded as the MIC. The assay performance was monitored by using laboratory quality control strains and compounds with defined MIC profiles according to CLSI guidelines.

Exemplary in vitro assay data for selected bacteria of the compounds in the examples of the present invention are provided in Table A. The compounds of the present invention do not inhibit Staphylococcus aureus (MIC value > 32 µg/mL). Table A: Compound No. E. coli ATCC25922 MIC (µg/mL) Klebsiella pneumoniae ATCC13883 MIC (µg/mL) Pseudomonas aeruginosa ATCC27853 MIC (µg/mL) Pseudomonas aureus PAO1 MIC (µg/mL) 1 1 0.5 2 4 2 2 0.5 1 4 3 3 2 4 8 4 4 2 2 8 7 1 2 16 8 13 0.50 2 4 2 14 1 2 4 2 15 1 2 4 2 16 1 4 4 2 17 0.5 1 8 2 18 4 8 8 8 19 0.18 0.25 8 3 20 2 4 >32 16 twenty one 0.25 0.25 8 4 twenty two 0.25 0.50 2 1.5 twenty three 0.5 1 4 2 twenty four 1 2 16 4 25 1 2 8 2 26 0.5 2 16 8 27 0.5 1 8 2 LpxC binding assay

_IC50 values against E. coli and P. aureus LpxC were determined using Rapid Fire MS analysis as described previously (J. Med. Chem. 2012, 55, 1662-1670).

The examples and embodiments described herein are for illustrative purposes only and various modifications or variations proposed by persons skilled in the art will be included within the spirit and scope of this application and the scope of the accompanying patent applications.

Claims (102)

A compound of formula (I): Formula (I) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ¹ is C ₁ -C ₄ alkyl; R ^2a and R ^2b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ⁴ is hydrogen or C ₁ -C ₄ alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or halogen; each R ⁷ is independently halogen or C ₁ -C ₄ alkyl; each R ⁸ is independently halogen or C ₁ -C ₄ alkyl; L wherein: ^X1 and ^X2 are independently selected from: -O-, -N(R10)-, ^-S- , -S(=O)-, _-S (=O) _2- and -S(=O)(= ^NR10 )-, wherein: ^R10 _is hydrogen or _{C1 -} ^C6 alkyl; ^R9 is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or ^{heterocycloalkyl} is unsubstituted or substituted with 1, 2 _or 3 ^R11 groups, wherein: each ^R11 _is independently selected from: halogen, ^-OR12 , -N( ^R12 ) ² _, -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pendooxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C ₆ cycloalkyl, and 4 to 6 membered heterocycloalkyl, which are unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, pendooxy, 4 to 6 membered heterocycloalkyl or C ₁ -C ₄ alkyl, which are unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ¹² attached to the same nitrogen are combined to form a 4-6 membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ and pendant oxygen; s is 0, 1 or 2; and t is 0, 1 or 2; and wherein when L ¹ is -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, and X ¹ or X ² is -N(R ¹⁰ )-, -S-, -S(═O)-, -S(═O) ₂ - or -S(═O)(═NR ¹⁰ )-, then R ⁹ is further selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ heteroalkyl, wherein the alkyl and heteroalkyl are unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups; wherein at least one of the following situations exists: (i) s is 1 or 2, and at least one R ⁷ is halogen; (ii) t is 1 or 2, and at least one R ⁸ is halogen; and (iii) the alkyl, heteroalkyl, cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl of R ⁹ is substituted with 1, 2 or 3 R ¹² groups, and at least one R ¹⁰ is halogen. The compound of claim 1, wherein at least one of R ⁷ , R ⁸ or R ¹² is -F. The compound of claim 2, wherein at least one R ⁷ or R ⁸ is -F. The compound of claim 2, wherein at least one R ¹² is -F. The compound of claim 1, wherein at least two of R ⁷ , R ⁸ or R ¹² are -F. The compound of claim 5, wherein at least two R ⁷ or R ⁸ are -F. The compound of claim 5, wherein at least two R ¹² are -F. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ¹ is -CH ₃ . The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ^2a is hydrogen; and R ^2b is hydrogen. The compound of any one of claims 1 to 9, wherein: R ⁴ is hydrogen. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁵ is hydrogen or -F. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: ^R6 is hydrogen or -F. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: each R ⁷ is -F. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: each R ⁸ is -F. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (IIa): Formula (IIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁶ is hydrogen or -F; each R ⁷ is -F; and each R ⁸ is -F. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (IIIa): Formula (IIIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁶ is hydrogen or -F; each R ⁷ is -F; and each R ⁸ is -F. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is -(C ₁ -C ₄ alkylene)-OH. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is -CH ₂ OH. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L ¹ is a bond, -(C ₁ -C ₄ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-, -N(H)-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NH)-. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L ¹ is a bond, -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are independently selected from: -O-. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: L ¹ is -O-. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -OCOR ¹² , pendoxy, phenyl, monocyclic heteroaryl, C ₁ -C 2 wherein: each R _{12 is} independently hydrogen _{, oxo} , 4 to ₆ membered heterocycloalkyl or C ₁ -C ₄ alkyl, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, -NH ₂ , -OMe ^, -N(CH 3 ) ₂ , -CO 2 H, -CONH ₂ , _{-SO 2} CH ₃ , phenyl, oxazolidinone and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) 2 , -CO ₂ H, -CONH 2 , -SO ₂ CH 3 , ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ . The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ¹² is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(=NH)NH ₂ and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group. A compound as claimed in any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: -F, -OH, -OCH ₃ and -NH ₂ . The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: L ¹ -R ⁹ are , or . The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: L ¹ -R ⁹ are , or . The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ¹ is -CH ₃ ; R ^2a and R ^2b are each hydrogen; R ³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH or -(C ₁ -C ₄ alkylene)-NH ₂ ; R ⁴ is hydrogen; each of R ⁵ and R ⁶ is a halogen; L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-; and R ⁹ is cyclopropyl, cyclopentyl, cyclohexyl or 4-8 membered heterocycloalkyl; wherein the cyclopropyl, cyclopentyl, cyclohexyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 R wherein: each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² _, -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ² R ¹² , -OCOR ¹² , pendooxy, phenyl, monocyclic heteroaryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ aminoalkyl, C ₃ -C ₆ cycloalkyl, and 4 to 6 membered heterocycloalkyl, which is unsubstituted or substituted with 1, 2 or 3 -OH groups; further wherein: each R ¹² is independently hydrogen, pendooxy, 4 to 6 membered heterocycloalkyl or C ₁ -C ₄ -alkyl, which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from the group consisting of: -F, -CN, -OH, _-NH2 , -OMe, -N( _CH3 ) ₂ , _-CO2H , _-CONH2 , _-SO2CH3 , phenyl, _{oxazolidinone} , and monocyclic heteroaryl, which 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} . The compound of claim 30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH; L ¹ is -X ¹ - or -X ² -(C ₁ -C ₄ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-; R ⁹ 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 ¹¹ groups, wherein: each R ¹¹ is independently selected from: halogen, -OH, -OMe, -N(R ¹² ) ₂ , -NHSO ₂ R ¹² and -CH ₂ CN; and each R ¹² is independently hydrogen, C ₁ -C ₂ alkyl or -C(═O)-C ₁ -C _2- alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazole. The compound of claim 30, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is CH ₂ OH; L ¹ and -O-; R ⁹ 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 ¹² groups, wherein: each R ¹² is independently selected from: -F, -OH, -OCH ₃ and -NH ₂ . The compound of claim 1, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (IV): Formula (IV) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; each R ⁷ and R ⁸ is independently -F, -Cl or C ₁ -C ₄ alkyl; L ¹ is -(C ₁ -C ₆ alkylene)-, -X ¹ - or -X ² -(C ₁ -C ₆ alkylene)-, wherein: X ¹ and X ² are each selected from: -O-, -N(R ¹⁰ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ¹⁰ )-, wherein: R ^{R 10} is hydrogen or C ₁ -C ₆ alkyl; each R ¹¹ is independently selected from: halogen, -OR ¹² , -N(R ¹² ) ₂ , -CO ₂ R ¹² , -CON(R ¹² ) ₂ , -CH ₂ N(R ¹² ) ₂ , -NHCOR ¹² , -NHSO ₂ R ¹² , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; further wherein: each R ¹² is independently hydrogen or C ₁ -C ₄ alkyl; s is 0, 1 or 2; t is 0, 1 or 2; and u is 0, 1 or 2. The compound of claim 33, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (V): Formula (V) or a pharmaceutically acceptable salt or solvent thereof. The compound of claim 33 or 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein s is 1 or 2; and at least one R ⁵ is -F. The compound of 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. The compound of 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. The compound of any one of claims 33 to 37, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein R ³ is -(C ₁ -C ₄ alkylene)-OH. The compound of any one of claims 33 to 37, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R ³ is -CH ₂ OH. The compound of claim 1, which is selected from: , , , , and ; or its pharmaceutically acceptable salt or solvent combination. A compound of formula (VI): Formula (VI) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²¹ is C ₁ -C ₄ alkyl; R ^22a and R ^22b are each independently hydrogen, halogen or C ₁ -C ₄ alkyl; R ²³ is hydrogen, -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; R ²⁴ is hydrogen or C ₁ -C ₄ alkyl; R ²⁵ is hydrogen or halogen; R ²⁶ is hydrogen or halogen; each of R ²⁷ and R ²⁸ is independently halogen or C ₁ -C ₄ alkyl; R ²⁹ is C ₁ -C C 1 -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(═O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy; wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C ₁ -C ₄ 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 following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C (= NH) NH ₂ , oxo, phenyl and monocyclic heteroaryl, which is unsubstituted or substituted with 1 or 2 groups selected from the following: -F, -CN, -OH, -NH ₂ , -OMe, -N (CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ and -SO ₂ CH ₃ ; or two R ³⁰ or two connected to the same nitrogen are combined to form a 4- to 6-membered heterocycloalkyl group, which is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: -F, -CN, -OH, _-NH2 , _-OMe , _-CO2H , _-CONH2 , _-SO2CH3 and pendoxy groups; ^L2 is a bond, -( _C1 - _C6 alkylene)-, ^-X3- or ^-X4- ( _C1 - _C6 alkylene)-, wherein: ^X3 and ^X4 are independently selected from: -O-, -N( ^R31 )-, -S-, -S(=O)-, -S(=O) _2- and -S(=O)(= ^NR31 )-, wherein: ^R31 is hydrogen or _C1 - _C6 alkyl; the proviso is that when ^L2 is a bond, -O- or -O-(C ^R29 is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted _{5 -} membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group; v is 0, 1 or 2; and w is 0, 1 or 2. The compound of claim 41, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²¹ is -CH ₃ . The compound of claim 41 or 42, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ^22a is hydrogen; and R ^22b is hydrogen. A compound as claimed in any one of claims 41 to 43, wherein: R ²⁴ is hydrogen. The compound of any one of claims 41 to 44, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: each R ²⁷ is independently -F, -Cl or -CH ₃ . The compound of any one of claims 41 to 44, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: each R ²⁷ is independently -F. The compound of any one of claims 41 to 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: each R ²⁸ is independently -F, -Cl or -CH ₃ . The compound of any one of claims 41 to 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: each R ²⁸ is independently -F. The compound of any one of claims 41 to 48, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (VIIa): Formula (VIIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof. The compound of any one of claims 41 to 48, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (VIIIa): Formula (VIIIa) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof. A compound as claimed in any one of claims 41 to 49, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: v is 1 or 2. A compound as claimed in any one of claims 41 to 49, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: v is 0. A compound as claimed in any one of claims 41 to 52, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein w is 1 or 2. A compound as claimed in any one of claims 41 to 52, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: w is 0. The compound of any one of claims 41 to 54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-; and X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ ). The compound of claim 55, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is hydrogen or -(C ₁ -C ₄ alkylene)-OH. The compound of claim 55, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -(C ₁ -C ₄ alkylene)-OH. The compound of claim 55, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -CH ₂ OH. The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ²⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl or 4-8 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 ³⁰ , -N(R ³⁰ ) 2 , -CO 2 R 30 , -CON(R 30 ) 2 , -CH 2 N(R 30 ) ₂ , -NHCOR 30 , -NHSO ₂ R 30 , -CH ₂ CN, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 heteroalkyl, C 3 -C 6 cycloalkyl or 4-8 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 ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) 2 , -CH 2 N(R ₃₀ ) ₂ , -NHCOR ₃₀ , -NHSO 2 _R ³⁰ , -CH ₂ CN, wherein: each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C (= O) -C _{1 -C 4} alkyl or a 4- to _{6 -} membered heterocycloalkyl group, wherein the alkyl or _{heterocycloalkyl} group is unsubstituted or substituted _{with 1} , ₂ , 3 or 4 groups independently selected from the following: -F, -CN, -OH, -CH ₂ OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , -SO ₂ CH ₃ , -C(=NH)NH ₂ , a pendoxy group, a phenyl group, and a monocyclic heteroaryl group, which are unsubstituted or substituted with 1 or 2 groups selected from the group consisting of -F, -CN, -OH, -NH ₂ , -OMe, -N(CH ₃ ) ₂ , -CO ₂ H, -CONH ₂ , and -SO ₂ CH ₃ . The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ²⁹ 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 ¹¹ groups independently selected from the following: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ hydroxyalkyl and C ₁ -C ₄ methoxyalkyl; and each R ³⁰ is independently hydrogen, C ₁ -C ₄ alkyl, -C(=O)-C ₁ -C 4 _4- membered 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, -CO ₂ H, -C(=NH)NH ₂ and 5-membered monocyclic heteroaryl, which is unsubstituted or substituted with 1 -CONH ₂ group. The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ²⁹ 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 ³⁰ ) ₂ , -NHSO ₂ R ³⁰ and -CH ₂ CN; and each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl or -C(=O)-C ₁ -C ₂ alkyl, wherein the alkyl group is unsubstituted or substituted with 1 or 2 groups independently selected from -CN, -OH and oxadiazolyl. The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²⁹ 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, -OCH ₃ and -NH ₂ . The compound of claim 41, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (IX): Formula (IX) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -(C ₁ -C ₄ alkylene)-OH, -(C ₁ -C ₄ alkylene)-NH ₂ , -(C ₃ -C ₆ cycloalkylene)-OH or -(C ₃ -C ₆ cycloalkylene)-NH ₂ ; each R ²⁷ and R ²⁸ is independently -F, -Cl or C ₁ -C ₄ alkyl; L ² is -X ³ - or -X ⁴ -(C ₁ -C ₆ alkylene)-; and X ³ and X ⁴ are each independently selected from: -N(R ³¹ )-, -S-, -S(=O)-, -S(=O) ₂ - and -S(=O)(=NR ³¹ ); R ³¹ is hydrogen or C ₁ -C ₆ alkyl; Each R ³² is independently selected from: halogen, -OR ³⁰ , -N(R ³⁰ ) ₂ , -CO ₂ R ³⁰ , -CON(R ³⁰ ) ₂ , -CH ₂ N(R ³⁰ ) ₂ , -NHCOR ³⁰ , -NHSO ₂ R ³⁰ , -CH ₂ CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, -C(=O)-C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ methoxyalkyl, C ₁ -C ₄ aminoalkyl and pendoxy group; further wherein: each R ³⁰ is independently hydrogen or C ₁ -C ₄ alkyl; v is 0, 1 or 2; w is 0, 1 or 2; and y is 0, 1 or 2. The compound of claim 63, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, has the structure of formula (X): Formula (X) or a pharmaceutically acceptable salt, solvent or stereoisomer thereof. The compound of claim 63 or 64, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: L ² is -N(R ³¹ )- or -S-. The compound of any one of claims 63 to 65, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -(C ₁ -C ₄ alkylene)-OH. The compound of any one of claims 63 to 66, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ²³ is -CH ₂ OH. A compound as claimed in any one of claims 63 to 67, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: w and v are each 0. The compound of any one of claims 41 to 54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^L2 is a bond, -O- or -O-( _C1 - _C6 alkylene)-; and ^R29 is an unsubstituted or substituted 3- to 6-membered sulfur-containing heterocycloalkyl group, an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group, an unsubstituted or substituted 7- to 8-membered heterocycloalkyl group, an unsubstituted or substituted 5-membered nitrogen-containing heterocycloalkyl group, an unsubstituted or substituted aziridinyl group, an unsubstituted or substituted oxirane group or an unsubstituted or substituted cyclohexyl group. The compound of claim 69, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: ^R29 is an unsubstituted or substituted 3-6-membered sulfur-containing heterocycloalkyl group or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group. The compound of claim 69, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: ^R29 is an unsubstituted or substituted 5-membered sulfur-containing heterocycloalkyl group or an unsubstituted or substituted 6-membered oxygen-containing heterocycloalkyl group. The compound of claim 69, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: ^R29 is unsubstituted or substituted tetrahydrothiophene-1-oxide or unsubstituted or substituted tetrahydropyran. The compound of claim 69, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: R ¹⁷ is , or . The compound of any one of claims 69 to 73, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein: ^L2 is -O-. The compound of claim 41, which is selected from: (*racemic-trans), , , , , , , (*racemic-cis) and (*racemic-trans), or a pharmaceutically acceptable salt, solvent or stereoisomer thereof. A compound selected from: (*racemic-trans), , , (*racemic-cis), (*racemic-trans), (*racemic-trans), , (*racemic-trans), , , and , or a pharmaceutically acceptable salt, solvent or stereoisomer thereof. A compound selected from: (*racemic-trans), , , (*racemic-cis), (*racemic-trans), (*racemic-trans), , (*racemic-trans), , , and . A pharmaceutical composition comprising the compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient. A method for treating or preventing Gram-negative bacterial infection in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition of claim 78. The method of claim 79, wherein the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa . The method of claim 79, wherein the Gram-negative bacterial infection is a respiratory tract infection. The method of claim 81, wherein the respiratory tract infection is pneumonia. The method of claim 82, wherein the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. A method for treating or preventing Pseudomonas aeruginosa infection in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition of claim 78. The method of any one of claims 79 to 84, wherein the patient has been identified as having lung disease. The method of claim 85, wherein the lung disease is a structural lung disease. The method of claim 85 or 86, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease, or a combination thereof. The method of any one of claims 79 to 87, wherein the administration is to treat an existing infection. The method of any one of claims 79 to 87, wherein the administration is provided in a prophylactic form. A method as claimed in any one of claims 79 to 89, wherein the compound as claimed in any one of claims 1 to 77, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition as claimed in claim 78 is administered in the form of a solution by inhalation, intravenous injection or intraperitoneal injection. A compound according to any one of claims 1 to 77 for use as a therapeutically active substance. A compound according to any one of claims 1 to 77, which is used for treating or preventing Gram-negative bacterial infections. The compound of claim 92, wherein the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa. The compound of claim 92, wherein the Gram-negative bacterial infection is a respiratory tract infection. The compound of claim 94, wherein the respiratory tract infection is pneumonia. The compound of claim 95, wherein the pneumonia is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. A compound according to any one of claims 1 to 77, which is used for treating or preventing Pseudomonas aeruginosa infection. The compound of any one of claims 92 to 97, wherein the patient has been identified as having a lung disease. The compound of claim 98, wherein the lung disease is structural lung disease. The compound of claim 98 or 99, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destructive lung disease, or a combination thereof. A use of a compound according to any one of claims 1 to 77 for preparing a medicament for treating or preventing Gram-negative bacterial infection. A use of a compound as claimed in any one of claims 1 to 77 for treating or preventing Gram-negative bacterial infection.