Macrocyclic compounds having farnesyltransferase inhibitory activity

Abstract

The present invention relates to macrocyclic compounds of any one of Formula (I), or a pharmaceutically acceptable form thereof, pharmaceutical compositions comprising the same, methods of preparing the same, and methods of treating cancer dependent on a famesylated protein, using the same.

Description

MACROCYCLIC COMPOUNDS AND COMPOSITIONS, AND METHODS OF PREPARING AND USING THE SAME 1. CROSS REFERENCE

[0001] This application claims the benefit of priority from Chinese Application No. 202111442658.4, filed November 30, 2021, U.S. Provisional Application No. 63 / 285,412, filed December 2, 2021, Chinese Application No. 202211471486.8, filed November 23, 2022, and U.S. Provisional Application No. 63 / 385,117, filed November 28, 2022. Each of the foregoing related applications, in its entirety, is incorporated herein by reference. 2. FIELD

[0002] The present invention relates to macrocyclic compounds, and pharmaceutical compositions comprising the same, that are useful in the treatment of cancer dependent on a farnesylated protein. The present invention also relates to methods of preparing such macrocyclic compounds, and pharmaceutical compositions comprising the same. This invention also relates to the use of such macrocyclic compounds, and pharmaceutical compositions comprising the same, in methods of inhibition of farnesyltransferase and methods of treating cancer dependent on a farnesylated protein. 3. BACKGROUND

[0003] Activated Ras oncogenes are frequently identified in cancerous tumors and transformed Ras protein is involved in the proliferation of cancer cells. Ras protein, the protein product of the ras oncogene, is a small GTPase that is important in signal transduction, cell growth, and cell proliferation. Shields, J. M., et al., Trends Cell Biol. 2000, 10, 147-154. Ras protein must associate (or bind) with the inner surface of the plasma membrane to transduce extracellular signals, which can lead to the proliferation of cancer cells.

[0004] To bind to the plasma membrane of the cell and transduce extracellular signals, the Ras protein must undergo several post-translational modifications, including famesylation of the cysteine in the CAAX box at the C-terminal end (where C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, E.K., et al., J. Clin. Oncol. 1999, 17, 3631-3652. The enzyme farnesyltransferase (FTase) recognizes the CAAX motif and famesylates the Ras protein (transferring a 15-carbon farnesyl isoprenoid from farnesyl diphosphate to the cysteine residue). Once farnesylated, the Ras protein can bind to the cell membrane. Inhibition of famesyltransferase, thereby blocking Ras protein cell membrane binding, represents a path to reducing cell proliferation of cancer cells and may offer potential clinical benefit to cancer patients. 4. SUMMARY

[0005] In one aspect, provided herein is a compound of Formula (I): Formula (I) or a pharmaceutically acceptable form thereof, wherein: the dashed line indicates a single bond or double bond between A1 and A2; A1 is independently N, NRla, CRlb, or -C(=O)-; A2 is independently N, NR2a, CR2b, or -C(=O)-; A3 is independently CR3 or N; A4 is CR8orN; A5 and A6 are each independently CR8 or N, or A5 and A6 taken together are O, NR9, or S; W is a C6-12 aryl or a 5-12 membered heteroaryl, each of which is optionally substituted with 1-4 R4 substituents; Y is a bond or a linker having a length of up to 6 atoms; Z is a Ce-12 aryl or a 5-12 membered heteroaryl, each of which is optionally substituted with 1-4 R5 substituents; Rla and R2a are each independently R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or-S(O)2NR10Rn; Rlb, R2b, R3, R5 and R8, at each occurrence, are each independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Ru, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or -NR10S(O)2NR10Ru; R4, at each occurrence, is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, -NR14R15, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C6-12 aryl, or 5-12 membered heteroaryl of the R4 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); R6 is CN, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10OR9, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Rn, -NR10S(O)2R9, -NR10C(NR10)NR10Rn, -S(O)PR9, -S(O)2NR10Rn, or -NR10S(O)2NR10R11; R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru and -NR10S(O)2NR10Ru; R9, at each occurrence, is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R9 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Ru, -NR10S(O)2R12, -S(O)PR12, -S(O)2NR10Rn, and -NR10S(O)2NR10R11; R10 and R11, at each occurrence, are each independently hydrogen, hydroxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, C6-12 aryl, or 5-12 membered heteroaryl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, C6-12 aryl, or 5-12 membered heteroaryl of the R10 and the R11 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci^ haloalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)OR13, -C(O)NR14R15, -NR14R15, -NR14C(O)R13, -NR14C(O)OR13, -NR14C(O)NR14R15, -NR14S(O)2R13, -S(O)pR13, -S(O)2NR14R15, and -NR14S(O)2NR14R15; R12, at each occurrence, is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R12 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(0)R13, -C(0)0R13, -0C(0)R13, -0C(0)0R13, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R13, -NR10C(O)OR13, -NR10C(O)NR10Ru, -NR10S(O)2R13, -S(O)PR13, -S(O)2NR10Rn, and -NR10S(O)2NR10Ru; R13, at each occurrence, is independently hydrogen, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, Cm hydroxyalkyl, C1.4 heteroalkyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or Ci-6 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; and each p is independently an integer of 0, 1 or 2.

[0006] In certain embodiments, the compound of Formula (I) is a compound of Formula (II): R1a A6 1 O A5^ Formula (II) wherein: W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together are O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S; Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; and R4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or a pharmaceutically acceptable form thereof.

[0007] In certain embodiments, the compound of Formula (I) is a compound of Formula Formula (III) wherein: W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S; Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; and R4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or a pharmaceutically acceptable form thereof.

[0008] In certain embodiments, the compound of Formula (I) is a compound of Formula (IV): Formula (IV) wherein: W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S; Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; and R4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or a pharmaceutically acceptable form thereof.

[0009] In certain embodiments, the compound of Formula (I) is a compound of Formula (V): Formula (V) wherein: W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together are O, NR4A, or S, or W2 and W3 taken together are O, NR4A, or S; Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together are O, NR5A, or S, or Z3 and Z4 taken together are O, NR5A, or S; and R4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or a pharmaceutically acceptable form thereof.

[0010] In certain embodiments, the compound of Formula (I) is a compound of Formula (VI): Formula (VI) wherein: W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together are O, NR4A, or S, or W2 and W3 taken together are O, NR4A, or S; Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together are O, NR5A, or S, or Z3 and Z4 taken together are O, NR5A, or S; and R4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or a pharmaceutically acceptable form thereof.

[0011] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein Y is a bond. In certain embodiments, Y is a linker having a length of up to 5 atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms. In certain embodiments, Y is in the direction of Z-Y-W (wherein Z refers to Z or the Z-containing ring and W refers to W or the W-containing ring as applicable in Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), and subformulae thereof). In certain embodiments, Y is a Ci-6 alkylene, wherein one or more -CH2- is optionally independently replaced by -0-, -C(O)-, -N(R10)-, -N(R10)C(O)-, -C(O)N(R10)-, -N(R10)C(O)N(Ru)-, -S(O)P- -N(R10)S(O)2-, -S(O)2N(R10)-, or -N(R10)S(O)2N(Rn)-. In certain embodiments, Y is -(CR16R17)q-, -(CR16R17)mO(CR16R17)n-, -(CR16R17)mC(O)(CR16R17)n- -(CR16R17)mN(R10)(CR16R17)n--(CR16R17)mN(R10)C(O)(CR16R17)n- -(CR16R17)mC(O)N(R10)(CR16R17)n--(CR16R17)mN(R10)C(O)N(Ru)(CR16R17)n- -(CR16R17)mS(O)p(CR16R17)n--(CR16R17)mN(R10)S(O)2(CR16R17)n- -(CR16R17)mS(O)2N(R10)(CR16R17)n-, or -(CR^R^mNCR^SCOhN^XCR1^^ wherein: R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, or 3-6 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

[0012] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a pyrimidinyl, each optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Ru, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru, or -NR10S(O)2NR10Ru

[0013] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein R6 is CN, R9, -OR9, -OC(O)R9, -OC(O)OR9, -NR10Rn, -NR10OR9, -NR10C(O)R9 or-NR10C(NR10)NR10Rn

[0014] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein R6 is CN, R9, -OR9, -OC(O)R9, -OC(O)OR9, -NR10Rn, -NR10OR9, or -NR10C(O)R9.

[0015] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein R10 and R11 together form a divalent group, such as -(CH2)x-, wherein x = 2-5, -CH2CH2OCH2CH2-, or -CH2CH2NR18CH2CH2-, wherein R18 is independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, 3-6 membered heterocycloalkyl, or 5-12 membered heteroaryl.

[0016] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein R6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3, or-NH(OCH3). In some embodiments, R6 is -NH(CH2CH2)C1, -NH(CH2CH2)F, orN-linked morpholino.

[0017] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein the compound has a MW of no more than 1,000 g / mol. In certain embodiments, the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol. In certain embodiments, the compound has a MW of no more than 600 g / mol. In certain embodiments, the compound has a MW of no more than 500 g / mol.

[0018] In certain embodiments, provided herein is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), wherein the compound is a racemate or a mixture of diasteromers, or a mixture of stereoisomers.

[0019] In certain embodiments, the compound of Formula (I) is a compound of Formula (la) or the compound of Formula (I) is a compound of Formula (lb): Formula (la) Formula (lb) or a pharmaceutically acceptable form thereof.

[0020] In certain embodiments, the compound of Formula (II) is a compound of Formula (Ila) or the compound of Formula (II) is a compound of Formula (lib):

[0021] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-l): Formula (II-1) or a pharmaceutically acceptable form thereof.

[0022] In certain embodiments, the compound of Formula (II-l) is a compound of Formula (IIa-1) or the compound of Formula (II-l) is a compound of Formula (IIb-1): R1a R5 Formula (IIa-1) R1a R5 Formula (IIb-1) or a pharmaceutically acceptable form thereof.

[0023] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-2): R1a R5 Formula (II-2) or a pharmaceutically acceptable form thereof.

[0024] In certain embodiments, the compound of Formula (II-2) is a compound of Formula (IIa-2) or the compound of Formula (II-2) is a compound of Formula (IIb-2): Formula (IIa-2)                    Formula (IIb-2) or a pharmaceutically acceptable form thereof.

[0025] In certain embodiments, the compound of Formula (III) is a compound of Formula (Illa) or the compound of Formula (III) is a compound of Formula (Illb): W1 Formula (Illb) Formula (Illa) or a pharmaceutically acceptable form thereof.

[0026] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-l): Formula (III-1) or a pharmaceutically acceptable form thereof.

[0027] In certain embodiments, the compound of Formula (III-1) is a compound of Formula (Illa-1) or the compound of Formula (III-1) is a compound of Formula (IIIb-1): R5 Formula (IIIb-1) Formula (Illa-1) or a pharmaceutically acceptable form thereof.

[0028] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-2): Formula (III-2) or a pharmaceutically acceptable form thereof.

[0029] In certain embodiments, the compound of Formula (III-2) is a compound of Formula (IIIa-2) or the compound of Formula (III-2) is a compound of Formula (IIIb-2): Formula (IIIa-2) or a pharmaceutically acceptable form thereof. Formula (IIIb-2)

[0030] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-3): Formula (III-3) or a pharmaceutically acceptable form thereof.

[0031] In some embodiments, the compound of Formula (III-3) is a compound of Formula (IIIa-3) or Formula (IIIb-3): Formula (IIIa-3) or a pharmaceutically acceptable form thereof.

[0032] In certain embodiments, the compound of Formula (IV) is a compound of Formula (IVa) or the compound of Formula (IV) is a compound of Formula (IVb): R1b R1b Formula (IVa)                    Formula (IVb) or a pharmaceutically acceptable form thereof.

[0033] In certain embodiments, the compound of Formula (IV) is a compound of Formula (IV-1): R1b R5 Formula (IV-1) or a pharmaceutically acceptable form thereof.

[0034] In certain embodiments, the compound of Formula (IV-1) is a compound of Formula (IVa-1) or the compound of Formula (IV-1) is a compound of Formula (IVb-1): Formula(IVa-l)           Formula(IVb-l) or a pharmaceutically acceptable form thereof.

[0035] In certain embodiments, the compound of Formula (IV) is a compound of Formula (IV-2): Formula (IV-2) or a pharmaceutically acceptable form thereof.

[0036] In certain embodiments, the compound of Formula (IV-2) is a compound of Formula (IVa-2) or the compound of Formula (IV-2) is a compound of Formula (IVb-2): R1b           R1b Formula (IVa-2)           Formula (IVb-2) or a pharmaceutically acceptable form thereof.

[0037] In some embodiments, the compound of Formula (V) is a compound of Formula (Va) or Formula (Vb): Formula (Va) or a pharmaceutically acceptable form thereof.

[0038] In some embodiments, the compound of Formula (V) is a compound of Formula (V-1): Formula (V-l) or a pharmaceutically acceptable form thereof.

[0039] In some embodiments, the compound of Formula (V-l) is a compound of Formula (Va-1) or Formula (Vb-1): R1b R1b R5 Formula (Vb-1) Formula (Va-1) or a pharmaceutically acceptable form thereof.

[0040] In some embodiments, the compound of Formula (VI) is a compound of Formula (Via) or Formula (VIb): Formula (VIb) Formula (Via) or a pharmaceutically acceptable form thereof.

[0041] In some embodiments, the compound of Formula (VI) is a compound of Formula (VI-1): Formula (VI-1) or a pharmaceutically acceptable form thereof.

[0042] In some embodiments, the compound of Formula (VI-1) is a compound of Formula (VIa-1) or Formula (VIb-1): Formula (VIa-1) R1b R6 Formula (VIb-1) or a pharmaceutically acceptable form thereof.

[0043] In certain embodiments, the compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (IIa-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, as disclosed herein, is a single enantiomer or a single diasteromer. In certain embodiments, a compound disclosed herein is a single enantiomer. In certain embodiments, a compound disclosed herein is an (R)-enantiomer. In certain embodiments, a compound disclosed herein has an enantiomeric excess of greater than 10% of the (R)-enantiomer, such as an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, of the (R)-enantiomer. In certain embodiments, a compound disclosed herein is an (S)-enantiomer. In certain embodiments, a compound disclosed herein has an enantiomeric excess of greater than 10% of the (S)-enantiomer, such as an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, of the (S)-enantiomer.

[0044] In certain embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (II), (II-l), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0045] In certain embodiments, the compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (IIa-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or a pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, as disclosed herein, is a farnesyltransferase inhibitor. In certain embodiments, the compound, or pharmaceutically acceptable form thereof, as disclosed herein, is a selective farnesyltransferase inhibitor, relative to inhibition of geranylgeranyl transferase type-1, such as geranylgeranyl transferase type-1.

[0046] In certain embodiments, the compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (IIa-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or a pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, as disclosed herein, is metabolically stable, for example, metabolically stable to liver metabolism in a subject, such as metabolically stable to liver metabolism in a human.

[0047] In certain embodiments, provided herein is a method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a compound of Formula (I), (II), (II-l), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In certain embodiments, provided herein is a method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (II-l), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (Illb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the method of inhibiting a famesyltransferase inhibits famesylation of H-Ras protein. In certain embodiments, the H-Ras protein has a mutation. In certain embodiments, the method of inhibiting a farnesyltransferase inhibits famesylation famesylation of N-Ras protein. In certain embodiments, the N-Ras protein has a mutation.

[0048] In certain embodiments, provided herein is a method of treating cancer dependent on a famesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (II-l), (11-2), (III), (III-l), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (Hb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, to the subject having cancer dependent on a famesylated protein. In certain embodiments, provided herein is a method of treating cancer dependent on a famesylated protein in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (II-l), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (Hb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (Illb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent to the subject having cancer dependent on a famesylated protein. In certain embodiments, the cancer dependent on a famesylated protein is a solid tumor. In certain embodiments, the cancer dependent on a famesylated protein is a cancer dependent on famesylated H-Ras protein. In certain embodiments, the cancer dependent on a famesylated protein has an H-Ras protein mutation. In certain embodiments, the cancer dependent on a famesylated protein is head and neck cancer. In certain embodiments, the cancer dependent on a famesylated protein is a squamous cell carcinoma (SCC). In certain embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In certain embodiments, provided herein is a method of treating cancer dependent on a famesylated protein in a subject, wherein the subject is a human.

[0049] In certain embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (11-1), (11-2), (III), (III-l), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, to the subject having cancer dependent on a farnesylated protein. In certain embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (II-l), (II-2), (III), (III-1), (III-2), (IV), (IV-1), or (IV-2), for example, the compound of Formula (la), (lb), (Ila), (Ila-1), (IIa-2), (lib), (IIb-1), (IIb-2), (Illa), (Illa-1), (IIIa-2), (Illb), (IIIb-1), (Illb-2), (IVa), (IVa-1), (IVa-2), (IVb), (IVb-1), or (IVb-2), or pharmaceutically acceptable form thereof, or the compound of Formula (III-3), (IIIa-3), (IIIb-3), (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent to the subject having cancer dependent on a farnesylated protein. In certain embodiments, the cancer dependent on a farnesylated protein is a solid tumor. In certain embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated N-Ras protein. In certain embodiments, the cancer dependent on a farnesylated protein has an N-Ras protein mutation. In certain embodiments, the cancer dependent on a farnesylated protein is melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma. In certain embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, wherein the subject is a human. 5. DETAILED DESCRIPTION

[0050] In one embodiment, provided herein are compounds having a structure of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having a structure of Formula (V) or (VI), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having a structure of any one of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having a structure of any one of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having a structure of any one of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In one embodiment, provided herein are compounds having a structure of any one of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[0051] In one embodiment, provided herein is a pharmaceutical composition comprising a compound having a structure of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound having a structure of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound having a structure of any one of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, provided herein is a pharmaceutical composition comprising a compound having a structure of any one of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0052] In another embodiment, provided are methods of treating cancer dependent on a famesylated protein, which comprises administering to a subject a therapeutically effective amount of a compound having a structure of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. In another embodiment, provided are methods of treating cancer dependent on a famesylated protein, which comprises administering to a subject a therapeutically effective amount of a compound having a structure of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. In another embodiment, provided are methods of treating cancer dependent on a farnesylated protein, which comprises administering to a subject a therapeutically effective amount of a compound having a structure of any one of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, or administering a pharmaceutical composition comprising the same. In another embodiment, provided are methods of treating cancer, which comprises administering to a subject a therapeutically effective amount of a compound having a structure of any one of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof or administering a pharmaceutical composition comprising the same. Examples of the cancers dependent on a farnesylated protein treated according to the methods of treating provided herein, are described herein.

[0053] While specific embodiments have been discussed, the specification is illustrative only and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon review of this specification.

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this specification pertains.

[0055] As used herein, the articles “a,” “an,” and “the” refer to one or to more than one of the grammatical object of the article. By way of example, a sample refers to one sample or two or more samples.

[0056] As used herein, and unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0057] As used herein, the term “administer,” “administering,” or “administration” refers to the act of delivering, or causing to be delivered, a compound or a pharmaceutical composition to the body of a subject by a method described herein or otherwise known in the art. Administering a compound or a pharmaceutical composition includes prescribing a compound or a pharmaceutical composition to be delivered into the body of a patient. Exemplary forms of administration include oral dosage forms, such as tablets, capsules, syrups, suspensions; injectable dosage forms, such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP); transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.

[0058] The term “effective amount” or “therapeutically effective amount” or “dose” or “dosage” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The specific dose will vary depending on, for example, the particular compound chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In certain embodiments, the therapeutically effective amount is sufficient to provide a therapeutic benefit in the treatment or management of the disease or disorder or to delay or minimize one or more symptoms associated with the disease or disorder. The term also refers to the amount of a compound that sufficiently elicits the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0059] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture. The term “(±)” or “(rac)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either A or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (5)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R)- and (5)- isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0060] The “enantiomeric excess” or “% enantiomeric excess” of composition, for example a composition comprising a mixture of enantiomers of a compound, can be calculated using the equation shown below. In the example shown below, a mixture containing 90% of one enantiomer, e.g., an 5 enantiomer, and 10% of the other enantiomer, e.g., an 7? enantiomer, is said to have an enantiomeric excess of 80%. ee= (90-10) / 100 = 80%. In some embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an enantiomeric excess of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98%, or about 99% of the 5 enantiomer. In other words, in some embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an enantiomeric excess of the 5 enantiomer over the R enantiomer. In other embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an enantiomeric excess of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98%, or about 99% of the / ? enantiomer. In other words, in some embodiments, a compound described herein is a mixture of enantiomers of the compound and contains an enantiomeric excess of the R enantiomer over the 5 enantiomer.

[0061] For instance, an isomer / enantiomer can, in some embodiments, be provided substantially free of the corresponding enantiomer, and can also be referred to as “optically enriched,” “enantiomerically enriched,” “enantiomerically pure” and “non-racemic,” as used interchangeably herein. These terms refer to compositions in which the amount of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer, means a preparation of the compound having greater than about 50% by weight of the S enantiomer relative to the total weight of the preparation (e.g., total weight of S and R isomers), such as at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, further such as at least about 80% by weight. In some embodiments, the enrichment can be much greater than about 80% by weight, providing a “substantially enantiomerically enriched,” “substantially enantiomerically pure” or a "substantially non-racemic" preparation, which refers to preparations of compositions which have at least about 85% by weight of one enantiomer relative to the total weight of the preparation, such as at least about 90% by weight, and further such as at least about 95% by weight. In certain embodiments, the compound provided herein is made up of at least about 90% by weight of one enantiomer. In other embodiments, the compound is made up of at least about 95%, about 98%, or about 99% by weight of one enantiomer.

[0062] In some embodiments, the compound is a racemic mixture of (5)- and (R)- isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (5)- or (R)- isomeric configuration. For example, in some embodiments, the compound mixture has an (5)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (5)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the compound mixture has an (5)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

[0063] In other embodiments, the compound mixture has an (7?)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (A’J-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the compound mixture has an (R)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

[0064] In other embodiments, the compound mixture contains identical chemical entities except for their stereochemical orientations, namely (5)- or (R)-isomers. For example, if a compound disclosed herein has -CH(R)- unit, and R is not hydrogen, then the -CH(R)- is in an (5)- or (R)- stereochemical orientation for each of the identical chemical entities (i.e., (5)- or (R)-stereoisomers). In some embodiments, the mixture of identical chemical entities (i.e., mixture of stereoisomers) is a racemic mixture of (5)- and (R)- isomers. In another embodiment, the mixture of the identical chemical entities (i.e., mixture of stereoisomers) contains predominately (5)-isomer or predominately (7?)-isomer. For example, in some embodiments, the (5)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of (5)- and (7?)-isomers. In some embodiments, the (5)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at an (5)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%. In other embodiments, the (A’)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of (5)- and (7?)-isomers. In some embodiments, the (7?)-i somers in the mixture of identical chemical entities (i. e., mixture of stereoisomers) is present at an (Ab-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%. Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and supercritical fluid chromatography (SFC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (E.L. Eliel, Ed., McGraw-Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0065] It is further understood that reference to a compound as disclosed herein having one or more sterocenters without designating the specific chirality (e.g., R- or S-enantionmer) will be understood to refer to the compound as racemic mixture (or a mixture of diastereomers), while inclusion of R- or S- designations will be understood to refer to an enantiomer (or a diastereomer) form of the compound, such as an enantiomerically (or diastereomerically) enriched form of the compound, or an enantiomeric excess of the specified enantiomer form of the compound, in accordance with discussion above regarding enantiomeric enriched and enantiomeric excess. Notation of a compound with an R- or S- designation is understood to include an enantiomerically enriched or an enantiomeric excess of the specified enantiomer of the compound, and not limited to only 100% of the single specified enantiomer of the compound.

[0066] In certain embodiments, the pharmaceutically acceptable form is an isomer. “Isomers” are different compounds that have the same molecular formula. In some embodiments, the isomer may be a stereoisomer. In some embodiments, the isomer may be a tautomer. In some embodiments, the isomer may be a geometric isomer. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomers” include geometric double bond cis- and Zraws-isomers, also termed E- and Z- isomers; R- and 5-enantiomers; diastereomers, (t / )-isomers and (Z)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[0067] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13C or 14C at one or more atoms in the molecule, are within the scope of this disclosure. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14C.

[0068] The term “isotopologue” refers to isotopically-enriched compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170,32P, 33P, 33S, 34S, 35S, 36S, 18F, 35C1,36C1, and 37C1, respectively, each of which is also within the scope of this description. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, are within the scope of this disclosure. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Isotopically-enriched compounds of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), such as a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, can generally be prepared using procedures known to persons of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically-enriched reagent.

[0069] When the compounds are enriched with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium-to-hydrogen ratio.

[0070] An embodiment described herein may include an isotopologue form of the compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), such as a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), ora pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-1), (Va-1), (Vb-1), (Via), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, wherein the isotopologue is substituted on one or more atom members of said compound, or a pharmaceutically acceptable form thereof, with one or more deuterium atoms in place of one or more hydrogen atoms. An embodiment described herein may include a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), such as a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, wherein a carbon atom may have from 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0071] As used herein, a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of compounds disclosed herein. In one embodiment, a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, such as a pharmaceutically acceptable salt, hydrate, stereoisomer, and isotopologue of a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein. In one embodiment, a pharmaceutically acceptable form includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or of Formula (Va), (Vb), (Via), or (VIb), as disclosed herein, such as a pharmaceutically acceptable salt, hydrate, stereoisomer, and isotopologue of a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or of Formula (Va), (Vb), (Via), or (VIb), as disclosed herein. In one embodiment, a pharmaceutically acceptable form includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (Illb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Vla-1), or (VIb-1), as disclosed herein. In one embodiment, a pharmaceutically acceptable form includes, but is not limited to, a pharmaceutically acceptable salt, hydrate, stereoisomer, and isotopologue of a compound of Formula (II-l), (H-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (Illb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or of Formula (HI-3), (HIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Vla-1), or (VIb-1), as disclosed herein. One of ordinary skill will recognize that free forms and salt forms of a compound may be in solvate form.

[0072] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases.

[0073] In certain embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term “solvate” refers to compounds (such as a free form of a compound, isomer, or isotopologue, or a pharmaceutically acceptable salt of any of the foregoing, e.g., a solvate of a free form or of a pharmaceutically acceptable salt form) that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate”. In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0074] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). “Tautomerization” includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations.

[0075] In certain embodiments, the pharmaceutically acceptable form of the compounds disclosed herein is exclusive of a salt form (i.e., is not a salt), sometimes referred to as a free base form, of the compounds disclosed herein. For example, in one embodiment, the pharmaceutically acceptable form of a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, is exclusive of a salt form and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, such as exclusive of a salt form and a hydrate, stereoisomer, and isotopologue of the compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein. In one embodiment, the pharmaceutically acceptable form is exclusive of a salt form and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or of Formula (Va), (Vb), (Via), or (VIb), as disclosed herein, such as exclusive of a salt form and a hydrate, stereoisomer, and isotopologue of the compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or of Formula (Va), (Vb), (Via), or (VIb), as disclosed herein. In one embodiment, the pharmaceutically acceptable form is exclusive of a salt form and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (Illb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Via-1), or (VIb-1), as disclosed herein, such as exclusive of a salt form and a hydrate, stereoisomer, and isotopologue of the compound of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or of Formula (HI-3), (IIIa-3), (HIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), as disclosed herein.

[0076] As used herein, the term “pharmaceutically acceptable carrier, excipient or diluent” means a carrier, excipient or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0077] Typical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form, as described herein, for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), such as a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (Ila-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form, as described herein. The compositions and single unit dosage forms can take the form of solutions or syrups (optionally with a flavoring agent), suspensions (optionally with a flavoring agent), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powder (optionally for reconstitution), taste-masked or sustained-release formulations, and the like.

[0078] Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, caplets, capsules, granules, powder, and liquids. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.

[0079] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[0080] As used herein, the terms “prevention” and “preventing” are used herein to refer to an approach for obtaining beneficial or desired results including, but not limited, to prophylactic benefit. For prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease or disorder, even though a diagnosis of this disease or disorder may not have been made.

[0081] As used herein, the term “stereoisomers” is understood to mean isomers that differ only in the way the atoms are arranged in space. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomers” include geometric double bond cis- and Zraws-isomers, also termed E- and Z- isomers; R- and A-enantiomers; diastereomers, (t / )-isomers and (Z)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[0082] In certain embodiments, the symbol------denotes a bond that can be a single or double as described herein.

[0083] In certain embodiments, provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.

[0084] Substituents around a carbon-carbon double bond alternatively can be referred to as “cA” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of the plane of the ring are designated “cis / trans”

[0085] As used herein, the term “subject” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, and / or rodents; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. The subject can be a patient, for example, a patient having a cancer dependent on a farnesylated protein.

[0086] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder, delaying, or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.

[0087] As used herein, the terms “treat,” “treating,” “treatment,” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disease or disorder. For example, when used in reference to a patient having cancer dependent on a famesylated protein, refers to an action that reduces the severity of the cancer, or retards or slows the progression of the cancer, including (a) inhibiting the cancer growth, or arresting development of the cancer, and (b) causing regression of the cancer, or delaying or minimizing one or more symptoms associated with the presence of the cancer.

[0088] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0089] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0090] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having, in some embodiments, from one to ten carbon atoms (e.g., C1-C10 alkyl). Linear or straight alkyl refers to an alkyl with no branching, e.g., methyl, ethyl, n-propyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Ce alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, —C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0091] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and in some embodiments, having from two to ten carbon atoms (i.e., C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C2-C5 alkenyl). The alkenyl is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1,4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4) and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless stated otherwise in the specification, an alkenyl group is optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0092] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having, in some embodiments, from two to ten carbon atoms (i.e., C2-Cio alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (e.g., C2-Cs alkynyl). The alkynyl is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, an alkynyl group is optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0093] The term “alkoxy” refers to the group -O-alkyl (in some embodiments, including from 1 to 10 carbon atoms), of a straight, branched, cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. “Lower alkoxy” refers to alkoxy groups containing one to six carbons. In some embodiments, C1-C4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group is optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “alkenoxy” and “alkynoxy” mirror the above description of “alkoxy” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.

[0094] “Aryl” refers to a radical with six to fourteen ring atoms (e.g., Ce-Cn or Ce-Cio aryl) which has at least one carbocyclic ring having a conjugated pi electron system which is aromatic (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) (e.g., phenyl, fluorenyl, and naphthyl). In one embodiment, bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. In other embodiments, bivalent radicals derived from univalent monocyclic or polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10 aryl” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise in the specification, an aryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In one embodiment, unless stated otherwise, “aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment to the parent molecular structure is on the aryl ring.

[0095] “Cycloalkyl,” or alternatively, “carbocyclyl,” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed “cycloalkenyl” if the carbocycle contains at least one double bond, or “cycloalkynyl” if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 10 ring atoms (e.g., C3-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10 carbon atoms. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. In some embodiments, it is a C3-C8 cycloalkyl radical. In some embodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moi eties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Examples of C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-1 / / -indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In one embodiment, unless stated otherwise, “cycloalkyl” or “carbocyclyl” also includes ring systems wherein the cycloalkyl or carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment to the parent molecular structure is on the cycloalkyl or carbocyclyl ring.

[0096] The term “halo”, “halide”, or, alternatively, “halogen” refers to fluoro, chloro, bromo, or iodo.

[0097] The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. In certain embodiments, all hydrogen atoms of the alkyl group are substituted with halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, or 3 halo atoms. In certain other embodiments, the alkyl group is substituted with 2 halo atoms. In certain embodiments, the alkyl group is substituted with 1 halo atom. In certain embodiments, haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1, 1, 1-trifluoroethanyl. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, wherein the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Each of the alkyl, alkenyl, alkynyl and alkoxy groups are as defined herein and can be optionally further substituted as defined herein.

[0098] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl, alkenyl and alkynyl radicals, respectively, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. A numerical range can be given, e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example can be up to 4 atoms long. For example, a -CH2OCH2CH3 radical is referred to as a “C4” heteroalkyl, which includes the heteroatom center in the atom chain length description. Connection to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain. For example, an A-containing heteroalkyl moiety refers to a group in which at least one of the skeletal atoms is a nitrogen atom. One or more heteroatom(s) in the heteroalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. For example, heteroalkyl also includes skeletal chains substituted with one or more nitrogen oxide (-O-) substituents. Exemplary heteroalkyl groups include, without limitation, ethers such as methoxyethanyl (-CH2CH2OCH3), ethoxymethanyl (-CH2OCH2CH3), (methoxymethoxy)ethanyl (-CH2CH2-OCH2OCH3), (methoxymethoxy) methanyl (-CH2OCH2OCH3), and (methoxyethoxy)methanyl(-CH2OCH2CH2OCH3), and the like; amines such as -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CEEN^CEECEEXCEE), and the like. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[0099] “Heteroaryl”, or alternatively, “heteroaromatic”, refers to a radical of a 5- to 18membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10 or 14 % electrons shared in a cyclic array) having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 18-membered heteroaryl”). Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or more rings. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms. In one embodiment, bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.

[00100] For example, an N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatom(s) in the heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quatemized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring(s).

[00101] “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like), the point of attachment to the parent molecular structure can be on either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 6membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

[00102] Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-U7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d] pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl).

[00103] Unless stated otherwise in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moi eties can be optionally substituted as defined herein.

[00104] “Heterocyclyl”, “heterocycloalkyl” or ‘heterocarbocyclyl” each refer to any 3- to 18-membered non-aromatic radical monocyclic or polycyclic moiety comprising at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heterocyclyl group can consist of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms. In one embodiment, bivalent radicals derived from univalent heterocyclyl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a piperidyl group with two points of attachment is a piperidylidene.

[00105] An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatom(s) in the heterocyclyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxides. The heterocyclyl is attached to the parent molecular structure through any atom of any of the ring(s).

[00106] “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“3- to 10-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

[00107] Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[00108] Unless stated otherwise, heterocyclyl moieties are optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

[00109] “Hydroxyalkyl” means a group of formula -R-(OH)Z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkyl is -ROH. In one embodiment, hydroxyalkyl includes -CH2OH. In one embodiment, hydroxyalkyl is -R(0H)2.

[00110] A “leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable non-limiting examples of such groups, unless otherwise specified, include halogen atoms, mesyloxy, o-nitrobenzensulphonyloxy, p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

[00111] “Protecting group” has the meaning conventionally associated with it in organic synthesis, e.g., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, New York (2006), incorporated herein by reference in its entirety. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups can similarly be protected.

[00112] As used herein, the terms “substituted” or “substitution” mean that at least one hydrogen present on a group atom (e.g, a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution for the hydrogen results in a stable compound, e.g, a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group can have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. Substituents, unless otherwise indicated, can include one or more group(s) individually and independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -O-P(=O)(ORa)2, where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. For example, a cycloalkyl substituent can have a halide substituted at one or more ring carbons, and the like. The protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts, above. 5.1 COMPOUNDS

[00113] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as disclosed herein, wherein A1 is N or NRla. In some embodiments, the compound of Formula (I), (la), or (lb), as disclosed herein, wherein A2 is CR2b or -C(=O)-. In some embodiments, the bond between A1 and A2 is a single bond, A1 is NRla, and A2 is -C(=O)-. In some embodiments, the bond between A1 and A2 is a double bond, A1 is N, and A2 is CR2b.

[00114] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as

[00115] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as R1a some embodiments, the In some embodiments, the

[00116] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as

[00117] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as disclosed herein, wherein Y and the fused-ring system containing A1, A2, and A3 are attached to W in a 1,2-relationship. In some embodiments, Y and the fused-ring system containing A1, A2, and A3 are attached to W in a 1,3-relationship. In some embodiments, W is C6-12 aryl. In some embodiments, W is phenyl. In some embodiments, W is 5-12 membered heteroaryl. In some embodiments, W is pyridyl. In some embodiments, W is substituted with one, two, three or four R4 substituents. In some embodiments, W is substituted with two R4 substituents. In some embodiments, W is substituted with one R4 substituent. In some embodiments, R4 is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, or -NR14R15, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, or 3-6 membered heterocycloalkoxy, of the R4 are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). For example, in some embodiments, R4 is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy, wherein each Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy of the R4 are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). In some embodiments, R4 is independently hydrogen.

[00118] In some embodiments, the compound is a compound of Formula (I), (la), or (lb), as disclosed herein, wherein the -(C(R6)(R7)(fused-ring system containing A4, A5, and A6)) group, and Y are attached to Z in a 1,2-relationship. In some embodiments, the -(C(R6)(R7)(fused-ring system containing A4, A5, and A6)) group, and Y are attached to Z in a 1,3-relationship. In some embodiments, Z is Ce-12 aryl. In some embodiments, Z is phenyl. In some embodiments, Z is 512 membered heteroaryl. In some embodiments, Z is pyridyl. In some embodiments, Z is substituted with one, two, three or four R5 substituents. In some embodiments, Z is substituted with two R5 substituents. In some embodiments, Z is substituted with one R5 substituent. In some embodiments, R5 independently is hydrogen, halo or CN. In some embodiments, R5 independently is hydrogen. In some embodiments, R5 is independently an electron-withdrawing group. In some embodiments, R5 independently is chloro. In some embodiments, R5 independently is CN.

[00119] In some embodiments, the compound is a compound of Formula (I) or (II), for example a compound of Formula (la), (lb), (Ila), or (lib), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein Rla is independently R9. For example, in some embodiments, Rla is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl, wherein the Ci-6 alkyl, or C3-6 cycloalkyl are optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Ru, -NR10S(O)2R12, -S(O)PR12, and -S(O)2NRl0R''. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, Rla is hydrogen, C1.3 alkyl, or C3-4 cycloalkyl, wherein the C1.3 alkyl, or C3-4 cycloalkyl are optionally independently substituted with one, two, or three substituents independently selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Ru, -NR10S(O)2R12, -S(O)PR12, and -S(O)2NR10Rn For example, in some embodiments, Rla is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl. In some embodiments, Rla is -CH3, -CD3, or cyclopropyl. In some embodiments, Rla is -CH3 or -CD3. In some embodiments, Rla is cyclopropyl. In some embodiments, the compound is a compound of Formula (II-l) or (II-2), such as a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), or a pharmaceutically acceptable form thereof.

[00120] In some embodiments, the compound is a compound of Formula (I) or (III), for example a compound of Formula (la), (lb), (Illa), or (Illb), or a pharmaceutically acceptable form thereof, or of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein R2b is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -S(O)PR9, or-S(O)2NR10Ru. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R2b is independently R9, -OR9, halo, CN, -C(O)NR10Ru, or -NR10Rn. In some embodiments, R2b is hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, hydroxy, Ci-6 alkoxy, C3-6 cycloalkoxy, C3-6 heterocycloalkoxy, halo, CN, -C(O)NR10Ru, or -NR10Rn; wherein R10 and R11, at each occurrence, are each independently hydrogen, Ci-6 alkyl, 3-6 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl. In some embodiments, R2b is independently hydrogen, C1.3 alkyl, C3-4 cycloalkyl, C1.3 alkoxy, C3-4 cycloalkoxy, C3-4 heterocycloalkoxy, halo, CN, -C(O)NR10Ru, or -NR1ORU; wherein R10 and R11, at each occurrence, are each independently hydrogen, C1.3 alkyl, 3-4 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 4-6 membered heterocycloalkyl. In some embodiments, R10 is H. In some embodiments, R11 is Ci-shaloalkyl, such as chloroethyl or fluoroethyl. For example, in some embodiments, R2b is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2. In some embodiments, R2b is -NH2. In some embodiments, R2b is independently an electron-withdrawing group. An electron-withdrawing group may include, for example, a halo, cyano, a nitro group, a carbonyl group, a carboxylic acid, a carboxylic ester, an amide, a sulfonyl group, a sulfonyl ester, or a sufonyl amide group. For example, in some embodiments, R2b is independently an electron-withdrawing group selected from halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or -S(O)2NR10Rn In some embodiments, R2b is chloro, CN, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(H)CH3, -C(O)N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(H)CH3, or-S(O)2N(CH3)2. In some embodiments, the compound is a compound of Formula (III-l) or (III-2), such as a compound of Formula (Illa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharmaceutically acceptable form thereof, or is a compound of Formula (III-3), (IIIa-3), or (IIIb-3), or a pharmaceutically acceptable form thereof.

[00121] In some embodiments, the compound is a compound of Formula (I), for example a compound of Formula (la) or (lb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein A1 is CRlb or -C(=O)-. In some embodiments, the compound of Formula (I), for example a compound of Formula (la) or (lb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein A2 is N or NR2a. In some embodiments, the bond between A1 and A2 is a double bond, A1 is CRlb, and A2 is N. In some embodiments, the bond between A1 and A2 is a single bond, A1 is -C(=O)-, and A2 is NR2a. In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (IV-1), (IVa-1), (IVb-1), (IV-2), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V), (Va), (Vb), (V-l), (Va-1), (Vb-1), (VI), (Via), (VIb), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00122] In some embodiments, the compound is a compound of Formula (I) or (IV), for example a compound of Formula (la), (lb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), for example a compound of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein Rlb is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn. For example, in some embodiments, Rlb is R9, -OR9, halo, CN, -C(O)R9, or -C(O)OR9. In some embodiments, Rlb is R9, -OR9, halo, or CN. For example, in some embodiments, Rlb is hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, halo or CN, wherein the Ci-6 alkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or C3-6 cycloalkoxy, are optionally independently substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NRl0R'-NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)PR12, and -SIOCNR^R1'. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, Rlb is hydrogen, C1.3 alkyl, C3-4 cycloalkyl, C1.3 alkoxy, C3-4 cycloalkoxy, halo or CN, wherein the C1.3 alkyl, C3-4 cycloalkyl, C1.3 alkoxy, or C3-4 cycloalkoxy are optionally independently substituted with one, two, or three substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)pR12, and -S(O)2NR10Ru For example, in some embodiments, Rlb is hydrogen, -CH3, -CD3, -CF3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl, cyclopropyl, -OCH3, -OCD3, -OCF3, -OCH2CH3, -OCD2CD3, isopropoxy, 2,3-dihydroxypropoxy, or cyclopropoxy. In some embodiments, the compound is a compound of Formula (IV-1) or (IV-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00123] In some embodiments, the compound is a compound of Formula (I), for example a compound of Formula (la) or (lb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein R2a is independently R9. For example, in some embodiments, R2a is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl, wherein the Ci-6 alkyl, or C3-6 cycloalkyl are optionally independently substituted with one, two, three, four, five, or six substituents independently selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)PR12, and -S(O)2NRl0R''. For example, in some embodiments, R2a is hydrogen, C1.3 alkyl, or C3-4 cycloalkyl, wherein the C1.3 alkyl, or C3-4 cycloalkyl are optionally independently substituted with one, two, or three substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Rn, -NR10S(O)2R12, -S(O)pR12, and -SIOCNR^R1'. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R2a is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl or cyclopropyl.

[00124] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (VI), (Via), or (VIb), as disclosed herein, wherein A3 is CR3. In some embodiments, R3 is independently R9, -OR9, halo, or CN. In some embodiments, R3 is hydrogen. In some embodiments, the compound is a compound of Formula (I), (II), (III), (IV), or (VI), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), (IVb), (Via), or (VIb), wherein A3 is N. In some embodiments, the compound is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or is a compound of Formula (Via) or (VIb), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (II-l), (11-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (Ila-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00125] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein A4 is CR8. In some embodiments, A4 is N. In some embodiments, A4 is N, and no more than one of A5 and A6 is N. In some embodiments, A5 is CR8. In some embodiments, A5 is N. In some embodiments, A5 is N, and no more than one of A4 and A6 is N. In some embodiments, A6 is CR8. In some embodiments, A6 is N. In some embodiments, A6 is N, and no more than one of A4 and A5 is N. In some embodiments, A4, A5 and A6 are each independently CR8. In some embodiments, R8 is independently R9, -OR9, halo, or CN. In some embodiments, R8is hydrogen. In some embodiments, A5 and A6 taken together is O, NR9, or S. For example, as a representative example of A5 and A6 taken together replaced with O, NR9, or S in a compound of Formula (I), is shown below as a compound of Formula (I-Al), Formula (I-A2), and Formula (I-A3), respectively: R9 Formul a (I-A1)             Formul a (I- A2)             Formul a (I-A3 ) or a pharmaceutically acceptable form thereof.

[00126] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI) such as Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein Y is a bond or is a linker having a length of up to 5 atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms. In some embodiments, Y is a bond. In some embodiments, Y is a linker having a length of 5 atoms. In some embodiments, Y is a linker having a length of 4 atoms. In some embodiments, Y is a linker having a length of 3 atoms. In some embodiments, Y is a linker having a length of 2 atoms. In some embodiments, Y is a linker having a length of 1 atom. In some embodiments, Y is a Ci-6 alkylene, wherein one or more -CH2- is optionally independently replaced by -O-, -C(O)-, -N(R10)-, -N(R10)C(O)-, -C(O)N(R10)-, -N(R10)C(O)N(Ru)-, -S(O)p-, -N(R10)S(O)2-, -S(O)2N(R10)-, or-N(R10)S(O)2N(Ru)-. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. In some embodiments, Y is in the direction of Z-Y-W (wherein Z refers to Z or the Z-containing ring and W refers to W or the W-containing ring as applicable in Formula (I), (II), (III), or (IV), and subformulae thereof). For example, as a representative example of Y written in the direction of Z-Y-W in a compound of Formula (I), wherein Y is -N(R10)C(O)- is shown below as a compound of Formula (I-A4): Formula (I-A4); whereas Y is -C(O)N(R10)- is shown below as a compound of Formula (I-A5): A6 A1 R6 Formula (I-A5). In some embodiments, the compound is a compound of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, as disclosed herein, or is a compound of Formula (III-3), (V-l), or (VI-1), such as Formula (IIIa-3), (IIIb-3), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00127] In some embodiments, Y is -(CR16R17)q-, -(CR16R17)mO(CR16R17)n-, -(CR16R17)mC(O)(CR16R17)n-, -(CR16R17)mN(R10)(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17)n-, -(CR16R17)mC(O)N(R10)(CR16R17)n-, -(CR16R17)mN(R10)C(O)N(Rn)(CR16R17)n-, -(CR16R17)mS(O)p(CR16R17)n-, -(CR16R17)mN(R10)S(O)2(CR16R17)n-, -(CR16R17)mS(O)2N(R10)(CR16R17)n-, or -(CR16R17)mN(R10)S(O)2N(R11)(CR16R17)n-; wherein: R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, or 3-6 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, n is 0, 1, or 2. In some embodiments, each m is independently an integer of 0 or 1; and each n is independently an integer of 1, 2 or 3; wherein the sum of m and n is 1, 2, 3, or 4. In some embodiments, each m is independently an integer of 0; and each n is independently an integer of 1, 2, or 3; wherein the sum of m and n is 1, 2, or 3. In some embodiments, each m is independently an integer of 0; and each n is independently an integer of 1 or 2; wherein the sum of m and n is 1 or 2. In some embodiments, each m is independently an integer of 1, 2, or 3; and each n is independently an integer of 0 or 1; wherein the sum of m and n is 1, 2, 3 or 4. In some embodiments, each m is independently an integer of 1, 2 or 3; and each n is independently an integer of 0; wherein the sum of m and n is 1, 2, or 3. In some embodiments, each m is independently an integer of 1 or 2; and each n is independently an integer of 0; wherein the sum of m and n is 1 or 2. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. In some embodiments, q is independently an integer of 1, 2, 3, 4, or 5. In some embodiments, q is independently an integer of 1, 2, 3, or 4. In some embodiments, q is independently an integer of 1, 2, or 3. In some embodiments, q is independently an integer of 2 or 3. In some embodiments, q is independently an integer of 1 or 2.

[00128] In some embodiments, Y is -(CR16R17)q-, -(CR16R17)mO(CR16R17)n-, -(CR16R17)mC(O)(CR16R17)n-, -(CR16R17)mN(R10)(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17)n-, 4CR16R17)mC(O)N(R10)(CR16R17)n-, -(CR16R17)mN(R10)S(O)2(CR16R17)n-, or 4CR16R17)mS(O)2N(R10)(CR16R17)n-. For example, in some embodiments, Y is -(CR16R17)q-, -(CR16R17)mO(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17)n-, or-(CR16R17)mC(O)N(R10)(CR16R17)n-. For example, in some embodiments, Y is -(CR16R17)q- For example, in some embodiments, Y is -(CR16R17)mO(CR16R17)n- For example, in some embodiments, Y is -(CR16R17)mN(R10)C(O)(CR16R17)n-. For example, in some embodiments, Y is or -(CR16R17)mC(O)N(R10)(CR16R17)n-. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, q is independently an integer of 1, 2, 3, 4, or 5. In some embodiments, q is independently an integer of 1, 2, 3, or 4. In some embodiments, q is independently an integer of 1, 2, or 3. In some embodiments, q is independently an integer of 2 or 3. In some embodiments, q is independently an integer of 1 or 2. In some embodiments, Y is R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, C1.3 hydroxyalkoxy, C1.3 heteroalkoxy, or 3-5 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-5 cycloalkyl, or 3-5 membered heterocycloalkyl. For example, in some embodiments, R16 and R17, at each occurrence, are each independently hydrogen, chloro, hydroxy, CN, NO2, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2OH, -(CH2)2OH, -(CH2)2OCH3, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -O(CH2)2OH, -O(CH2)2OCH3, or 3-oxetanylalkoxy, or together with the C to which each is attached are combined to form a C(O), cyclopropyl, or 3-5 membered heterocycloalkyl. In some embodiments, R16 and R17 are each hydrogen. In some embodiments, Y is -(CH2)O-, -O(CH2)-, -(CFb^O- -O(CH2)2-, or -(CH2)2-. For example, in some embodiments, Y is -(CH2)O-. In some embodiments, Y is -O(CH2)-. In some embodiments, Y is -(CFb^O- In some embodiments, Y is -O(CH2)2-. In some embodiments, Y is -(CH2)2- In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein. In some embodiments, the compound is a compound of Formula (II-l) or (II-2), such as a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-1) or (III-2), such as a compound of Formula (Illa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (IV-1) or (IV-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-l), (Va-1), (Vb-1), (VI-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00129] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S. In some embodiments, at least one of W1, W2, W3, and W4 is N. In some embodiments, W1, W2, and W3 are each independently CR4, and W4 is N. In some embodiments, W1, W2, and W4 are each independently CR4, and W3 is N. In some embodiments, W1, W3, and W4 are each independently CR4, and W2 is N. In some embodiments, W2, W3, and W4 are each independently CR4, and W1 is N. In some embodiments, W1, W2, W3, and W4 are each independently CR4. In some embodiments, W2 and W3 are each independently CR4, and W1 and W4 are each independently N. In some embodiments, W1 and W2 are each independently CR4, and W3 and W4 are each independently N. In some embodiments, W1 and W4 are each independently CR4, and W2 and W3 taken together is O, NR4A, or S. In some embodiments, W3 and W4 are each independently CR4, and W1 and W2 taken together is O, NR4A, or S. In some embodiments, W1 is CR4, W4 is N, and W2 and W3 taken together is O, NR4A, or S. In some embodiments, W3 is CR4, W4 is N, and W1 and W2 taken together is O, NR4A, or S.

[00130] In some embodiments, R4, at each occurrence, is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, or-NR14R15, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, or 3-6 membered heterocycloalkoxy, of the R4 are optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). For example, in some embodiments, R4 is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy, wherein each Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy of the R4 are optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). In some embodiments, R4 is independently hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl, C3-5 cycloalkyl, C1.3 alkoxy, or C1.3 haloalkoxy. In some embodiments, R4 is independently hydrogen.

[00131] In some embodiments, R4A is independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 512 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). For example, in some embodiments, R4A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl of the R4A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, and (0). In some embodiments, R4A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R4A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, or cyclopropyl.

[00132] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S. In some embodiments, at least one of Z1, Z2, Z3, and Z4 is N. In some embodiments, Z1, Z2, and Z3 are each independently CR5, and Z4 is N. In some embodiments, Z1, Z2, and Z4 are each independently CR5, and Z3 is N. In some embodiments, Z1, Z3, and Z4 are each independently CR5, and Z2 is N. In some embodiments, Z2, Z3, and Z4 are each independently CR5, and Z1 is N. In some embodiments, Z1, Z2, Z3, and Z4 are each independently CR5. In some embodiments, Z2 and Z3 are each independently CR5, and Z1 and Z4 are each independently N. In some embodiments, Z3 and Z4 are each independently CR5, and Z1 and Z2 are each independently N. In some embodiments, Z1 and Z4 are each independently CR5, and Z2 and Z3 taken together is O, NR5A, or S. In some embodiments, Z1 and Z2 are each independently CR5, and Z3 and Z4 taken together is O, NR5A, or S. In some embodiments, Z1 is N, Z2 and Z3 taken together is O, NR5A, or S, and Z4 is CR5. In some embodiments, Z1 is N, Z2 is CR5, and Z3 and Z4 taken together is 0, NR5A, or S. In some embodiments, R5, at each occurrence, is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -S(O)PR9, or -S(0)2NRIOR'1. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R5, at each occurrence, is independently hydrogen halo, CN, NO2, -C(O)(Ci-6 alkyl), -C(O)OH, -C(O)O(Ci-6 alkyl), -C(O)NR10Ru, -S(O)p(Ci-6 alkyl), or -S(O)2NR10Rn In some embodiments, R5, at each occurrence, is independently halo, CN, NO2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)N(CH3)2, -S(O)2CH3, or -S(O)2N(CH3)2. In some embodiments, R5 independently is hydrogen, halo or CN. In some embodiments, R5 independently is hydrogen. In some embodiments, R5 is independently an electron-withdrawing group. In some embodiments, R5 independently is chloro. In some embodiments, R5 independently is CN.

[00133] In some embodiments, R5A is independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R5A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (0). For example, in some embodiments, R5A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl of the R5A is optionally independently substituted with 1-6 substituents selected from halo, hydroxy, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, and (0). In some embodiments, R5A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R5A is independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, or cyclopropyl.

[00134] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein R6 is CN, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Rn, -NR1ORU, -NR10OR9, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -NR10C(NR10)NR10Rn, -S(O)PR9, -S(O)2NR10Rn or -NR10S(O)2NR10Rn In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R6 is CN, R9, -OR9, -OC(O)R9, -OC(O)OR9, -NR1ORU, -NR10OR9, -NR10C(O)R9 or -NR10C(NR10)NR10R11. In some embodiments, R6 is CN, R9, -OR9, -OC(O)R9, -OC(O)OR9, -NR1ORU, -NR10OR9, or -NR10C(O)R9. In some embodiments, R6 is CN, R9, -OR9, -NR10Rn, or -NR10OR9. In some embodiments, R6 is CN, R9, -OR9, or -NR10Rn. For example, in some embodiments, R9 is independently hydrogen or C1.3 alkyl, wherein the C1.3 alkyl is optionally substituted with CN. In some embodiments, R10 and R11 are each independently hydrogen, Ci-6 alkyl or Ci-6 alkoxy. In some embodiments, R10 and R11 together is a divalent group, such as -(CH2)X-, wherein x = 2-5, -CH2CH2OCH2CH2-, or -CH2CH2NR18CH2CH2-, wherein R18 is independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, 3-6 membered heterocycloalkyl, or 5-12 membered heteroaryl. In some embodiments, R6 is hydroxy, -OCH3, CN, hydrogen, -CH3, -CH2CN, -NH2, -NHCH3, or -NH(OCH3). In some embodiments, R6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3, or -NH(OCH3). In some embodiments, R6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2, or-NHCH3. In some embodiments, R6 is -NH(CH2CH2)C1, -NH(CH2CH2)F, orN-linked morpholino. In some embodiments, R6 is hydroxy. In some embodiments, R6 is hydrogen. In some embodiments, R6 is NH2. In some embodiments, the compound is a compound of Formula (II-1) or (II-2), such as a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-l) or (III-2), such as a compound of Formula (Illa-1), (IIIb-1), (IIIa-2), or (Illb- 2), or a pharmaceutically acceptable form thereof, or is a compound of Formula (III-3), (IIIa-3), or (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (IV-1) or (IV-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00135] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or -NR10S(O)2NR10R11. For example, in some embodiments, R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a pyrimidinyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru, or-NR10S(O)2NR10R11. In some embodiments, p is independently 0. In some embodiments, p is independently an integer of 1 or 2. For example, in some embodiments, R7 is imidazolyl or triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn. In some embodiments, R7 is a C-linked imidazolyl or a C-linked triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Ru. In some embodiments, R7 is an N-linked imidazolyl or an N-linked triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn. In some embodiments, R7 is a methyl-substituted imidazolyl or a methylsubstituted triazolyl. In some embodiments, R7 is a C-methyl-substituted imidazolyl or a C-methyl-substituted triazolyl. In some embodiments, R7 is an V-m ethyl-substituted imidazolyl or an A-methyl-substituted triazolyl. In some embodiments, R7 is some embodiments, the compound is a compound of Formula (II-1) or (II-2), such as a compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-1) or (III-2), such as a compound of Formula (Illa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or a pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (IV-1) or (IV-2), such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof.

[00136] In some embodiments, the compound disclosed herein is a compound of Formula (I), such as a compound of Formula (la), or (lb), or pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (I), such as a compound of Formula (la), or (lb), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (I), such as a compound of Formula (la), or (lb), respectively.

[00137] In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (II), (Ila), or (lib), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (II-1) or (II-2), or pharmaceutically acceptable form thereof, such as a compound of Formula (Ila-1), (IIb-1), (IIa-2), or (IIb-2), or pharmaceutically acceptable form thereof, respectively. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (II), (Ila), or (lib), for example the compound of Formula (II-l) or (II-2), such as the compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (II), (Ila), or (lib), for example the compound of Formula (II-l) or (II-2), such as the compound of Formula (IIa-1), (IIb-1), (IIa-2), or (IIb-2), respectively.

[00138] In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (III), (Illa), or (Illb), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (III-1) or (III-2), or pharmaceutically acceptable form thereof, such as a compound of Formula (Illa-1), (IIIb-1), (IIIa-2), or (IIIb-2), or pharmaceutically acceptable form thereof, respectively, or a compound of Formula (III-3), (IIIa-3), or (IIIb-3), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (III), (Illa), or (Illb), for example the compound of Formula (III-l) or (III-2), such as the compound of Formula (IIIa-1), (Illb-1), (IIIa-2), or (IIIb-2), or of Formula (III-3), (IIIa-3), or (IIIb-3), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (III), (Illa), or (Illb), for example the compound of Formula (III-l) or (III-2), such as the compound of Formula (IIIa-1), (Illb-1), (IIIa-2), or (IIIb-2), respectively, or of Formula (III-3), (IIIa-3), or (IIIb-3).

[00139] In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (IV-1) or (IV-2), or pharmaceutically acceptable form thereof, such as a compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, respectively. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (IV), (IVa), or (IVb), for example the compound of Formula (IV-1) or (IV-2), such as the compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (IV), (IVa), or (IVb), for example the compound of Formula (IV-1) or (IV-2), such as the compound of Formula (IVa-1), (IVb-1), (IVa-2), or (IVb-2), respectively.

[00140] In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (V), (Va), or (Vb), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (V-l), or pharmaceutically acceptable form thereof, such as a compound of Formula (Va-1) or (Vb-1), or pharmaceutically acceptable form thereof, respectively. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (V), (Va), or (Vb), for example the compound of Formula (V-l), such as the compound of Formula (Va-1) or (Vb-1), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (V), (Va), or (Vb), for example the compound of Formula (V-l), such as the compound of Formula (Va-1) or (Vb-1).

[00141] In some embodiments, the compound of Formula (I), (la), or (lb), or pharmaceutically acceptable form thereof, is a compound of Formula (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, respectively. In some embodiments, the compound is a compound of Formula (VI-1), or pharmaceutically acceptable form thereof, such as a compound of Formula (VIa-1) or (VIb-1), or pharmaceutically acceptable form thereof, respectively. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (VI), (Via), or (VIb), for example the compound of Formula (VI-1), such as the compound of Formula (VIa-1) or (VIb-1), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (VI), (Via), or (VIb), for example the compound of Formula (VI-1), such as the compound of Formula (VIa-1) or (VIb-1).

[00142] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is -(CR16R17)q- or -(CR16R17)mO(CR16R17)n-; Rla is independently R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or -S(O)2NR10Ru; R2b and R5, at each occurrence, are each independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Ru, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or -NR10S(O)2NR10Ru; R6 is CN, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10OR9, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Rn, -NR10S(O)2R9, -NR10C(NR10)NR10R11, -S(O)PR9, -S(O)2NR10Rn or -NR10S(O)2NR10R11; R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or-NR10S(0)2NR10R11; R9, at each occurrence, is independently hydrogen, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, Cm hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl, wherein each C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, CN, NO2, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Cm haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, Cm haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Ru, -NR10S(O)2R12, -S(O)pR12, -S(O)2NR10Ru and -NR10S(O)2NR10Rn; R10 and R11, at each occurrence, are each independently hydrogen, hydroxy, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, phenyl, or 5-9 membered heteroaryl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, phenyl, or 5-9 membered heteroaryl of the R10 and R11 are each optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, CN, NO2, Cm alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, Cm heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, (O), -C(0)R13, -C(0)0R13, -0C(0)R13, -0C(0)0R13, -C(O)NR14R15, -NR14R15, -NR14C(O)R13, -NR14C(O)OR13, -NR14C(O)NR14R15, -NR14S(O)2R13, -S(O)PR13, -S(O)2NR14R15 and -NR14S(O)2NR14R15; R12, at each occurrence, is independently hydrogen, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, Cm hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl, wherein each C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl, of the R12 are optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, CN, NO2, Cm alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, Cm haloalkoxy, (O), -C(0)R13, -C(0)0R13, -0C(0)R13, -0C(0)0R13, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R13, -NR10C(O)OR13, -NR10C(O)NR10Ru, -NR10S(O)2R13, -S(O)PR13, -S(O)2NR10Rn; and -NR10S(O)2NR10Ru; R13, at each occurrence, is independently hydrogen, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl; R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.4 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C1.4 hydroxyalkoxy, C1.4 heteroalkoxy, or 3-6 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

[00143] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III), or a pharmaceutically acceptable form thereof, wherein: Y is —(CH2)q— or -(CH2)mO(CH2)n-; Rla is independently R9; R2b is independently R9, -OR9, halo, CN, -C(O)NR10Ru, or -NR10Rn; R5 is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -S(O)PR9, or -S(O)2NR10Rn; R6 is CN, R9, -OR9, -NR10Rn, or -NR10OR9; R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or -NR10S(O)2NR10R11; R9, at each occurrence, is independently hydrogen, C1.4 alkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each C1.4 alkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, is optionally independently substituted with 1-5 substituents independently selected from halo, hydroxy, CN, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, (O), and -NR10Rn; R10 and R11, at each occurrence, are each independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, of the R10 and R11 are each optionally independently substituted with 1-5 substituents selected from halo, hydroxy, CN, C1-3 alkyl, C1.3 haloalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, (O), and-NR14R15; R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1.3 alkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, or 5; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[00144] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form, wherein: Y is —(CH2)q— or -(CH2)mO(CH2)n-; Rla is independently R9; R2b is independently R9, -OR9, halo, CN, -C(O)NR10Ru, or -NR10Rn; R5 is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -S(O)PR9, or -S(O)2NR10Rn; R6 is R9, -OR9, -NR1ORU, or -NR10OR9; R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R9, -NR10S(O)2R9, -S(O)PR9, or -S(O)2NR10Ru; R9, at each occurrence, is independently hydrogen, C1.4 alkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each C1.4 alkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, is optionally independently substituted with 1-5 substituents independently selected from halo, hydroxy, CN, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, (O), and -NR10Rn; R10 and R11, at each occurrence, are each independently hydrogen, C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each C1.3 alkyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, of the R10 and R11 are each optionally independently substituted with 1-5 substituents independently selected from halo, hydroxy, CN, C1.3 alkyl, C1.3 haloalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, (O), and -NR14R15; R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1.3 alkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-6 membered heterocycloalkyl, or C1.3 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, or 5; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[00145] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is —(CH2)q— or -(CH2)mO(CH2)n-; Rla is independently R9; R2b is independently R9, -OR9, halo, CN, -C(O)NR10Rn, or -NR10Rn; R5 is independently R9, halo, CN, NO2, -C(O)R9, -S(O)PR9, or -S(O)2NRl0R'4; R6 is R9, -OR9, or -NR1ORU; R7 is a 5-9 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)NR10Rn, -NR1ORU, -NR10C(O)R9, -NR10S(O)2R9, -S(O)PR9, or -S(O)2NR10Ru; R9, at each occurrence, is independently hydrogen, C1.3 alkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each C1.3 alkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl, is optionally independently substituted with one, two, or three substituents independently selected from halo, hydroxy, CN, C1.3 alkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, or C1.3 alkoxy; R10 and R11, at each occurrence, are each independently hydrogen, C1.3 alkyl, C1.3 heteroalkyl, or 3-6 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each C1.3 alkyl, C1.3 heteroalkyl, or 3-6 membered heterocycloalkyl, of the R10 and R11 are each optionally independently substituted with one, two, or three substituents independently selected from halo, hydroxy, CN, C1.3 alkyl, C1.3 heteroalkyl, or 3-6 membered heterocycloalkyl; each m is independently an integer of 0, 1, 2, or 3; each n is independently an integer of 0, 1, 2, or 3; wherein the sum of m and n is 0, 1, 2, 3, 4, or 5; each p is independently an integer of 0, 1, or 2; and each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[00146] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, ora compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is —(CH2)q— or -(CH2)mO(CH2)n-; Rla is hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD2, isopropyl, 2,3-dihydroxypropyl or cyclopropyl; R2b is (a) hydrogen, -CH3, -CD3, -CH2CH3, CD?CD,, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or-C(O)NH2; orR2b is (b) -NH2; R5 is hydrogen, halo, CN, NO2, -C(O)CH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, or -S(O)2N(CH3)2; R6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3, or -NH(OCH3); or R6 is -NH(CH2CH2)C1, -NH(CH2CH2)F, orN-linked morpholino. R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a pyrimidinyl, optionally substituted with 1-4 substituents independently selected from -CH3, -CD3, -CH2CH3, CD?CD,, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, chloro, and CN; each m is independently an integer of 0, 1, or 2; each n is independently an integer of 0, 1, or 2; wherein the sum of m and n is 0, 1, 2, 3, or 4; and each q is independently an integer of 0, 1, 2, 3, 4, or 5.

[00147] In some embodiments, the compound is a compound of Formula (II-l), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, ora compound of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is -(CH2)2- -O(CH2)-, -O(CH2)2- -(CH2)O- or -(CH2)2O-; Rla is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl, or cyclopropyl; R2b is (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or R2b is (b) -NH2; R5 is hydrogen, chloro, bromo, or CN; R6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2, or -NHCH3; and R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a pyrimidinyl, optionally substituted with 1-4 substituents independently selected from -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, chloro, and CN.

[00148] In some embodiments, the compound is a compound of Formula (II-l), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O-, or -(CH2)2O-; Rla is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl, or cyclopropyl; R2b is (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or R2b is (b) -NH2; R5 is hydrogen, chloro, bromo, or CN; R6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2, or -NHCH3; and R7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl.

[00149] In some embodiments, the compound is a compound of Formula (II-l), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O-, or -(CH2)2O-; Rla is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl, or cyclopropyl; R2b is (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or R2b is (b) -NH2; R5 is hydrogen, chloro, bromo, or CN; R6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2, or -NHCH3; and

[00150] In some embodiments, the compound is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), or a pharmaceutically acceptable form thereof, wherein: Y is -(CH2)2-, -O(CH2)-, -O(CH2)2-, -(CH2)O-, or -(CH2)2O-; Rla is hydrogen, -CH3, -CD3, 2,3-dihydroxypropyl, or cyclopropyl; R2b is (a) -OCH3, -OCD3, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or R2b is (b) -NH2; R5 is hydrogen, chloro, bromo, or CN; R6 is hydrogen, hydroxy, -OCH3, -OCD3, -NH2, or -NHCH3; and R7 is

[00151] In some embodiments, the compound is a compound of Formula (II-l), such as a compound of Formula (Il-la) or Formula (II- lb), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (II-2), such as a compound of Formula (II-2a) or Formula (II-2b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-l), such as a compound of Formula (III-1 a) or Formula (III-lb), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-2), such as a compound of Formula (III-2a) or Formula (III-2b), or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), such as a compound of Formula (III-3a) or Formula (III-3b), or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutically acceptable form of the compound of Formula (II-l), Formula (II-2), Formula (III-1), or Formula (III-2), for example the compound of Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), or of Formula (III-3), (IIIa-3), or (IIIb-3), is exclusive of a salt form (i.e., is not a salt), and includes a pharmaceutically acceptable solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of the compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), for example the compound of Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), respectively, or of Formula (III-3), (IIIa-3), or (IIIb-3).

[00152] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (V), (Va), (Vb), (VI), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein the compound has a MW of no more than 1,000 g / mol. In some embodiments, the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol. In some embodiments, the compound has a MW of no more than 600 g / mol. In some embodiments, the compound has a MW of no more than 500 g / mol. In some embodiments, the compound is a compound of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, as disclosed herein.

[00153] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), for example a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (V), (V-l), (VI), or (VI-1), or a pharmaceutically acceptable form thereof, as disclosed herein, wherein the compound is a racemate or a mixture of diasteromers, or a mixture of stereoisomers. In some embodiments, the compound is a single enantiomer or a single diasteromer. In some embodiments, the compound is a single enantiomer. For example, in some embodiments, the compound is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), such as a compound of Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (Illa-1), (IIIb-1), (Va-1), (Vb-1), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof, as disclosed herein. In some embodiments, the compound is an (R)-enantiomer. In some embodiments, the compound has an enantiomeric excess of greater than 10% of the (R)-enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, of the (R)-enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R)-enantiomer. In some embodiments, the compound is an (S)-enantiomer. In some embodiments, the compound has an enantiomeric excess of greater than 10% of the (S)-enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, of the (S)-enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S)-enantiomer.

[00154] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate and is selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, ora pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a single enantiomer. In some embodiments, the compound is an (R)-enantiomer of Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. For example, in some embodiments, the compound is an (R)-enantiomer of Compound 4, 6, 7, 8, 9, 14, 15, 18, 19, 20, 21, 25, 27, 28, 29, 30, 34, 35, 36, 37, 39, 46, 47, 48, 51, 55, 56, 57, 58, 66, 70, 76, 77, 78, 79, 80, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof. For example, in some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 14, 15, 18, 19, 20, 21, 25, 27, 28, 29, 30, 34, 35, 36, 37, 39, 46, 47, 48, 51, 55, 56, 57, 58, 66, 69, or 70, or a pharmaceutically acceptable form thereof.

[00155] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 1, 2, 3, 4, 6, 7, 8, 11, 13, 14, 15, 17, 18, 19, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 50, 51, 54, 55, 56, 57, 61, 62, 63, 65, 69, 76, 77, 79, 80, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, and 110, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, 8, 76, 77, 79, or 80, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 14, 15, 18, 19, 20, 25, 27, 28, 29, 30, 34, 35, 36, 37, 39, 46, 47, 51, 55, 56, 57, 69, 79, or 80, or a pharmaceutically acceptable form thereof.

[00156] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 5, 9, 10, 12, 16, 21, 24, 40, 43, 48, 49, 52, 53, 58, 59, 60, 64, 66, 67, 68, 70, 71, 72, 73, 74, 75, 78, 89, 90, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 9, 78, 89, 90, 91,or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 21, 48, 58, 66, 70, 78, 89, 90, 91,or a pharmaceutically acceptable form thereof.

[00157] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 81, 82, 83, 84, 85, 86, 87, 88, 89, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 4, 6, 7, 8, 9, 14, 15, 18, 19, 20, 21, 25, 27, 28, 29, 30, 36, 37, 46, 47, 48, 55, 56, 57, 58, 66, 86, or 89, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 6, 7, 8, 9, 14, 15, 18, 19, 20, 21, 25, 27, 28, 29, 30, 36, 37, 46, 47, 48, 55, 56, 57, 58, 66, 69, 70, 76, 77, 86, or 89, or a pharmaceutically acceptable form thereof.

[00158] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 31, 32, 33, 34, 35, 38, 39, 49, 50, and 51, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 34, 35, 39, or 51, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 34, 35, 39, or 51, or a pharmaceutically acceptable form thereof.

[00159] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 1, 2, 3, 5, 6, 10, 11, 12, 13, 14, 16, 17, 18, 22, 23, 24, 25, 26, 28, 29, 31, 32, 36, 38, 40, 41, 42, 43, 44, 45, 49, 52, 53, 54, 55, 59, 60, 61, 63, 64, 65, 71, 72, 73, 78, 81, 83, 84, 85, 87, 88, 93, 94, 95, 112, 113, 114, 115, 117, 118, 119, and 120, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer or Compound 6, 14, 18, 25, 28, 29, 36, 55, or 78, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 6, 14, 18, 25, 28, 29, 36, 55, or 78, or a pharmaceutically acceptable form thereof.

[00160] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 4, 7, 8, 9, 16, 19, 20, 21, 27, 30, 34, 35, 37, 39, 46, 47, 48, 51, 56, 57, 58, 62, 66, 67, 68, 69, 70, 74, 75, 82, 86, 89, and 92, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 4, 7, 8, 9, 15, 19, 20, 21, 27, 30, 34, 35, 37, 39, 46, 48, 51, 56, 57, 58, 66, 70, 86, or 89, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 4, 8, 9, 19, 20, 21, 27, 30, 34, 35, 37, 39, 46, 47, 48, 51, 56, 57, 58, 66, 69, 70, 86, or 89, or a pharmaceutically acceptable form thereof.

[00161] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 3, 4, 12, 13, 14, 15, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 43, 44, 45, 46, 47, 48, 49, 50, 51, 59, 64, 65, 76, 77, 80, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 4, 14, 15, 25, 27, 28, 29, 30, 34, 35, 46, 47, 48, 51, 76, 77, or 80, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 14, 15, 25, 27, 28, 29, 30, 34, 35, 46, 47, 48, 51, 71, 77, or 80, or a pharmaceutically acceptable form thereof.

[00162] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 5, 6, 7, 8, 9, 16, 17, 18, 19, 20, 21, 36, 37, 38, 39, 53, 54, 55, 56, 57, 58, 60, 61, 62, 66, 67, 68, 69, 70, 72, 73, 78, 85, 86, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, 8, 9, 18, 19, 20, 21, 36, 37, 39, 55, 56, 57, 58, 66, 70, 78, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 6, 7, 8, 9, 18, 19, 20, 21, 36, 37, 39, 55, 56, 57, 58, 66, 69, 70, 78, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof.

[00163] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 93, 98, 103, 108, 113, 118, 123, 128, and 133, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 4, 6, 7, 8, or 9, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 6, 7, 8, or 9, or a pharmaceutically acceptable form thereof.

[00164] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 92, 96, 101, 106, 111, 116, 121, 126, and 131, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 14, 15, 18, 19, 20, or 21, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 14, 15, 18, 19, 20, or 21, or a pharmaceutically acceptable form thereof.

[00165] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 97, 102, 107, 112, 117, 122, 127, and 132, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 25, 27, 28, 29, 30, 34, 35, 36, 37, or 39, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 25, 27, 28, 29, 30, 34, 35, 36, 37, or 39, or a pharmaceutically acceptable form thereof.

[00166] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 95, 100, 105, 110, 115, 120, 125, 130, and 135, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 46, 47, 48, 51, 55, 56, 57, 58, 66, 70, 76, 77, 78, 79, 80, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 46, 47, 48, 51, 55, 56, 57, 58, 66, 69, 70, 76, 77, 78, 79, 80, 86, 89, 90, or 91, or a pharmaceutically acceptable form thereof.

[00167] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 63, 64, 65, 94, 99, 104, 109, 114, 119, 124, 129, and 134, or a pharmaceutically acceptable form thereof.

[00168] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, or a pharmaceutically acceptable form thereof, is a farnesyltransferase inhibitor. For example, in some embodiments, the compound disclosed herein has an IC50 for inhibition of farnesyltransferase of 300 nM or less, for example, 250 nM or less, 200 nM or less, 150 nM or less, 125 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 25 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. In some embodiments, the compound disclosed herein is a selective farnesyltransferase inhibitor. In some embodiments, the compound disclosed herein selectively inhibits farnesyltransferase with greater potentcy (lower IC50 value) relative to the level of inhibition of geranylgeranyl transferase type-1. For example, in some embodiments, the compound disclosed herein has an IC50 for inhibition of geranylgeranyl transferase type-1 of 100 nM or more, for example, 300 nM or more, 500 nM or more, 750 nM or more, or 1,000 nM or more. For example, in some embodiments, the compound disclosed herein selectively inhibits famesyltransferase relative to geranylgeranyl transferase type-1, wherein said compound has an IC50 ratio of IC50 (famesyltransferase) to IC50 (geranylgeranyl transferase type-1) of at least 1:5, for example an IC50 ratio of 1:10, 1:25: 1:50, 1:100, 1:300, 1:500, 1:750, or 1:1000, or more.

[00169] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 3, 4, 5, 6, 7, 8, 9, 11, 14, 15, 17, 18, 19, 20, 21, 23, 25, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39, 42, 44, 45, 46, 47, 48, 50, 51, 53, 54, 55, 56, 57, 58, 61, 62, 65, 66, 69, 70, 72, 78, 82, 83, 86, 88, 89, and 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, 8, 9, 66, or 91, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 3, 4, 14, 15, 18, 19, 20, 21, 25, 27, 28, 29, 30, 34, 35, 36, 37, 39, 46, 47, 48, 51, 55, 56, 57, 58, 66, 69, 78, 86, or 89, or a pharmaceutically acceptable form thereof.

[00170] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 4, 6, 7, 8, 9, 18, 19, 20, 21, 23, 26, 27, 28, 36, 37, 39, 46, 55, 56, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, 8, or 9, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 4, 18, 19, 20, 21, 27, 28, 36, 37, 39, 46, 55, 56, 57, or 58, or a pharmaceutically acceptable form thereof.

[00171] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 4, 6, 7, 8, 18, 27, 34, 37, 46, 47, 48, 55, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, or 8, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 4, 18, 27, 34, 37, 46, 47, 48, 55, 57, or 58, or a pharmaceutically acceptable form thereof.

[00172] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from Compounds 4, 6, 7, 8, 18, 27, 37, 46, 55, 57, and 58, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (R)-enantiomer of Compound 6, 7, or 8, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is an (S)-enantiomer of Compound 4, 18, 27, 37, 46, 55, 57, or 58, or a pharmaceutically acceptable form thereof.

[00173] In some embodiments, the compound is a compound of Formula (I), (II), (III), or (IV), or of Formula (V) or (VI), as disclosed herein, wherein the compound is a racemate or a single enantiomer thereof, such as the (R)-enantiomer or the (S)-enantiomer thereof, and is selected from: 3-hydroxy-3-(l-methyl-l / 7-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (001); 3-hydroxy-21-methyl-3-(l-methyl-l / 7-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (002); 44-chloro-3-hydroxy-2l-methyl-3-(l-methyl-IT / -imidazol-5-yl)-2l,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (003); 3-amino-44-chloro-21-methyl-3-(1 -methyl-l / 7-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (004); 3-hydroxy-22-methoxy-3-(l-methyl-l / / -imidazol-5-yl)-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (005); 3-hydroxy-21-methyl-3-(l-methyl-l / 7-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile (006); 3-amino-2'-methyl -3-(1 -methyl-l / 7-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile (007); 3-amino-21-(methyl-t / 3)-3-(l-methyl-lJ7-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile (008); 3-amino-3-(l-methyl-lJH-imidazol-5-yl)-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (009); 22-methoxy-3-(l-methyl-lJH-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (010); 3-hydroxy-21-methyl-3-(l-methyl-lZ / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (Oil); 44-chloro-22-methoxy-3-(l-methyl-lJH-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (012); 44-chloro-3-hydroxy-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (013); 44-chloro-3-hydroxy-21-methyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (014); 3-amino-44-chloro-21-methyl-3-(1 -methyl-lZ / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (015); 3-hydroxy-22-methoxy-3-(l-methyl-l / / -imidazol-5-yl)-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (016); 3-hydroxy-3-(l-methyl-lJH-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (017); 3-hydroxy-21-methyl-3-(l-methyl-lZ / -imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (018); S-amino^^methyl-3-(1-methyl-lZ / -imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (019); 3-amino-21-(methyl-6?3)-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (020); 3-amino-3-(l -methyl-lJ7-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-l, 4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (021); 3-hydroxy-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one (022); 3-hydroxy-21-methyl-3-(l-methyl-lZ / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphan-22-one (023); 44-chloro-22-methoxy-3-(l-methyl-177-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol (024); 44-chloro-3-hydroxy-3-(l-methyl-177-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphan-22-one (025); 44-chloro-3-hydroxy-21-methyl-3-(l-methyl-177-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (026); S-amino^-chloro^1-methyl-3-(1-methyl-177-imidazol-5-yl )-2',22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphan-22-one (027); 44-chloro-3-hydroxy-21-(methyl-t / 3)-3-(l-methyl-177-imidazol-5-yl )-2',22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (028); 44-chloro-21-cyclopropyl-3-hydroxy-3-(l-methyl-177-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (029); 3-amino-44-chloro-21-cyclopropyl-3-(l-methyl-177-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (030); 44-chloro-3-hy droxy-3-(4-methyl-477-1,2,4-tri azol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (031); 44-chl oro-3-hy droxy ^-(methyl-d3)-3-(4-methyl -477-1,2,4-tri azol-3-yl)-21,22-dihy dro-5-oxa-2(4,6)-quinolina-1,4(1,3 )-dibenzenacycloheptaphan-22-one (032); 44-chl oro-3 -(methoxy-^)-21 -(methyl-^)-3 -(4-m ethyl-477-1,2,4-tri azol-3 -yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (033); 3-amino-44-chloro-21-(methyl-t / 3)-3-(4-methyl-477-1,2,4-tri azol-3-yl)-21,22-dihy dro-5-oxa-2(4,6)-quinolina-1,4(1,3 )-dibenzenacy cloheptaphan-22-one (034); 3-amino-44-chloro-21-cy clopropyl-3-(4-methyl-477-1,2,4-tri azol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3 )-dibenzenacy cloheptaphan-22-one (035); 3-hydroxy-21-methyl-3-(l-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphane-44-carbonitrile (036); 3-amino-21 -methyl -3-(1 -methyl- 177-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphane-44-carbonitrile (037); 3-hydroxy-21-methyl-3-(4-methyl-477-1,2,4-tri azol-3-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile (038); 3-amino-21-methyl-3-(4-methyl-4 / / -1,2,4-triazol-3-yl)-22-oxo-21,22-dihydro-5-oxa- 2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile (039); 22-methoxy-3-(l-methyl-17 / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)- dibenzenacyclohexaphan-3-ol (040); 3-hydroxy-3-(l-methyl-17 / -imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one (041); 3-hydroxy-21-methyl-3-(l-methyl-17 / -imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (042); 44-chloro-22-methoxy-3-(l-methyl-lZ / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)- dibenzenacyclohexaphan-3-ol (043); 44-chloro-3-hydroxy-3-(l-methyl-l / / -imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (044); 44-chloro-3-hydroxy-21-methyl-3-(l-methyl-17 / -imidazol-5-yl)-21,22-dihydro-6-oxa- 2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (045); 3-amino-44-chloro-21-methyl-3-(1 -methyl-17 / -imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one (046); 3-amino-44-chloro-21-(methyl-t / 3)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (047); 3 -amino-44-chl oro-3 -(1 -methyl- 17 / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22-carbonitrile (048); 44-chloro-22-methoxy-3-(4-methyl-4Z / -l,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-3-ol (049); 44-chloro-21-methyl-3-(4-methyl-4 / / -1,2,4-triazol-3-yl)-3-(methylamino)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (051); 3-amino-44-chloro-21-methyl-3-(4-methyl-4 / / -l,2,4-triazol-3-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (051); 44-bromo-22-methoxy-3-(l-methyl-l / / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-3-ol (052); 3-hydroxy-22-methoxy-3-(l-methyl-l / / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (053); 3-hydroxy-3-(l-methyl-lJ7-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (054); S-hydroxy^l^methyl-^-S-Q-methyl-l / Z-imidazol-S-y^^-oxo^^-dihydro-b-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (055); S-amino^^methyl-^-S-Q-methyl-lJT-imidazol-S-y^^-oxo^^-dihydro-b-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (056); 3-amino-21-cy cl opropyl-3-(l-methyl-17 / -imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (057); 3-amino-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (058); 46-chloro-22-methoxy-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-l(l,3)-benzenacyclohexaphan-3-ol (059); 3-hydroxy-22-methoxy-3-(l-methyl-177-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-l(l,3)-benzenacyclohexaphane-46-carbonitrile (060); 3-hydroxy-21-(methyl-t / 3)-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-l(l,3)-benzenacyclohexaphane-46-carbonitrile (061); 3-amino-2l-(methyl-t / 3)-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-2l,22-dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-l(l,3)-benzenacyclohexaphane-46-carbonitrile (062); 3-hydroxy-21-methyl-3-(l-methyl-lZ / -imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphan-22-one (063); 44-chloro-22-methoxy-3-(l-methyl-lJH-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol (064); 44-chloro-3-hydroxy-21-methyl-3-(l-methyl-l / / -imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one (065); 3-amino-3-(l-methyl-lJ7-imidazol-5-yl)-22-morpholino-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (066); 3-amino-3-(l-methyl-lJH-imidazol-5-yl)-22-(piperazin-l-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (067); 3-amino-3-(l-methyl-lJH-imidazol-5-yl)-22-(oxetan-3-ylamino)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (068); 3-amino-21-(2,3-dihydroxypropyl)-3-(l-methyl-l / 7-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (069); 3-amino-3-(l-(methyl-t / 3)-l / / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (070); 44-bromo-22-chl oro-3 -(1 -methyl- l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (071); 3-hydroxy-3-(l-methyl-l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (072); 44-cy ano-3-hy droxy-3-(l-methyl-l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(1,3)-dibenzenacyclohexaphane-22-carboxamide (073); 44-bromo-22-chl oro-3 -(1 -methyl- l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine (074); 44-bromo-3-(l-methyl-l / 7-imidazol-5-yl)-22-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine (075); 44-chloro-21-(methyl-t / 3)-3-(5-methyl-17 / -imidazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (076); and 44-chloro-21-(methyl-t / 3)-3-(4-methyl-17 / -imidazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one (077); or a pharmaceutically acceptable form thereof.

[00174] In some embodiments, the compound is selected from: (R)-3-hy droxy-21-methyl -3-(1 -methyl-17 / -imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile ((l?)-006); (R)-3-amino-21-methyl-3-(l-methyl-l / Z-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile ((l?)-007); (R)-3-amino-21-(methyl-t / 3)-3-(l-methyl-lJH-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphane-44-carbonitrile ((l?)-008); (R)-3-amino-3-(l-methyl-l / 7-imidazol-5-yl)-2(4,6)-quinolina-l,4(l,3)- dibenzenacyclohexaphane-22,44-dicarbonitrile ((l?)-009); and (R)-44-chloro-21-(methyl-t / 3)-3-(4-methyl-l / 7-imidazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((l?)-077); or a pharmaceutically acceptable form thereof.

[00175] In some embodiments, the compound is selected from: (S)-44-chloro-3-hydroxy-2l-methyl-3-(l-methyl-l / / -imidazol-5-yl)-2l,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one ((5)-003); (S)-3-amino-44-chloro-21-methyl-3-(l -methyl-l / 7-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4( 1,3)-dibenzenacyclohexaphan-22-one ((5)-004); (S)-44-chloro-3-hydroxy-21-methyl-3-(l-methyl-17 / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((5)-014); (S)-3-amino-44-chloro-21-methyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((5)-015); (S)-3-hydroxy-21-methyl-3-(l-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-018); (S)-3-amino-21-methyl-3-(l-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-019); (S)-3-amino-2l-(methyl-t / 3)-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-2l,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-020); (S)-3-amino-3-(l-methyl-lJH-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-l,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-021); (S)-44-chl oro-3-hy droxy-3-(l -methyl- 17 / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4( 1,3)-dibenzenacycloheptaphan-22-one ((5)-025); (S)-3-amino-44-chloro-21-methyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-027); (S)-44-chloro-3-hydroxy-2l-(methyl-t / 3)-3-(l-methyl-l / / -imidazol-5-yl)-2l,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-028); (S)-44-chloro-2'-cyclopropyl-3-hydroxy-3-(l-methyl-l 7 / -imidazol-5-yl )-2',22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-029); (S)-3-amino-44-chloro-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-030); (S)-3-amino-44-chloro-2l-(methyl-t / 3)-3-(4-methyl-4 / / -l,2,4-triazol-3-yl)-2l,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-034); (S)-3-amino-44-chloro-21-cyclopropyl-3-(4-methyl-4JH-l,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one ((5)-035); (S)-3-hydroxy-21-methyl-3-(l-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile ((3)-036); (S)-3-amino-21-methyl-3-(l-methyl-l / 7-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile ((3)-037); (S)-3-amino-21-methyl-3-(4-methyl-477-1,2,d-triazol-S-y^^-oxo^^-dihydro-S-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile ((5)-039); (S)-3-amino-44-chloro-21-methyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((3)-046); (S)-3-amino-44-chl oro^-Qnethyl-^)-3-(1-methyl-ITZ-imidazol-S-y^^^-dihydro-b-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((3)-047); (S)-3-amino-44-chloro-3-(l-methyl-177-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22-carbonitrile ((3)-048); (S)-3-amino-44-chloro-2l-methyl-3-(4-methyl-47 / -l,2,4-triazol-3-yl)-2l,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((3)-051); (S)-3-hy droxy-2 l-(methyl-t / 3)-3-(l-methyl-ITZ-imidazol-S-y^^-oxo^^-dihydro-b-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-051); (S)-3-amino-21-(methyl-^)-3-(1-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((3)-056); (S)-3-amino-21-cyclopropyl-3-(1-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((3)-057); (S)-3-amino-3-(l-methyl-177-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-058); (S)-3-amino-3-(l-methyl-l / / -imidazol-5-yl)-22-morpholino-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((3)-066); (S)-3-amino-21-(2,3-dihydroxypropyl)-3-(l-methyl-lJH-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((3)-069); and (S)-3-amino-3-(l-(methyl-t / 3)-17 / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-070); or a pharmaceutically acceptable form thereof.

[00176] In some embodiments, the compound is selected from: (7?)-3-hydroxy-3-(l-(methyl-t / 3)-l / / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((l?)-078); (5)-3-hy droxy-3-(l-(methyl-t / 3)-17 / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-078); (7?)-44-chloro-21-(methyl-d3)-3-(5-methyl-177-l,2,4-triazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((l?)-079); (5)-44-chloro-21-(methyl-d3)-3-(5-methyl-lJH-l,2,4-triazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((3)-079); (7?)-44-chloro-21-(methyl-d3)-3 -(3 -methyl- 1H-1,2,4-triazol-1 -yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((l?)-080); (5)-44-chloro-21-(methyl-d3)-3-(3-methyl-lJH-l,2,4-triazol-l-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one ((3)-080); 44-bromo-22-chl oro-3 -(1 -methyl- lJH-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol (081); 44-bromo-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-l,4(1,3)-dibenzenacyclohexaphane-22,3-diamine (082); 44-bromo-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(4,6)-isoquinolina-l,4(1,3)-dibenzenacyclohexaphan-3-ol (083); 44-bromo-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(1,3)-dibenzenacyclohexaphan-3-ol (084); 3-hydroxy-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (085); 3-amino-3-(l-methyl-l / / -imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (086); (7?)-3-amino-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((l?)-086); (5)-3 -amino-3 -(1 -methyl- l / / -imidazol-5-yl)-6-oxa-2( 1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-086); 44-bromo-27-m ethoxy-3-(1 -methyl-lJH-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-l, 4(1,3)-dibenzenacyclohexaphan-3-ol (087); 3-hydroxy-27-methoxy-3-(l-methyl-l / 7-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (088); (7?)-3-amino-3-(l-methyl-l / / -imidazol-5-yl)-22-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile (( / ?)-089); (5)-3-amino-3-(l-methyl-lJH-imidazol-5-yl)-22-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile ((5)-089); (5)-3 -(4-methyl- 1 / 7-imidazol-1 -yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-090); (7?)-3-(4-methyl-lZ / -imidazol-l-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (( / ?)-090); (5)-3 -(5-methyl- 1 / 7-imidazol-1 -yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((5)-091); (7?)-3-(5-methyl-lZ / -imidazol-l-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (( / ?)-091); ( / 0-3-amino-44-chloro-2l-methyl-3-(l-methyl-l / / -imidazol-5-yl)-2l,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (5)-3 -hydroxy-21 -m ethyl -3-(1 -methyl - 1 / 7-imidazol -5 -yl)-22-oxo-2 4,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (5)-3-amino-2l-methyl-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-2l,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (5)-3 -amino-2 ^(methyl      -(1 -methyl - 1 / 7-imidazol -5 -yl)-22-oxo-2 4,22- dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (5)-3-amino-3-(l-methyl-17 / -imidazol-5-yl)-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile; (R)-44-chl oro-3 -hydroxy-21-methyl-3-(l -methyl-l / / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (5)-3-amino-44-chloro-2l-methyl-3-(l -methyl-l / Z-imidazol-S-yl)^1,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (R)-3-hy droxy-21-methyl-3-(l -methyl-l / / -imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44- ( / 0-004 (5)-006 (5)-007 (5)-008 (5)-009 ( / 0-014 ( / 0-015 ( / 0-018 carbonitrile; (JO^-amino^-methyl-3-(1-methyl-l / T-imidazol-S-yO^-oxo^1^2-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (70-3-amino-21-(methyl-t / 3)-3-(l-methyl-lJH-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (7?)-3-amino-3-(l-methyl-l / / -imidazol-5-yl)-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile; (7?)-44-chloro-3-hydroxy-3-(l-methyl-l / / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (R)-3-amino-44-chloro-21-methyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; ( / O^-chloro^-hydroxy-21-(methyl-t / 3)-3-(l-methyl-l / / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (7?)-44-chloro-21-cyclopropyl-3-hydroxy-3-(l-methyl-l / / -imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (7?)-3-amino-44-chloro-21-cyclopropyl-3 -(l-methyl-l / / -imidazol-5-yl)- 21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (7?)-3-amino-44-chloro-21-(methyl-t / 3)-3-(4-methyl-4Z / -l,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (7?)-3-amino-44-chloro-21-cyclopropyl-3 -(4-methyl-4Z / -l,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; (R)-3-hydroxy-21-methyl-3-(l-methyl-l / / -imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile; (JO^-amino^-methyl-3-(1-methyl-l / T-imidazol-S-yO^-oxo^1^2-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile; (R)-3 -amino-21 -methyl-3 -(4-methyl -4 / / -1,2,4-tri azol-3 -yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphane-44-carbonitrile; ( / 0-019 ( / 0-020 ( / 0-021 ( / 0-025 ( / 0-027 ( / 0-028 ( / 0-029 ( / 0-030 ( / 0-034 ( / 0-035 ( / 0-036 ( / 0-037 ( / 0-039 ( / O^-amino-d^chloro^-methyl-S-Q-methyl-lZZ-imidazol-S-yl)^1^2-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (7?)-3-amino-44-chl oro-21-(methyl-^)-3-(1-methyl-177-imidazol-5-yl)- 21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (7?)-3-amino-44-chloro-3-(l-methyl-l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22-carbonitrile; ( / 0-3-amino-44-chloro-21-methyl-3-(4-methyl-4JH-l,2,4-triazol-3-yl)- 21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; (R)-3-hy droxy-21-(methyl-^)-3-(1-methyl-177-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacy cl ohexaphane-44-carbonitrile; (7?)-3-amino-21-(methyl-t / 3)-3-(l-methyl-lJH-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (R)-3-amino-21-cy cl opropyl-3-(l -methyl- l / / -imidazol-5-yl)-22-oxo-2', 22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (7?)-3-amino-3-(l-methyl-l / 7-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacy cl ohexaphane-22,44-di carbonitrile; (R)-3-amino-3-(l -methyl-l / / -imidazol-5-yl)-22-morpholino-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-44-carbonitrile; (R)-3-amino-3-(l-(methyl-t / 3)-lJH-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile; (5)-44-chloro-2'-(methyl-t / 3)-3-(5-methyl-l / / -imidazol-I-yl )-2',22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; and (5)-44-chloro-2'-(methyl-t / 3)-3-(4-methyl-l / / -imidazol-I-yl )-2',22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; or a pharmaceutically acceptable form thereof.

[00177] In some embodiments, the compound is selected from: 3-amino-44-chl oro-21-cy clopropyl-3-(l-methyl-17 / -imidazol-5-yl)-2l, 22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; ( / 0-046 ( / 0-047 ( / 0-048 ( / 0-051 ( / 0-055 ( / 0-056 ( / 0-057 ( / 0-058 ( / 0-066 ( / 0-070 (5)-076 (5)-077 092 44-chloro-21-cyclopropyl-3-hy droxy-3-(l-methyl-l / Z-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-21-cyclopropyl-3-hy droxy-3-(l-methyl-l / Z-imidazol-5-yl)- 21,22-dihydro-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chloro-21-cyclopropyl-3-hy droxy-3-(l-methyl-l / Z-imidazol-5-yl)- 21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 093 094 095 096 097 098 099 100 101 102 103 44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-2\22-dihydro-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(l-methyl-lJH-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chl oro-21 -cyclopropyl -3-(1 -methyl -1ZZ-imidazol -5 -yl)-3 -morpholino-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chl oro-21 -cy cl opropyl -3-(1 -methyl - 17 / -i m i dazol -5 -yl)-3 -morpholino-21,22-dihydro-5-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chl oro-21 -cyclopropyl -3-(1 -methyl -1ZZ-imidazol -5 -yl)-3 -morpholino-21,22-dihydro-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphan-22-one; 44-chl oro-21 -cy cl opropyl -3-(1 -methyl - 17 / -i m i dazol -5 -yl)-3 -morpholino-21,22-dihydro-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-22-one; 44-chl oro-21 -cy cl opropyl -3-(1 -methyl - 17 / -i m i dazol -5 -yl)-3 -morpholino-21,22-dihydro-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane; 44-chl oro-3-(l-methyl-l / / -imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacy cl ohexaphan-3-amine; 44-chl oro-3-(l-methyl-l / / -imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol; 44-chl oro-3-(l-methyl-l / / -imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol; 44-chloro-3-(l-methyl-l / / -imidazol-5-yl)-7-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacycloheptaphan-3-ol; 44-chl oro-3 -(1 -methyl- l / / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol; 44-chl oro-3-(l-methyl-lZ / -imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina-1,4( 1,3)-dibenzenacy cl ohexaphan-3 -amine; 44-chl oro-3-(l-methyl-lZ / -imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina- 1,4( 1,3)-dibenzenacycloheptaphan-3 -ol; 104 105 106 107 108 109 110 111 112 113 114 115 116 117 44-chl oro-3-(l -methyl-lJ7-imidazol-5-yl)-2(l,7)-isoquinolina-l, 4(1,3)-dibenzenacyclohexaphan-3-ol; 44-chl oro-3-(l-methyl-lJ7-imidazol-5-yl)-7-oxa-2(l,7)-isoquinolina- 1,4( 1,3)-dibenzenacycloheptaphan-3 -ol; 44-chl oro-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina- 1,4( 1,3)-dibenzenacyclohexaphan-3 -ol; 44-chl oro-N-(2-fluoroethyl)-3-(l-methyl-lZ / -imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chl oro-N-(2-fluoroethyl)-3-(l-methyl-lZ / -imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphan-3-amine; 44-chl oro-N-(2-fluoroethyl)-3-(l -methyl-lZ / -imidazol-5-yl)-2(l, 7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chl oro-N-(2-fluoroethyl)-3-(l-methyl-lZ / -imidazol-5-yl)-7-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphan-3-amine; 44-chl oro-N-(2-fluoroethyl)-3-(l-methyl-lZ / -imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chloro-N-(2-chloroethyl)-3-(l-methyl-lJH-imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chloro-N-(2-chloroethyl)-3-(l-methyl-lJH-imidazol-5-yl)-5-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphan-3-amine; 44-chloro-N-(2-chloroethyl)-3-(l-methyl-lJH-imidazol-5-yl)-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chloro-N-(2-chloroethyl)-3-(l-methyl-l / / -imidazol-5-yl)-7-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphan-3-amine; 44-chloro-N-(2-chloroethyl)-3-(l-methyl-lJH-imidazol-5-yl)-6-oxa-2(l,7)-isoquinolina-l,4(l,3)-dibenzenacyclohexaphan-3-amine; 44-chl oro-3-(l -methyl-lJH-imidazol-5-yl)-3-morpholino-5-oxa-2(l, 7)-isoquinolina-1,4( 1,3)-dibenzenacyclohexaphane; 44-chl oro-3-(l -methyl-lJH-imidazol-5-yl)-3-morpholino-5-oxa-2(l, 7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphane; 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 4-(44-chloro-3-(l-methyl-lJ / -imidazol-5-yl)-2(l,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane-3-yl)morpholine; 44-chl oro-3-(l -methyl-17 / -imidazol-5-yl)-3-morpholino-7-oxa-2(l, 7)-isoquinolina-l,4(l,3)-dibenzenacycloheptaphane; and 44-chl oro-3-(l-methyl-17 / -imidazol-5-yl)-3-morpholino-6-oxa-2(l,7)-isoquinolina-1,4( 1,3)-dibenzenacyclohexaphane; and stereoisomers thereof, and pharmaceutically acceptable forms thereof. 5.2 PHARMACEUTICAL COMPOSITIONS

[00178] In some embodiments, provided herein is a pharmaceutical composition containing a therapeutically effective amount of a compound having a structure of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof (e.g., pharmaceutically acceptable salt, solvate, isomer, or isotopologue thereof), or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. For example, in some embodiments, the pharmaceutical composition provided herein contains a therapeutically effective amount of a compound having a structure of any one of Formula (la), (lb), (Ila), (lib), (Illa), (IITb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. For example, in some embodiments, the pharmaceutical composition provided herein contains a therapeutically effective amount of a compound having a structure of any one of Formula (II-1), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (Hb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (Illa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or a pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VI-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[00179] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically the compound disclosed herein is formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[00180] The compositions can be formulated for single dosage administration. To formulate a composition, the weight fraction of the compound disclosed herein is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds disclosed herein provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[00181] In addition, the compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, can be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other therapeutically active ingredients.

[00182] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans.

[00183] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[00184] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, metabolism, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

[00185] The compositions are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[00186] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

[00187] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

[00188] Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 °C, resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S—S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[00189] Dosage forms or compositions containing active ingredient in the range of 0.001% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% to 100% active ingredient, in certain embodiments, about 0.1-85%, about 75-95%, or about 80-98%.

[00190] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, can be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[00191] The compositions can include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, can also be administered together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress.

[00192] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[00193] In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.

[00194] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[00195] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[00196] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[00197] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil.

[00198] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[00199] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[00200] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in LT.S. Patent Nos 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[00201] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[00202] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[00203] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

[00204] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also provided herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow release or sustained release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and crosslinked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[00205] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[00206] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[00207] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[00208] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[00209] Injectables are designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w / w up to about 90% w / w or more, such as more than 1% w / w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[00210] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, can be suspended in micronized or other suitable form produce a more soluble active product. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.

[00211] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

[00212] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, or pharmaceutical composition comprising the same, can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic solutions, pH about 5-7, with appropriate salts.

[00213] Other routes of administration, such as transdermal patches, and rectal administration are also contemplated herein. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono , di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

[00214] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, or pharmaceutical composition comprising the same, can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461,6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of the compounds disclosed herein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[00215] In certain embodiments, the compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, can be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984).

[00216] The compound of any one of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, or pharmaceutical composition comprising the same, can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable form thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer dependent on a farnesylated protein, and a label that indicates that the compound or pharmaceutically acceptable form thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer dependent on a farnesylated protein.

[00217] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated.

[00218] In some embodiments, the article of manufacture is a kit. The kit can include a compound or pharmaceutical composition as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the pharmaceutical composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.

[00219] In some embodiments, a memory aid is provided with the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. A “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.

[00220] Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and can be included in the kit. In other embodiments, kits can further comprise devices that are used to administer the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits can also, in some embodiments, be marketed directly to the consumer.

[00221] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. The strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[00222] Kits can further comprise pharmaceutically acceptable vehicles that can be used to administer the active agent. For example, if an active agent is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active agent can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. 5.3    USES AND METHODS 5.3.1   THERAPEUTIC USES AND METHODS

[00223] RAS isoforms associate with the inner surface of the plasma membrane to transduce extracellular signals. To become active, RAS undergoes several post-translational modifications. Among the first steps in becoming activated is the farnesylation of the cysteine in the CAAX box at the C-terminal end (where C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, E.K., et al., J. Clin. Oncol. 1999, 17, 3631-3652. The enzyme famesyltransferase (FTase) recognizes the CAAX motif and transfers a 15-carbon farnesyl isoprenoid from farnesyl diphosphate to the cysteine residue. The AAX amino acids subsequently are cleaved by Ras-converting enzyme I, and the farnesylated cysteine is carboxymethylated by isoprenylcysteine carboxyl methyltransferase. Prior, I. A., et al., J. Cell Sci. 2001, 114, 1603-1608. Further palmitoylation (KRAS4A, NRAS, and HRAS or the presence of a polybasic domain (KRAS4B) leads to anchoring of the protein in the plasma membrane. Hancock, J.F., et al., Cell 1990, 63, 133-139. The observations suggest prenylation is required for the function of all RAS isoforms, including their mutated forms. However, some farnesylated proteins - including KRAS and NRAS - can be rescued from membrane displacement in the presence of a famesyltransferase inhibitor (FTI) by an alternative prenylation by the enzyme geranylgeranyltransferase (GGTase). Zhang, F.L., et al., J. Biol. Chern. 1997, 272, 10232-10239; Whyte, D.B., et al., J. Biol. Chern. 1997, 272, 14459-14464. Conversely, the third family member, HRAS, is not a GGTase substrate, and thus its membrane localization and cellular function are diminished by an FTI. Whyte, D.B., et al. Accordingly, the use of FTIs to target enriched patient populations of tumors, for example tumors dependent on farnesylated proteins, such as HRAS, for example tumors harboring HRAS mutations, should provide clinical benefit.

[00224] One particular FTI that is in clinical development is tipifarnib. The efficacy of tipifarnib was examined in a series of cell- and patient-derived xenograft models of head and neck squamous cell carcinoma (HNSCC). Gilardi, M., et al., Mol. Cancer Ther. 2020, 19, 17841796. Genomic analyses have revealed that HRAS mutations occur in 6% of HNSCC at initial diagnosis (Hoadley, K.A., et al., Cell 2018, 173, 291-304) and in 15% of patients during acquisition of resistance to cetuximab (Braig, F., et al., Oncotarget 2016, 7, 42988-42995), and HRAS mutations have been demonstrated to correlate with reduced response of HNSCC patients to cetuximab treatment. “Rampias, T., et al., Clin. Cancer Res. 2014, 20, 2933-2946.

[00225] HRAS is also recurrently mutated in other cancer types, including urothelial cell carcinoma and salivary gland tumors, and 24% of HRAS mutant metastatic urothelial carcinoma patients treated with tipifarnib experienced an objective response. In addition, of 13 pts with recurrent / metastatic salivary gland tumors (SGT) treated with tipifarnib, one experienced an objective response and an additional seven patients had stable disease as best response. Ho, A.L., et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types exhibiting recurrent HRAS driver mutations include lung squamous cell carcinoma, thyroid cancer, pheochromocytoma and paraganglioma. Hoadley, K.A., et al.

[00226] In certain embodiments, the compound as disclosed herein is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (11-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, is a farnesyltransferase inhibitor. In some embodiments, the compound as disclosed herein is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, is a farnesyltransferase inhibitor. In certain embodiments, the compound, or pharmaceutically acceptable form thereof, as disclosed herein, is a selective farnesyltransferase inhibitor, relative to inhibition of geranylgeranyl transferase type-1, such as geranylgeranyl transferase type-1.

[00227] In some embodiments, provided herein is a method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of the compound of Formula (I), (II), (III), or (IV), as disclosed herein, or pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of the compound of Formula (V) or (VI), as disclosed herein, or pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (Illb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the method of inhibiting a famesyltransferase comprises contacting the famesyltransferase with an effective amount of a pharmaceutical composition, as disclosed herein, containing the compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the method of inhibiting a famesyltransferase comprises contacting the famesyltransferase with an effective amount of a pharmaceutical composition, as disclosed herein, containing the compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition contains compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the contacting of the famesyltransferase takes place in a cell. In some embodiments, the famesyltransferase is present in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. In some embodiments, the subject suffers from a cancer dependent on a farnesylated protein. In some embodiments, the subject is a human.

[00228] In some embodiments, the method inhibits famesylation of H-Ras protein. In some embodiments, the H-Ras protein has a mutation. In some embodiments, the H Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein. In some embodiments, the inhibiting of the famesylation of the H-Ras protein, such as an H-Ras protein having a mutation, takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. In some embodiments, the inhibition of the famesyltransferase present in the cell takes place in a subject suffering from cancer dependent on a farnesylated protein. In some embodiments, the cancer dependent on a farnesylated protein is a solid tumor. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on one or more farnesylated proteins. In some embodiments, the cancer dependent on a farnesylated protein is dependent on the farnesylated protein(s) for the progression and / or survival of said cancer. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated H-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein has an H-Ras protein mutation. In some embodiments, the H Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the head and neck cancer, for example, HNSCC, is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the head and neck cancer, for example, HNSCC, has an H-Ras protein mutation. In some embodiments, the cancer dependent on a farnesylated protein is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer dependent on a farnesylated protein is thyroid cancer, head and neck cancers, urothelial cancers, salivary cancers, cancers of the upper digestive tract, bladder cancer, breast cancer, ovarian cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer. In some embodiments, the cancer is Squamous Cell Carcinoma (SCC). For example, in some embodiments, the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC) or urothelial carcinoma (UC). In some embodiments, the SCC is HNSCC. In some embodiments, the SCC is human papillomavirus (HPV)-negative SCC. In some embodiments, the HNSCC is HPV-negative HNSCC. For example, in some embodiments, the HNSCC is HNSCC of the trachea, HNSCC of the maxilla, HNSCC of the oral cavity. In some embodiments, the SCC, for example, HNSCC, lung SCC, thyroid SCC, esophagus SCC, bladder SCC or urothelial carcinoma, is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the HNSCC is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the SCC, for example, HNSCC, lung SCC, thyroid SCC, esophagus SCC, bladder SCC or urothelial carcinoma, has an H-Ras protein mutation. In some embodiments, the HNSCC has an H-Ras protein mutation. In some embodiments, the subject is a human.

[00229] In some embodiments, the method inhibits famesylation of N-Ras protein. In some embodiments, the N-Ras protein has a mutation. In some embodiments, the N Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein. In some embodiments, the inhibiting of the famesylation of the N-Ras protein, such as an N-Ras protein having a mutation, takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. In some embodiments, the inhibition of the farnesyltransferase present in the cell takes place in a subject suffering from cancer dependent on a famesylated protein. In some embodiments, the cancer dependent on a farnesylated protein is a solid tumor. In some embodiments, the cancer dependent on a famesylated protein is a cancer dependent on one or more farnesylated proteins. In some embodiments, the cancer dependent on a farnesylated protein is dependent on the famesylated protein(s) for the progression and / or survival of said cancer. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on famesylated N-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein has an N-Ras protein mutation. In some embodiments, the N-Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein is melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma is dependent on one or more famesylated proteins, such as dependent on a famesylated N-Ras protein. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma has an N-Ras protein mutation. In some embodiments, the subject is a human.

[00230] In some embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of the compound of Formula (I), (II), (III), or (IV), as disclosed herein, or pharmaceutically acceptable form thereof, to the subject having cancer dependent on a farnesylated protein. In some embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of the compound of Formula (V) or (VI), as disclosed herein, or pharmaceutically acceptable form thereof, to the subject having cancer dependent on a farnesylated protein. In some embodiments, the compound is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the method of treating cancer dependent on a farnesylated protein in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition, as disclosed herein, containing the compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, or of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient, to the subject having cancer dependent on a farnesylated protein. In some embodiments, the pharmaceutical composition contains compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (Illb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition contains compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the cancer dependent on a farnesylated protein is a solid tumor. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on one or more farnesylated proteins. In some embodiments, the cancer dependent on a farnesylated protein is dependent on the farnesylated protein(s) for the progression and / or survival of said cancer. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated H-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein has an H-Ras protein mutation. In some embodiments, the H Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein is head and neck cancer. In some embodiments, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the head and neck cancer, for example, HNSCC, is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the head and neck cancer, for example, HNSCC, has an H-Ras protein mutation. In some embodiments, the cancer dependent on a farnesylated protein is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancer dependent on a farnesylated protein is thyroid cancer, head and neck cancers, urothelial cancers, salivary cancers, cancers of the upper digestive tract, bladder cancer, breast cancer, ovarian cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer. In some embodiments, the cancer dependent on a farnesylated protein is Squamous Cell Carcinoma (SCC). For example, in some embodiments, the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC) or urothelial carcinoma (UC). In some embodiments, the SCC is HNSCC. In some embodiments, the SCC is human papillomavirus (HPV)-negative SCC. In some embodiments, the HNSCC is HPV-negative HNSCC. For example, in some embodiments, the HNSCC is HNSCC of the trachea, HNSCC of the maxilla, HNSCC of the oral cavity. In some embodiments, the SCC, for example, HNSCC, lung SCC, thyroid SCC, esophagus SCC, bladder SCC or urothelial carcinoma, is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the HNSCC is dependent on one or more farnesylated proteins, such as dependent on a farnesylated H-Ras protein. In some embodiments, the SCC, for example, HNSCC, lung SCC, thyroid SCC, esophagus SCC, bladder SCC or urothelial carcinoma, has an H-Ras protein mutation. In some embodiments, the HNSCC has an H-Ras protein mutation. In some embodiments, the subject is a human.

[00231] In some embodiments, provided herein is a method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of the compound of Formula (I), (II), (III), or (IV), as disclosed herein, or pharmaceutically acceptable form thereof, to the subject having cancer dependent on a famesylated protein. In some embodiments, provided herein is a method of treating cancer dependent on a famesylated protein in a subject, comprising administering a therapeutically effective amount of the compound of Formula (V) or (VI), as disclosed herein, or pharmaceutically acceptable form thereof, to the subject having cancer dependent on a famesylated protein. In some embodiments, the compound is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the method of treating cancer dependent on a famesylated protein in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition, as disclosed herein, containing the compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient, to the subject having cancer dependent on a famesylated protein. In some embodiments, the method of treating cancer dependent on a famesylated protein in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition, as disclosed herein, containing the compound of Formula (V) or (VI), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient, to the subject having cancer dependent on a famesylated protein. In some embodiments, the pharmaceutical composition contains compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition contains compound of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (Via-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the cancer dependent on a famesylated protein is a solid tumor. In some embodiments, the cancer dependent on a famesylated protein is dependent on one or more famesylated proteins. In some embodiments, the cancer dependent on a famesylated protein is dependent on the farnesylated protein(s) for the progression and / or survival of said cancer. In some embodiments, the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated N-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein has an N-Ras protein mutation. In some embodiments, the N Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein. In some embodiments, the cancer dependent on a farnesylated protein is melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma is dependent on one or more farnesylated proteins, such as dependent on a farnesylated N-Ras protein. In some embodiments, the melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma has an N-Ras protein mutation. In some embodiments, the subject is a human.

[00232] In some embodiments, the method of treating cancer dependent on a farnesylated protein, as disclosed herein, wherein the method further comprises determining the presence or absence of the H-Ras mutation. In some embodiments, the method of treating cancer dependent on a farnesylated protein, as disclosed herein, wherein the method further comprises determining the presence or absence of the N-Ras mutation. In some embodiments, determining the presence or absence of the H-Ras mutation comprises analyzing nucleic acids obtained from a sample from the subject. In some embodiments, determining the presence or absence of the N-Ras mutation comprises analyzing nucleic acids obtained from a sample from the subject. In some embodiments, said sample is a tissue biopsy. In some embodiments, said sample is a tumor biopsy. In some embodiments, the H-Ras mutation or the N-Ras mutation is determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay. In some embodiments, the H-Ras mutation is determined by PCR. In some embodiments, the N-Ras mutation is determined by PCR. In some embodiments, the H-Ras mutation is determined by sequencing. In some embodiments, the N-Ras mutation is determined by sequencing.

[00233] In some embodiments, the compound as disclosed herein is a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), for example a compound of Formula (II-l), (11-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (Ila-1), (IIb-1), (IIa-2), (IIb-2), (Illa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, or of Formula (III-3), (IIIa-3), (IIIb-3), (Va), (Vb), (V-l), (Va-1), (Vb-1), (Via), (VIb), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, and is metabolically stable, for example, metabolically stable to liver metabolism in a subject, such as metabolically stable to liver metabolism in a human. 5.3.2 DOSES AND REGIMENS

[00234] A compound described herein can be delivered in the form of a pharmaceutical composition which comprises a therapeutically effective amount of a compound of any one of Formula (I), (II), (III), or (IV), such as a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or a pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), such as a compound of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof. The pharmaceutical compositions disclosed herein are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. In some embodiments, a selected dosage level will depend upon a variety of factors including, for example, the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts

[00235] A suitable daily dose of a compound described herein administered to a subject will be that amount of the compound which, in some embodiments, can be the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described herein. In some embodiments, a therapeutically effective amount of the compound of any one of Formula (I), (II), (III), or (IV), such as a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), such as a compound of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, as the active ingredient, is in an amount of from about 0.01 up to about 500 mg / kg daily, either as a single dose or subdivided into more than one dose, or more particularly in an amount of from about 0.01 to about 400 mg / kg daily, such as in an amount of from about 0.01 to about 300 mg / kg daily, about 0.01 to about 200 mg / kg daily, about 0.01 to 100 mg / kg daily, about 0.01 to about 50 mg / kg daily, about 0.01 to about 25 mg / kg daily, or about 0.01 to about 10 mg / kg daily, such as in an amount of about 0.01 mg / kg daily, about 0.025 mg / kg daily, about 0.05 mg / kg daily, about 0.075 mg / kg daily, about 0.1 mg / kg daily, about 0.25 mg / kg daily, about 0.5 mg / kg daily, about 0.75 mg / kg daily, about 1 mg / kg daily, about 2.5 mg / kg daily, about 5 mg / kg daily, about 7.5 mg / kg daily, about 10 mg / kg daily, about 15 mg / kg daily, about 20 mg / kg daily, about 25 mg / kg daily, about 50 mg / kg daily, about 75 mg / kg daily, about 100 mg / kg daily, about 100 mg / kg daily, about 200 mg / kg daily, about 300 mg / kg daily, about 400 mg / kg daily, or about 500 mg / kg daily. For example, in some embodiments, the dosage or therapeutically effective amount of the compound, or pharmaceutically acceptable form thereof, disclosed herein, is in an amount of from about 0.01 to about 25 mg / kg daily, about 0.01 to about 20 mg / kg daily, about 0.01 to about 15 mg / kg daily, about 0.01 to about 10 mg / kg daily, about 0.01 to about 7.5 mg / kg daily, about 0.01 to about 5 mg / kg daily, or about 0.01 to about 2.5 mg / kg daily, such as in an amount of about 0.01 mg / kg daily, about 0.025 mg / kg daily, about 0.05 mg / kg daily, about 0.075 mg / kg daily, about 0.1 mg / kg daily, about 0.25 mg / kg daily, about 0.5 mg / kg daily, about 0.75 mg / kg daily, about 1 mg / kg daily, about 2.5 mg / kg daily, about 5 mg / kg daily, about 7.5 mg / kg daily, about 10 mg / kg daily, about 15 mg / kg daily, about 20 mg / kg daily. In some embodiments, the compound is a compound of Formula (II-l), (II-2), (III-1), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof. In some embodiments, the therapeutically effective amount of the compound of any one of Formula (I), (II), (III), or (IV), for example a compound of Formula (la), (lb), (Ila), (lib), (Illa), (Illb), (IVa), or (IVb), or pharmaceutically acceptable form thereof, or a compound of Formula (V) or (VI), such as a compound of Formula (Va), (Vb), (Via), or (VIb), or a pharmaceutically acceptable form thereof, is contained in a pharmaceutical composition as described herein. In some embodiments, the therapeutically effective amount of the compound of any one of Formula (II-l), (II-2), (III-l), (III-2), (IV-1), or (IV-2), such as Formula (IIa-1), (IIb-1), (IIa-2), (IIb-2), (IIIa-1), (IIIb-1), (IIIa-2), (IIIb-2), (IVa-1), (IVb-1), (IVa-2), or (IVb-2), or pharmaceutically acceptable form thereof, or a compound of Formula (III-3), (IIIa-3), (IIIb-3), (V-l), (Va-1), (Vb-1), (VIa-1), or (VIb-1), or a pharmaceutically acceptable form thereof, is contained in a pharmaceutical composition as described herein. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, such as a human patient, composition, and mode of administration, without being toxic to the subject. In some instances, dosage levels below the lower limit of the aforesaid range can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout t...

Claims

1. A compound which is a compound of Formula (II), Formula (III), Formula (IV),Formula (V), or Formula (VI):Formula (II)                Formula (III)                Formula (IV)Formula (V)Formula (VI)wherein:A2 is independently N, NR2a, CR2b, or -C(=O)-;A3 is independently CR3 or N;A4 is CR8 or N;A5 and A6 are each independently CR8 or N, or A5 and A6 taken together are O, NR9, or S;W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S;Y is a bond or a linker having a length of up to 6 atoms;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S;2022399572   16 Jun 2026R1a and R2a are each independently R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10R11, -S(O)pR9, or -S(O)2NR10R11;R1b, R2b, R3, R5 and R8, at each occurrence, are each independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10R11, -NR10R11, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)pR9, -S(O)2NR10R11 or -NR10S(O)2NR10R11;R4, at each occurrence, is independently hydrogen, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C1-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, -NR14R15, C6-12 aryl, or 5-12 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C1-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C6-12 aryl, or 5-12 membered heteroaryl of the R4 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and (O);R4A and R5A are independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and (O);R6 is CN, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10R11, -NR10R11, -NR10OR9, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -NR10C(NR10)NR10R11, -S(O)pR9, -S(O)2NR10R11, or -NR10S(O)2NR10R11;R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10R11, -NR10R11, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)pR9, -S(O)2NR10R11 and -NR10S(O)2NR10R11;2022399572   16 Jun 2026R9, at each occurrence, is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R9 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10R11, -NR10R11, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)pR12, -S(O)2NR10R11, and -NR10S(O)2NR10R11;R10 and R11, at each occurrence, are each independently hydrogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C6-12 aryl, or 5-12 membered heteroaryl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C6-12 aryl, or 5-12 membered heteroaryl of the R10 and the R11 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, (O), -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)OR13, -C(O)NR14R15, -NR14R15, -NR14C(O)R13, -NR14C(O)OR13, -NR14C(O)NR14R15, -NR14S(O)2R13, -S(O)pR13, -S(O)2NR14R15, and -NR14S(O)2NR14R15;R12, at each occurrence, is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R12 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, (O), -C(O)R13,2022399572   16 Jun 2026-C(O)OR13, -OC(O)R13, -OC(O)OR13, -C(O)NR10R11, -NR10R11, -NR10C(O)R13, -NR10C(O)OR13, -NR10C(O)NR10R11, -NR10S(O)2R13, -S(O)pR13, -S(O)2NR10R11, and -NR10S(O)2NR10R11;R13, at each occurrence, is independently hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl;R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; andeach p is independently an integer of 0, 1 or 2.or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a mixture of diastereomers, or a mixture of stereoisomers thereof.

2. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 1, wherein:A3 is CR3 or N, wherein R3 is hydrogen;A4 is CR8, wherein R8 is hydrogen;A5 is CR8, wherein R8 is hydrogen;A6 is CR8 or N, wherein R8 is hydrogen;each of W1, W2, W3, and W4 is independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S;Y is a linker having a length of up to 3 atoms; wherein Y is in the direction of Z-Y-W, wherein Z is the ring comprising Z1 to Z4 and W is the ring comprising W1 to W4, and said Y is -(CH2)1-3-, -O-, -O(CH2)1-2-, or -(CH2)1-2O-;each of Z1, Z2, Z3, and Z4 is independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S;R6 is CN, R9, -OR9, -NR10R11, or -NR10OR9; wherein R9 is independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, or 3-6 membered heterocycloalkyl; and wherein each of R10 and R11 is independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 hydroxyalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; and2022399572   16 Jun 2026R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, R9, -OH, or -OR9; wherein R9 is independently C1-3 alkyl or C1-3 haloalkyl; wherein the 5-12 membered heteroaryl comprises 1-4 ring heteroatoms independently selected from oxygen, nitrogen, sulfur, and phosphorus; wherein:i) each 3-6 membered heterocycloalkyl independently comprises at least one ring heteroatom independently selected from oxygen, nitrogen, sulfur and phosphorus; andii) each 6 membered heteroaryl independently comprises 1-4 ring heteroatoms independently selected from oxygen, nitrogen, sulfur and phosphorus.

3. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 2, wherein the compound is a compound of Formula (II):Formula (II)wherein:R1a is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 hydroxyalkyl;each of W1, W2, W3, and W4 is independently N, CH, or CR4, wherein R4, at each occurrence, is independently halo; andeach of Z1, Z2, Z3, and Z4 is independently N, CH, or CR5, wherein R5, at each occurrence, is independently R9, -OH, -OR9, halo, or CN; wherein R9 is independently C1-6 alkyl or C1-6 haloalkyl.

4. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture2022399572   16 Jun 2026of stereoisomers thereof, of claim 3, wherein the compound is a compound of Formula (IIa)or a compound of Formula (IIb):Formula (IIa)Formula (IIb).

5. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 3, wherein the compound is a compound of Formula (II-1), (IIa-1), (IIb-1), (II-2), (IIa-2), or (IIb-2):Formula (II-1)Formula (IIa-1)Formula (IIb-1)2022399572   16 Jun 2026R1aR5Formula (II-2)Formula (IIa-2)                    Formula (IIb-2).

6. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 2, wherein the compound is a compound of Formula (III):Formula (III)wherein:R2b is -R9, -OR9, halo, CN, -NR10R11, or -C(O)NR10R11, wherein R9 is independently hydrogen or C1-6 alkyl, or 3-6 membered heterocycloalkyl, and wherein R10 and R11 are2022399572   16 Jun 2026independently hydrogen or a 3-6 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl;each of W1, W2, W3, and W4 is independently N, CH, or CR4, wherein R4, at each occurrence, is independently halo; andeach of Z1, Z2, Z3, and Z4 is independently N, CH, or CR5, wherein R5, at each occurrence, is independently R9, -OH, -OR9, halo, or CN; wherein R9 is independently C1-6 alkyl or C1-6 haloalkyl.

7. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixtureof stereoisomers thereof, of claim 6, wherein the compound is a compound of Formula (IIIa)or a compound of Formula (IIIb):Formula (IIIb).

8. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 6, wherein the compound is a compound of Formula (III-1), (IIIa-1), (IIIb-1), (III-2), (IIIa-2), (IIIb-2), (III-3), (IIIa-3), or (IIIb-3):Formula (III-1)2022399572   16 Jun 2026r; £ T R5 Formula (IIIa-1) R7 R6JV N<. r£ r; £ T CjlX R5 Formula (IIIa-2) R7 R6— R2b    R\ I (T jT 'X <r? R5 Formula (IIIb-1) N<5::>^ R2b Formula (III-2) R2b     R2b ^N j        |T jX X ^7 1   CaXj R5 Formula (IIIb-2) ^N.    p2b n r X Xl R5 Formula (III-3)2022399572   16 Jun 2026Formula (IIIa-3)Formula (IIIb-3).

9. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 2, wherein the compound is a compound of Formula (IV):Formula (IV)wherein:R1b is hydrogen;each of W1, W2, W3, and W4 is independently N, CH, or CR4, wherein R4, at each occurrence, is independently halo; andeach of Z1, Z2, Z3, and Z4 is independently N, CH, or CR5, wherein R5, at each occurrence, is independently R9, -OH, -OR9, halo, or CN; wherein R9 is independently C1-6 alkyl or C1-6 haloalkyl.

10. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture2022399572   16 Jun 2026of stereoisomers thereof, of claim 9, wherein the compound is a compound of Formula (IVa)or a compound of Formula (IVb):Formula (IVa)Formula (IVb).

11. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 9, wherein the compound is a compound of Formula (IV-1), (IVa-1), (IVb-1), (IV-2), (IVa-2), or (IVb-2):Formula (IV-1)2022399572   16 Jun 2026R1b                  R1bFormula (IVa-1)            Formula (IVb-1)R1bR5Formula (IV-2)R1b                  R1bFormula (IVa-2)            Formula (IVb-2).

12. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 2, wherein the compound is a compound of Formula (V):2022399572   16 Jun 2026wherein:R1b is hydrogen;each of W1, W2, W3, and W4 is independently N, CH, or CR4, wherein R4, at each occurrence, is independently halo; andeach of Z1, Z2, Z3, and Z4 is independently N, CH, or CR5, wherein R5, at each occurrence, is independently R9, -OH, -OR9, halo, or CN; wherein R9 is independently C1-6 alkyl or C1-6 haloalkyl.

13. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixtureof stereoisomers thereof, of claim 12, wherein the compound is a compound of Formula (Va)or a compound of Formula (Vb):Formula (Va)Formula (Vb).

14. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 12, wherein the compound is a compound of Formula (V-1), (Va-1), or (Vb-1):2022399572   16 Jun 2026Formula (V-1)Formula (Va-1)Formula (Vb-1).

15. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 2, wherein the compound is a compound of Formula (VI):wherein:R1b is hydrogen;each of W1, W2, W3, and W4 is independently N, CH, or CR4, wherein R4, at each occurrence, is independently halo; and2022399572   16 Jun 2026each of Z1, Z2, Z3, and Z4 is independently N, CH, or CR5, wherein R5, at each occurrence, is independently R9, -OH, -OR9, halo, or CN; wherein R9 is independently C1-6 alkyl or C1-6 haloalkyl.

16. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 15, wherein the compound is a compound of Formula (VIa)or a compound of Formula (VIb):Formula (VIa)17. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 15, wherein the compound is a compound of Formula (VI-1), (VIa-1), or (VIb-1):Formula (VI-1)2022399572   16 Jun 2026Formula (VIa-1)Formula (VIb-1).

18. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 5, wherein R1a is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 hydroxyalkyl.

19. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 5, wherein R1a is hydrogen, C1-3 alkyl, C3-4 cycloalkyl, or C1-3 hydroxyalkyl.

20. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 5, wherein R1a is:(a) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl, or cyclopropyl; or(b) -CH3, -CD3, or cyclopropyl; or(c) -CH3 or -CD3; or(d) cyclopropyl.

21. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1, 2, and 6 to 8, wherein R2b is:(a) hydrogen, C1-6 alkyl, C1-6 alkoxy, -OR9 wherein R9 is 3-6 membered heterocycloalkyl, halo, CN, -C(O)NR10R11, or -NR10R11;2022399572   16 Jun 2026wherein each of R10 and R11, at each occurrence, is independently hydrogen or 3-6 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; or(b) hydrogen, C1-3 alkyl, C1-3 alkoxy, -OR9 wherein R9 is 3-4 membered heterocycloalkyl, halo, CN, -C(O)NR10R11, or -NR10Rn;wherein each of R10 and R11, at each occurrence, is independently hydrogen or 3-4 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 4-6 membered heterocycloalkyl; or(c) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or(d) CN.

22. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 to 21, wherein:(a) A3 is CR3, wherein R3 hydrogen;(b) A6 is CR8; wherein R8 is hydrogen; or(c) each of A4, A5 and A6 is independently CR8, wherein R8 is hydrogen.

23. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 22, wherein Y is -(CH2)O-, -O(CH2)-, -(CH2)2O-, -O(CH2)2-, or -(CH2)2-.

24. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 2 to 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 to 23, wherein at least one of W1, W2, W3, and W4 is N, optionally, wherein:each of W1, W2, and W3 is independently CH or CR4, and W4 is N;each of W1, W2, and W4 is independently CH or CR4, and W3 is N;each of W1, W3, and W4 is independently CH or CR4, and W2 is N; oreach of W2, W3, and W4 is independently CH or CR4, and W1 is N.2022399572   16 Jun 202625. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 2 to 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 to 23, wherein each of W1, W2, W3, and W4 is independently CH or CR4.

26. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 2 to 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 to 25, wherein at least one of Z1, Z2, Z3, and Z4 is N, optionally wherein:each of Z1, Z2, and Z3 is independently CH or CR5, and Z4 is N;each of Z1, Z2, and Z4 is independently CH or CR5, and Z3 is N;each of Z1, Z3, and Z4 is independently CH or CR5, and Z2 is N; oreach of Z2, Z3, and Z4 is independently CH or CR5, and Z1 is N.

27. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 2 to 4, 6, 7, 9, 10, 12, 13, 15, 16, and 18 to 25, wherein each of Z1, Z2, Z3, and Z4 is independently CH or CR5.

28. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 26 or claim 27, wherein R5, at each occurrence, is independently R9, halo, or CN; or each R5 independently is halo or CN.

29. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 26 or claim 27, wherein R5 is independently an electronwithdrawing group, optionally wherein R5 independently is chloro or R5 independently is CN.

30. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 29, wherein R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a2022399572   16 Jun 2026pyrimidinyl, optionally substituted with 1-4 substituents independently selected from halo,CN, R9, OH, or-OR9, wherein R9 is independently C1-3 alkyl or C1-3 haloalkyl;optionally wherein R7 is imidazolyl or triazolyl, optionally substituted with 1-3 substituents independently selected from halo, CN, R9, OH, or -OR9;optionally wherein R7 is a C-linked imidazolyl or a C-linked triazolyl, optionally substituted with 1-3 substituents independently selected from halo, CN, R9, OH, or -OR9.

31. The compound, pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 30, wherein R7 is an N-linked imidazolyl or an N-linked triazolyl, optionally substituted with 1-3 substituents independently selected from halo, CN, R9, OH, or -OR9, wherein R9 is independently C1-3 alkyl or C1-3 haloalkyl;optionally wherein R7 is a methyl-substituted imidazolyl or a methyl-substituted triazolyl, or R7 is a C-methyl-substituted imidazolyl or a C-methyl-substituted triazolyl, optionallyoror R7 is an N-methyl-substituted imidazolyl or an N-methyl-substituted triazolyl; optionallywherein R7 is:or, or R7 is32. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 31, wherein R6 is CN, R9, -OR9, -NR10R11, or-NR10OR9, wherein R9 is independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, or 3-6 membered heterocycloalkyl; and wherein each of R10 and R11 is independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 hydroxyalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl,2022399572   16 Jun 2026optionally wherein R9 is independently hydrogen or C1-3 alkyl, and optionally wherein R10 and R11 are each independently hydrogen, C1-3 alkyl or C1-3 alkoxy.

33. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 31, wherein R6 is hydrogen, -CH3, hydroxy,-OCH3, -OCD3, -NH2, -NHCH3, or -NH(OCH3), or R6 is hydroxy, or R6 is hydrogen, or R6 is NH2, or R6 is -NH(CH2CH2)Cl, -NH(CH2CH2)F, or N-linked morpholino.

34. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 33, wherein:the compound has a MW of no more than 1,000 g / mol; orthe compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol; orthe compound has a MW of no more than 600 g / mol; orthe compound has a MW of no more than 500 g / mol.

35. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of claim 1, wherein the compound is selected from the group consisting of:3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-2022399572   16 Jun 2026quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclo-hexaphane-22,44-dicarbonitrile;22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-ol;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;44-chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphane-22,44-dicarbonitrile;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-2022399572   16 Jun 2026quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol;44-chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-amino-44-chloro-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-hydroxy-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-amino-44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-hydroxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-hydroxy-21-(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-(methoxy-d3)-21-(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-amino-44-chloro-21-(methyl-d3)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-amino-44-chloro-21-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-44-carbonitrile;3-amino-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-44-carbonitrile;3-hydroxy-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-44-carbonitrile;3-amino-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-22-oxo-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphane-44-carbonitrile;2022399572   16 Jun 202622-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-ol;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;44-chloro-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22-carbonitrile;44-chloro-22-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;44-chloro-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-3-(methylamino)-21,22-di-hydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-amino-44-chloro-21-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-bromo-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-hydroxy-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;2022399572   16 Jun 20263-amino-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphane-22,44-dicarbonitrile;46-chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphan-3-ol;3-hydroxy-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-46-carbonitrile;3-hydroxy-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-46-carbonitrile;3-amino-21-(methyl-d3)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-4(3,5)-pyridina-1(1,3)-benzenacyclohexaphane-46-carbonitrile;3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-22-methoxy-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol;44-chloro-3-hydroxy-21-methyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-morpholino-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(piperazin-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(oxetan-3-ylamino)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-21-(2,3-dihydroxypropyl)-3-(1-methyl-1H-imidazol-5-yl)-22-oxo-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile;44-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphane-22,44-dicarbonitrile;44-cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22-carboxamide;2022399572   16 Jun 202644-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-bromo-3-(1-methyl-1H-imidazol-5-yl)-22-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-21-(methyl-d3)-3-(5-methyl-1H-imidazol-1-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-(methyl-d3)-3-(4-methyl-1H-imidazol-1-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;3-hydroxy-3-(1-(methyl-d3)-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-di-benzenacyclohexaphane-22,44-dicarbonitrile;44-chloro-21-(methyl-d3)-3-(5-methyl-1H-1,2,4-triazol-1-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-(methyl-d3)-3-(3-methyl-1H-1,2,4-triazol-1-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-bromo-22-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;44-bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinazolina-1,4(1,3)-dibenzen-acyclohexaphane-22,3-diamine;44-bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-ol;44-bromo-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-ol;3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphane-44-carbonitrile;44-bromo-27-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;3-hydroxy-27-methoxy-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(5,3)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-amino-3-(1-methyl-1H-imidazol-5-yl)-22-(oxetan-3-yloxy)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-44-carbonitrile;3-(4-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclo-hexa-phane-22,44-dicarbonitrile;2022399572   16 Jun 20263-(5-methyl-1H-imidazol-1-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexa-phane-22,44-dicarbonitrile;3-amino-44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-((2-fluoroethyl)amino)-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-3-((2-chloroethyl)amino)-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;2022399572   16 Jun 202644-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-21,22-dihydro-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-21,22-dihydro-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-22-one;44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-21,22-dihydro-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-22-one;44-chloro-21-cyclopropyl-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-21,22-dihydro-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexa-phan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacycloheptaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-amine;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acycloheptaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclo-hexaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acycloheptaphan-3-ol;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzen-acyclohexaphan-3-ol;44-chloro-N-(2-fluoroethyl)-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-N-(2-fluoroethyl)-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphan-3-amine;2022399572   16 Jun 202644-chloro-N-(2-fluoroethyl)-3-(1-methyl-1H-imidazol-5-yl)-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-N-(2-fluoroethyl)-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphan-3-amine;44-chloro-N-(2-fluoroethyl)-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-N-(2-chloroethyl)-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-N-(2-chloroethyl)-3-(1-methyl-1H-imidazol-5-yl)-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphan-3-amine;44-chloro-N-(2-chloroethyl)-3-(1-methyl-1H-imidazol-5-yl)-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-N-(2-chloroethyl)-3-(1-methyl-1H-imidazol-5-yl)-7-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphan-3-amine;44-chloro-N-(2-chloroethyl)-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphan-3-amine;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-5-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphane;4-(44-chloro-3-(1-methyl-1H-imidazol-5-yl)-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclo-hexaphane-3-yl)morpholine;44-chloro-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-7-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacycloheptaphane; and44-chloro-3-(1-methyl-1H-imidazol-5-yl)-3-morpholino-6-oxa-2(1,7)-isoquinolina-1,4(1,3)-dibenzenacyclohexaphane;including (R)- or (S)-enantiomers or racemates thereof, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, mixtures of diastereomers, and mixtures of stereoisomers thereof.

36. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, according to claim 35, wherein the compound is:2022399572   16 Jun 20263-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzen-acyclohexaphane-22,44-dicarbonitrile;or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a tautomer, and / or an (R)- or (S)-enantiomer thereof.

37. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 35, wherein the compound is a racemate, a mixture of diastereomers, or a mixture of stereoisomers, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

38. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 36, wherein the compound is a single enantiomer or a single diastereomer, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.

39. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 36 and 38, wherein the compound is a single enantiomer with an (R)-configuration at the R6 / R7-substituted carbon, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.

40. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, of any one of claims 1 to 36 and 38, wherein the compound is a single enantiomer with an (S)-configuration at the R6 / R7-substituted carbon, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.

41. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, according to any one of claims 1 to 40, wherein the compound is in a free base form or a pharmaceutically acceptable solvate thereof.2022399572   16 Jun 202642. The compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, enantiomer, diastereomer, racemate, mixture of diastereomers, or mixture of stereoisomers thereof, according to claim 6, wherein the compound is:N XNCNor a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

43. A pharmaceutical composition comprising the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a mixture of diastereomers, or a mixture of stereoisomers thereof, or the compound according to claim 42, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

44. A method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a mixture of diastereomers, or a mixture of stereoisomers thereof, or with the compound according to claim 42, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, or with the pharmaceutical composition of claim 43, optionally wherein the farnesyltransferase is present in a cell, optionally wherein the contacting of the farnesyltransferase takes place in a cell, optionally wherein the cell is in a subject, optionally wherein the cell is a mammalian cell, optionally wherein the cell is a human cell, andoptionally wherein the subject suffers from a cancer dependent on a farnesylated protein.

45. A method of treating cancer dependent on a farnesylated protein in a subject, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a2022399572   16 Jun 2026tautomer, an enantiomer, a diastereomer, a racemate, a mixture of diastereomers, or a mixture of stereoisomers thereof, or the compound according to claim 42, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, or the pharmaceutical composition of claim 43, to the subject having cancer dependent on a farnesylated protein, optionally wherein the subject is human.

46. The method of claim 44 or claim 45, wherein the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated H-Ras protein, optionally wherein the cancer dependent on a farnesylated protein has an H-Ras protein mutation, optionally wherein the H-Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof, in the corresponding mutant H-Ras protein;optionally wherein:(i) the presence or absence of the H-Ras mutation has been determined by analysis of nucleic acids obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or is a tumor biopsy; or(ii) the presence or absence of the H-Ras mutation has been determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay; or (iii) a combination thereof.

47. The method of any one of claims 44 to 46, wherein the cancer dependent on a farnesylated protein is a cancer dependent on farnesylated N-Ras protein, optionally wherein the cancer dependent on a farnesylated protein has an N-Ras protein mutation, optionally wherein the N-Ras mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof, in the corresponding mutant N-Ras protein;optionally wherein:(i) the presence or absence of the N-Ras mutation has been determined by analysis of nucleic acids obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or is a tumor biopsy; or(ii) the presence or absence of the N-Ras mutation has been determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS),2022399572   16 Jun 2026Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay; or (iii) a combination thereof.

48. The method of any one of claims 44 to 47, wherein the cancer dependent on a farnesylated protein is:melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma;carcinoma, melanoma, sarcoma, or chronic granulomatous disease; orthyroid cancer, head and neck cancers, urothelial cancers, salivary cancers, cancers of the upper digestive tract, bladder cancer, breast cancer, ovarian cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer.

49. The method of any one of claims 44 to 47, wherein the cancer dependent on a farnesylated protein is head and neck cancer, optionally wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC); orwherein the cancer dependent on a farnesylated protein is Squamous Cell Carcinoma (SCC), optionally wherein the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC) or urothelial carcinoma (UC), optionally wherein the SCC is HNSCC, optionally wherein the HNSCC is HNSCC of the trachea, HNSCC of the maxilla, HNSCC of the oral cavity.

50. The method of any one of claims 44 to 49, wherein the cancer dependent on a farnesylated protein is a solid tumor.

51. Use of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a mixture of diastereomers, or a mixture of stereoisomers thereof, or the compound according to claim 42, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, or the pharmaceutical composition of claim 43, in the manufacture of a medicament for treating cancer dependent on a farnesylated protein.